Depression and thoughts of self-harm or suicide among gender and sexually diverse people in a regional Australian community.

ISSUES ADDRESSED: There is a paucity of data regarding depression and thoughts of self-harm or suicide among gender and sexually diverse (GSD) people living within Australian regional/rural locations. This study aims to elucidate these issues and fill a critical gap. METHODS: The sample included 91 GSD people from a regional community in South-West Queensland utilising the PHQ-9 to determine presence/severity of depression and self-harm/suicide ideation. These data were drawn from a larger health and wellbeing survey. Raw mean scores were calculated to determine prevalence/severity of clinical symptoms. Bayesian ordinal regression models were employed to analyse between-subgroup differences in depression and self-harm/suicide ideation. RESULTS: Overall, 80.2% of GSD sample experienced depression (35.2% severe, 45.1% mild/moderate) and 41.8% experienced self-harm/suicide ideation in the past two-weeks. Trans and nonbinary people experienced higher levels of depressions than sexually diverse cisgender people. Pansexual and bisexual people experienced higher levels of depression than gay people. Trans people experienced higher prevalence of self-harm/suicide ideation than cisgender and nonbinary people, with no differences between sexuality subgroups. CONCLUSIONS: These findings contribute to deeper and more nuanced insights regarding clinically salient depressive and self-harm/suicide ideation symptoms among trans, nonbinary, bisexual, pansexual and queer people in regional Australian communities, with the aim to ultimately reduce mental health prevalence, improve mental health outcomes and health promotion among GSD people. SO WHAT?: The current findings revealed GSD people experience high prevalence of depression and self-harm/suicide ideation indicating tailored mental health awareness-raising, training and health promotion is warranted to enhance psychological support.

Molecular structure discovery for untargeted metabolomics using biotransformation rules and global molecular networking.

Although untargeted mass spectrometry-based metabolomics is crucial for understanding life's molecular underpinnings, its effectiveness is hampered by low annotation rates of the generated tandem mass spectra. To address this issue, we introduce a novel data-driven approach, Biotransformation-based Annotation Method (BAM), that leverages molecular structural similarities inherent in biochemical reactions. BAM operates by applying biotransformation rules to known 'anchor' molecules, which exhibit high spectral similarity to unknown spectra, thereby hypothesizing and ranking potential structures for the corresponding 'suspect' molecule. BAM's effectiveness is demonstrated by its success in annotating suspect spectra in a global molecular network comprising hundreds of millions of spectra. BAM was able to assign correct molecular structures to 24.2 % of examined anchor-suspect cases, thereby demonstrating remarkable advancement in metabolite annotation.

Multiphoton Phosphorescence Quenching Microscopy Reveals Kinetics of Tumor Oxygenation during Antiangiogenesis and Angiotensin Signaling Inhibition.

PURPOSE: The abnormal function of tumor blood vessels causes tissue hypoxia, promoting disease progression and treatment resistance. Although tumor microenvironment normalization strategies can alleviate hypoxia globally, how local oxygen levels change is not known because of the inability to longitudinally assess vascular and interstitial oxygen in tumors with sufficient resolution. Understanding the spatial and temporal heterogeneity should help improve the outcome of various normalization strategies. EXPERIMENTAL DESIGN: We developed a multiphoton phosphorescence quenching microscopy system using a low-molecular-weight palladium porphyrin probe to measure perfused vessels, oxygen tension, and their spatial correlations in vivo in mouse skin, bone marrow, and four different tumor models. Further, we measured the temporal and spatial changes in oxygen and vessel perfusion in tumors in response to an anti-VEGFR2 antibody (DC101) and an angiotensin-receptor blocker (losartan). RESULTS: We found that vessel function was highly dependent on tumor type. Although some tumors had vessels with greater oxygen-carrying ability than those of normal skin, most tumors had inefficient vessels. Further, intervessel heterogeneity in tumors is associated with heterogeneous response to DC101 and losartan. Using both vascular and stromal normalizing agents, we show that spatial heterogeneity in oxygen levels persists, even with reductions in mean extravascular hypoxia. CONCLUSIONS: High-resolution spatial and temporal responses of tumor vessels to two agents known to improve vascular perfusion globally reveal spatially heterogeneous changes in vessel structure and function. These dynamic vascular changes should be considered in optimizing the dose and schedule of vascular and stromal normalizing strategies to improve the therapeutic outcome.

Modeling the onset of symptoms of COVID-19: Effects of SARS-CoV-2 variant.

Identifying order of symptom onset of infectious diseases might aid in differentiating symptomatic infections earlier in a population thereby enabling non-pharmaceutical interventions and reducing disease spread. Previously, we developed a mathematical model predicting the order of symptoms based on data from the initial outbreak of SARS-CoV-2 in China using symptom occurrence at diagnosis and found that the order of COVID-19 symptoms differed from that of other infectious diseases including influenza. Whether this order of COVID-19 symptoms holds in the USA under changing conditions is unclear. Here, we use modeling to predict the order of symptoms using data from both the initial outbreaks in China and in the USA. Whereas patients in China were more likely to have fever before cough and then nausea/vomiting before diarrhea, patients in the USA were more likely to have cough before fever and then diarrhea before nausea/vomiting. Given that the D614G SARS-CoV-2 variant that rapidly spread from Europe to predominate in the USA during the first wave of the outbreak was not present in the initial China outbreak, we hypothesized that this mutation might affect symptom order. Supporting this notion, we found that as SARS-CoV-2 in Japan shifted from the original Wuhan reference strain to the D614G variant, symptom order shifted to the USA pattern. Google Trends analyses supported these findings, while weather, age, and comorbidities did not affect our model's predictions of symptom order. These findings indicate that symptom order can change with mutation in viral disease and raise the possibility that D614G variant is more transmissible because infected people are more likely to cough in public before being incapacitated with fever.

Modeling the Onset of Symptoms of COVID-19.

COVID-19 is a pandemic viral disease with catastrophic global impact. This disease is more contagious than influenza such that cluster outbreaks occur frequently. If patients with symptoms quickly underwent testing and contact tracing, these outbreaks could be contained. Unfortunately, COVID-19 patients have symptoms similar to other common illnesses. Here, we hypothesize the order of symptom occurrence could help patients and medical professionals more quickly distinguish COVID-19 from other respiratory diseases, yet such essential information is largely unavailable. To this end, we apply a Markov Process to a graded partially ordered set based on clinical observations of COVID-19 cases to ascertain the most likely order of discernible symptoms (i.e., fever, cough, nausea/vomiting, and diarrhea) in COVID-19 patients. We then compared the progression of these symptoms in COVID-19 to other respiratory diseases, such as influenza, SARS, and MERS, to observe if the diseases present differently. Our model predicts that influenza initiates with cough, whereas COVID-19 like other coronavirus-related diseases initiates with fever. However, COVID-19 differs from SARS and MERS in the order of gastrointestinal symptoms. Our results support the notion that fever should be used to screen for entry into facilities as regions begin to reopen after the outbreak of Spring 2020. Additionally, our findings suggest that good clinical practice should involve recording the order of symptom occurrence in COVID-19 and other diseases. If such a systemic clinical practice had been standard since ancient diseases, perhaps the transition from local outbreak to pandemic could have been avoided.

The Ethics of Emergent Health Technologies: Implications of the 21st Century Cures Act for Nursing.

The 21st Century Cures Act, passed in December 2016 by the United States Congress, is a public law aimed at accelerating the time it takes to get pharmaceutical drugs and medical devices into the market, in addition to shifting connected review processes from randomized controlled trials to real-world efficacy tests. As of December 2019, efforts are underway to introduce a "Cures Act 2.0" bill, with particular attention to the implementation of digital health within health systems. Research on the development of emergent health technologies is nascent; research examining health technology implications of 21st Century Cures Act for the health care workforce is nonexistent. This article fills a crucial gap in public awareness, discussing ethical implications of the 21st Century Cures Act and centering nursing. Nursing is a profession frequently acknowledged as practicing on "the front lines of care" and frequently responsible for the trialing of products in clinical settings. The article summarizes and evaluates key components of the 21st Century Cures Act related to health technology development. Discrete health technologies addressed are (a) breakthrough devices, (b) digital health software, and (c) combination products. It then connects these provisions to ethical considerations for nursing practice, research, and policy. The article concludes by discussing the relevance of emerging digital health technologies to the crafting of a "Cures 2.0" bill, with particular attention to this moment in light of digital care precedents set during the COVID-19 pandemic.

TGF-ß inhibition combined with cytotoxic nanomedicine normalizes triple negative breast cancer microenvironment towards anti-tumor immunity.

Tumor normalization strategies aim to improve tumor blood vessel functionality (i.e., perfusion) by reducing the hyper-permeability of tumor vessels or restoring compressed vessels. Despite progress in strategies to normalize the tumor microenvironment (TME), their combinatorial antitumor effects with nanomedicine and immunotherapy remain unexplored. Methods: Here, we re-purposed the TGF-ß inhibitor tranilast, an approved anti-fibrotic and antihistamine drug, and combined it with Doxil nanomedicine to normalize the TME, increase perfusion and oxygenation, and enhance anti-tumor immunity. Specifically, we employed two triple-negative breast cancer (TNBC) mouse models to primarily evaluate the therapeutic and normalization effects of tranilast combined with doxorubicin and Doxil. We demonstrated the optimized normalization effects of tranilast combined with Doxil and extended our analysis to investigate the effect of TME normalization to the efficacy of immune checkpoint inhibitors. Results: Combination of tranilast with Doxil caused a pronounced reduction in extracellular matrix components and an increase in the intratumoral vessel diameter and pericyte coverage, indicators of TME normalization. These modifications resulted in a significant increase in tumor perfusion and oxygenation and enhanced treatment efficacy as indicated by the notable reduction in tumor size. Tranilast further normalized the immune TME by restoring the infiltration of T cells and increasing the fraction of T cells that migrate away from immunosuppressive cancer-associated fibroblasts. Furthermore, we found that combining tranilast with Doxil nanomedicine, significantly improved immunostimulatory M1 macrophage content in the tumorigenic tissue and improved the efficacy of the immune checkpoint blocking antibodies anti-PD-1/anti-CTLA-4. Conclusion: Combinatorial treatment of tranilast with Doxil optimizes TME normalization, improves immunostimulation and enhances the efficacy of immunotherapy.

Dexamethasone Increases Cisplatin-Loaded Nanocarrier Delivery and Efficacy in Metastatic Breast Cancer by Normalizing the Tumor Microenvironment.

Dexamethasone is a glucocorticoid steroid with anti-inflammatory properties used to treat many diseases, including cancer, in which it helps manage various side effects of chemo-, radio-, and immunotherapies. Here, we investigate the tumor microenvironment (TME)-normalizing effects of dexamethasone in metastatic murine breast cancer (BC). Dexamethasone normalizes vessels and the extracellular matrix, thereby reducing interstitial fluid pressure, tissue stiffness, and solid stress. In turn, the penetration of 13 and 32 nm dextrans, which represent nanocarriers (NCs), is increased. A mechanistic model of fluid and macromolecule transport in tumors predicts that dexamethasone increases NC penetration by increasing interstitial hydraulic conductivity without significantly reducing the effective pore diameter of the vessel wall. Also, dexamethasone increases the tumor accumulation and efficacy of ∼30 nm polymeric micelles containing cisplatin (CDDP/m) against murine models of primary BC and spontaneous BC lung metastasis, which also feature a TME with abnormal mechanical properties. These results suggest that pretreatment with dexamethasone before NC administration could increase efficacy against primary tumors and metastases.

Pairing pedagogical and genomic advances to prepare advanced practice nurses for the era of precision health.

BACKGROUND: Broadly accessible curriculum that equips Advanced Practice Nurses (APNs) with knowledge and skills to apply genomics in practice in the era of precision health is needed. Increased accessibility of genomics courses and updated curriculum will prepare APNs to be leaders in the precision health initiative. METHODS: Courses on genomics were redesigned using contemporary pedagogical approaches to online teaching. Content was based on the Essential Genetic and Genomic Competencies for Nurses with Graduate Degrees. RESULTS: The number of students enrolled (n = 10) was comparable to previous years with greater breadth of representation across nursing practice specialty areas (53% vs. 20%). Prior to the first course, students reported agreement with meeting 8% (3/38) of the competencies. By completion of the 3rd course, students reported 100% (38/38) agreement with meeting the competencies. CONCLUSIONS: Content on genomics sufficient to obtain self-perceived attainment of genomics competencies can be successfully delivered using contemporary pedagogical teaching approaches.

Development of a New Scale to Measure Ambiguity Tolerance in Veterinary Students.

The ability to cope with ambiguity and feelings of uncertainty is an essential part of professional practice. Research with physicians has identified that intolerance of ambiguity or uncertainty is linked to stress, and some authors have hypothesized that there could be an association between intolerance of ambiguity and burnout. We describe the adaptation of the TAMSAD (Tolerance of Ambiguity in Medical Students and Doctors) scale for use with veterinary students. Exploratory factor analysis supports a uni-dimensional structure for the Ambiguity tolerance construct. Although internal reliability of the 29-item TAMSAD scale is reasonable (α=.50), an alternative 27-item scale (drawn from the original 41 items used to develop TAMSAD) shows higher internal reliability for veterinary students (α=.67). We conclude that there is good evidence to support the validity of this latter TAVS (Tolerance of Ambiguity in Veterinary Students) scale to study ambiguity tolerance in veterinary students.

Quantum dot/antibody conjugates for in vivo cytometric imaging in mice.

Multiplexed, phenotypic, intravital cytometric imaging requires novel fluorophore conjugates that have an appropriate size for long circulation and diffusion and show virtually no nonspecific binding to cells/serum while binding to cells of interest with high specificity. In addition, these conjugates must be stable and maintain a high quantum yield in the in vivo environments. Here, we show that this can be achieved using compact (∼15 nm in hydrodynamic diameter) and biocompatible quantum dot (QD) -Ab conjugates. We developed these conjugates by coupling whole mAbs to QDs coated with norbornene-displaying polyimidazole ligands using tetrazine-norbornene cycloaddition. Our QD immunoconstructs were used for in vivo single-cell labeling in bone marrow. The intravital imaging studies using a chronic calvarial bone window showed that our QD-Ab conjugates diffuse into the entire bone marrow and efficiently label single cells belonging to rare populations of hematopoietic stem and progenitor cells (Sca1(+)c-Kit(+) cells). This in vivo cytometric technique may be useful in a wide range of structural and functional imaging to study the interactions between cells and between a cell and its environment in intact and diseased tissues.

Trace gluten contamination may play a role in mucosal and clinical recovery in a subgroup of diet-adherent non-responsive celiac disease patients.

BACKGROUND: Patients with persistent symptoms and/or villous atrophy despite strict adherence to a gluten-free diet (GFD) have non-responsive celiac disease (NRCD). A subset of these patients has refractory celiac disease (RCD), yet some NRCD patients may simply be reacting to gluten cross-contamination. Here we describe the effects of a 3-6 month diet of whole, unprocessed foods, termed the Gluten Contamination Elimination Diet (GCED), on NRCD. We aim to demonstrate that this diet reclassifies the majority of patients thought to have RCD type 1 (RCD1). METHODS: We reviewed the records of all GFD-adherent NRCD patients cared for in our celiac center from 2005-2011 who were documented to have started the GCED. Response to the GCED was defined as being asymptomatic after the diet, with normal villous architecture on repeat biopsy, if performed. RESULTS: Prior to the GCED, all patients were interviewed by an experienced dietitian and no sources of hidden gluten ingestion were identified. 17 patients completed the GCED; 15 were female (88%). Median age at start of the GCED was 42 years (range 6-73). Fourteen patients (82%) responded to the GCED. Six patients met criteria for RCD prior to the GCED; 5 (83%) were asymptomatic after the GCED and no longer meet RCD criteria. Of the 14 patients who responded to the GCED, 11 (79%) successfully returned to a traditional GFD without resurgence of symptoms. CONCLUSIONS: The GCED may be an effective therapeutic option for GFD-adherent NRCD patients. Response to this diet identifies a subgroup of patients, previously classified as RCD1, that is not truly refractory to dietary treatment. Preventing an inaccurate diagnosis of RCD1 avoids immunotherapy. Most patients are able to return to a traditional GFD without return of symptoms.

Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy.

The recent approval of a prostate cancer vaccine has renewed hope for anticancer immunotherapies. However, the immunosuppressive tumor microenvironment may limit the effectiveness of current immunotherapies. Antiangiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy, but they often are used at high doses in the clinic to prune tumor vessels and paradoxically may compromise various therapies. Here, we demonstrate that targeting tumor vasculature with lower vascular-normalizing doses, but not high antivascular/antiangiogenic doses, of an anti-VEGF receptor 2 (VEGFR2) antibody results in a more homogeneous distribution of functional tumor vessels. Furthermore, lower doses are superior to the high doses in polarizing tumor-associated macrophages from an immune inhibitory M2-like phenotype toward an immune stimulatory M1-like phenotype and in facilitating CD4(+) and CD8(+) T-cell tumor infiltration. Based on this mechanism, scheduling lower-dose anti-VEGFR2 therapy with T-cell activation induced by a whole cancer cell vaccine therapy enhanced anticancer efficacy in a CD8(+) T-cell-dependent manner in both immune-tolerant and immunogenic murine breast cancer models. These findings indicate that vascular-normalizing lower doses of anti-VEGFR2 antibody can reprogram the tumor microenvironment away from immunosuppression toward potentiation of cancer vaccine therapies. Given that the combinations of high doses of bevacizumab with chemotherapy have not improved overall survival of breast cancer patients, our study suggests a strategy to use antiangiogenic agents in breast cancer more effectively with active immunotherapy and potentially other anticancer therapies.

Diagnosing Patients with Age-Related Hearing Loss and Tinnitus: Supporting GP Clinical Engagement through Innovation and Pathway Redesign in Audiology Services.

The public health challenge of hearing impairment is growing, as age is the major determinant of hearing loss. Almost one in four (22.6%) over 75-year olds reports moderate or severe worry because of hearing problems. There is a 40% comorbidity of tinnitus and balance disorders. Good outcomes depend on early presentation and appropriate referral. This paper describes how the NHS Improvement Programme in England used service improvement methodologies to identify referral pathways and tools which were most likely to make significant improvements in diagnosing hearing loss, effective referrals and better patient outcomes. An audiometric screening device was used in GP surgeries to enable thresholds for effective referrals to be measured in the surgery. Revised referral criteria, the use of this device, new "assess and fit" technology in the audiology clinic, and direct access pathways can transform audiology service delivery so that patient outcomes are measurably better. This, in turn, changes the experience of GPs, so they are more likely to refer patients who can benefit from treatment. At the end of 2011, 51 GP practices in one of the audiology pilot areas had bought HearCheck screeners, a substantial development from the 4 practices who first engaged with the pilot.

Configuration of a high-content imaging platform for hit identification and pharmacological assessment of JMJD3 demethylase enzyme inhibitors.

The biological complexity associated with the regulation of histone demethylases makes it desirable to configure a cellular mechanistic assay format that simultaneously encompasses as many of the relevant cellular processes as possible. In this report, the authors describe the configuration of a JMJD3 high-content cellular mechanistic imaging assay that uses single-cell multiparameter measurements to accurately assess cellular viability and the enzyme-dependent demethylation of the H3K27(Me)3 mark by exogenously expressed JMJD3. This approach couples robust statistical analyses with the spatial resolving power of cellular imaging. This enables segregation of expressing and nonexpressing cells into discrete subpopulations and consequently pharmacological quantification of compounds of interest in the expressing population at varying JMJD3 expression levels. Moreover, the authors demonstrate the utility of this hit identification strategy through the successful prosecution of a medium-throughput focused campaign of an 87 500-compound file, which has enabled the identification of JMJD3 cellular-active chemotypes. This study represents the first report of a demethylase high-content imaging assay with the ability to capture a repertoire of pharmacological tools, which are likely both to inform our mechanistic understanding of how JMJD3 is modulated and, more important, to contribute to the identification of novel therapeutic modalities for this demethylase enzyme.

Material and clinical considerations for full-coverage indirect restorations.

Because dental ceramics have been used for decades and continuously improved over the years, there is a plethora of information regarding their material characteristics, applications, and contraindications. Each restorative ceramic material demonstrates benefits and disadvantages, making it difficult for dentists to research, retain, and apply the ideal material for individual restorations and/or combination cases. This article outlines the applications and benefits of dental ceramics in general and examines and reviews the current ceramic alternatives available for restorative dentistry today. It also discusses the material composition and properties of a recently introduced new classification of indirect material: resin nano-ceramic.

Redesigning care at the Flinders Medical Centre: clinical process redesign using "lean thinking".

*The Flinders Medical Centre (FMC) Redesigning Care program began in November 2003; it is a hospital-wide process improvement program applying an approach called "lean thinking" (developed in the manufacturing sector) to health care. *To date, the FMC has involved hundreds of staff from all areas of the hospital in a wide variety of process redesign activities. *The initial focus of the program was on improving the flow of patients through the emergency department, but the program quickly spread to involve the redesign of managing medical and surgical patients throughout the hospital, and to improving major support services. *The program has fallen into three main phases, each of which is described in this article: "getting the knowledge"; "stabilising high-volume flows"; and "standardising and sustaining". *Results to date show that the Redesigning Care program has enabled the hospital to provide safer and more accessible care during a period of growth in demand.

Racial differences in the living kidney donation experience and implications for education.

CONTEXT: Much has been written about the barriers to deceased organ donation in the African American community. However, relatively little research has been conducted on barriers to living donation among African Americans. A shortage of suitable deceased donor kidneys among African Americans has encouraged donation from living donors. OBJECTIVE: As a follow-up to several focus groups with health professionals about barriers to living donation and suggestions for educational interventions, we sought to determine kidney donors' thoughts and feelings about their donation. DESIGN: Telephone interviews with past donors. PARTICIPANTS: Nine African Americans and 9 whites were selected from a database of laparoscopic donor nephrectomies from 1993 to 2003. OUTCOME MEASURES: Transcribed phone interviews were reviewed by 3 researchers to determine recurring themes and categorize responses. RESULTS: Responses were categorized into 8 areas of concern: health, financial, life with 1 kidney, procreation, psychosocial matters, surgery related, success of the transplant, and concerns about the future. Whites (n = 9) tended to volunteer more for laparoscopic kidney donation than did African Americans (n = 2). African American concerns focused on future health and living with only 1 kidney, whereas whites had concerns about the surgery and the medical system. CONCLUSIONS: Findings indicated that education is the best way to reach living donors and dispell fears. Promoting general health of African Americans may increase their willingness to be a living donor. Altruistic motives are the main motivation for donation, and intervention programs should target groups on a personal level to help individuals see that they can make a difference in improving or saving lives.

Lean thinking across a hospital: redesigning care at the Flinders Medical Centre.

Lean thinking is a method for organising complex production processes so as to encourage flow and reduce waste. While the principles of lean thinking were developed in the manufacturing sector, there is increasing interest in its application in health care. This case history documents the introduction and development of Redesigning Care, a lean thinking-based program to redesign care processes across a teaching general hospital. Redesigning Care has produced substantial benefits over the first two-and-a-half years of its implementation, making care both safer and more accessible. Redesigning Care has not been aimed at changing the specifics of clinical practice. Rather, it has been concerned with improving the flow of patients through clinical and other systems. Concepts that emerged in the manufacturing sector have been readily translatable into health care. Lean thinking may play an important role in the reform of health care in Australia and elsewhere.