Establishment of Hematological and Plasma Biochemical Reference Values and Analysis of Risk Factors for Pet Sugar Gliders (Petaurus breviceps) in Taiwan.

Hematological and plasma biochemical examination are crucial in the veterinary care of sugar gliders, which are increasingly popular in Taiwan and the United States. However, published research of the species' reference interval and related influencing factors were rare. The objectives of this study were to establish the hematological and plasma biochemical reference values for captive sugar gliders in Taiwan and to evaluate the influence of factors including age, gender, neuter status, location, season, diet, caging arrangement, and other pets in the household. A total of 42 clinically healthy pet sugar gliders were recruited. Morphometrical measurements and physiological data were collected, and hematological and plasma biochemical examinations were performed. The reference value of each index was calculated using Reference Value Advisor (RVA) software, following the American Society for Veterinary Clinical Pathology (ASVCP) guidelines. Normality of data distribution was tested, and data transformation was conducted. The parametric method and robust method were used to determine reference limits. Univariate analysis was performed, and multiple regression models were built for each hematological and plasma biochemical parameter. Red blood cell, hematocrit, and hemoglobin levels were higher in males, compared to females, while they were lower in the neutered group, compared to the intact group. Relative neutrophil counts were higher in elder sugar gliders, while relative lymphocyte counts were lower. Aspartate transaminase levels were higher in elder sugar gliders, while albumin levels were lower. Blood urea nitrogen levels were highest in spring. The blood profile and related effects presented in this study can provide useful information for veterinary care in pet sugar gliders.

Transcriptomic-Metabolomic Profiling in Mouse Lung Tissues Reveals Sex- and Strain-Based Differences.

Omics analyses are commonly used for identifying pathways and genes responsible for physiologic and pathologic processes. Though sex is considered a biological variable in rigorous assessments of pulmonary responses to oxidant exposures, the contribution of the murine strain is largely ignored. This study utilized an unbiased integrated assessment of high-resolution metabolomic profiling and RNA-sequencing to explore sex- and strain-dependent pathways in adult mouse lungs. The results indicated that strain exhibited a greater influence than sex on pathways associated with inflammatory and oxidant/antioxidant responses and that interaction metabolites more closely resembled those identified as differentially expressed by strain. Metabolite analyses revealed that the components of the glutathione antioxidant pathway were different between strains, specifically in the formation of mixed disulfides. Additionally, selenium metabolites such as selenohomocystiene and selenocystathionine were similarly differentially expressed. Transcriptomic analysis revealed similar findings, as evidenced by differences in glutathione peroxidase, peroxiredoxin, and the inflammatory transcription factors RelA and Jun. In summary, an multi-omics integrated approach identified that murine strain disproportionately impacts baseline expression of antioxidant systems in lung tissues. We speculate that strain-dependent differences contribute to discrepant pulmonary responses in preclincal mouse models, with deleterious effects on clinical translation.

Healthy cities initiative in China: Progress, challenges, and the way forward.

China implemented the first phase of its National Healthy Cities pilot program from 2016-20. Along with related urban health governmental initiatives, the program has helped put health on the agenda of local governments while raising public awareness. Healthy City actions taken at the municipal scale also prepared cities to deal with the COVID-19 pandemic. However, after intermittent trials spanning the past two decades, the Healthy Cities initiative in China has reached a crucial juncture. It risks becoming inconsequential given its overlap with other health promotion efforts, changing public health priorities in response to the pandemic, and the partial adoption of the Healthy Cities approach advanced by the World Health Organization (WHO). We recommend aligning the Healthy Cities initiative in China with strategic national and global level agendas such as Healthy China 2030 and the Sustainable Development Goals (SDGs) by providing an integrative governance framework to facilitate a coherent intersectoral program to systemically improve population health. Achieving this alignment will require leveraging the full spectrum of best practices in Healthy Cities actions and expanding assessment efforts. Funding: Tsinghua-Toyota Joint Research Fund "Healthy city systems for smart cities" program.

Evaluation of a novel CFTR potentiator in COPD ferrets with acquired CFTR dysfunction.

RATIONALE: The majority of chronic obstructive pulmonary disease (COPD) patients have chronic bronchitis, for which specific therapies are unavailable. Acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction is observed in chronic bronchitis, but has not been proven in a controlled animal model with airway disease. Furthermore, the potential of CFTR as a therapeutic target has not been tested in vivo, given limitations to rodent models of COPD. Ferrets exhibit cystic fibrosis-related lung pathology when CFTR is absent and COPD with bronchitis following cigarette smoke exposure. OBJECTIVES: To evaluate CFTR dysfunction induced by smoking and test its pharmacological reversal by a novel CFTR potentiator, GLPG2196, in a ferret model of COPD with chronic bronchitis. METHODS: Ferrets were exposed for 6 months to cigarette smoke to induce COPD and chronic bronchitis and then treated with enteral GLPG2196 once daily for 1 month. Electrophysiological measurements of ion transport and CFTR function, assessment of mucociliary function by one-micron optical coherence tomography imaging and particle-tracking microrheology, microcomputed tomography imaging, histopathological analysis and quantification of CFTR protein and mRNA expression were used to evaluate mechanistic and pathophysiological changes. MEASUREMENTS AND MAIN RESULTS: Following cigarette smoke exposure, ferrets exhibited CFTR dysfunction, increased mucus viscosity, delayed mucociliary clearance, airway wall thickening and airway epithelial hypertrophy. In COPD ferrets, GLPG2196 treatment reversed CFTR dysfunction, increased mucus transport by decreasing mucus viscosity, and reduced bronchial wall thickening and airway epithelial hypertrophy. CONCLUSIONS: The pharmacologic reversal of acquired CFTR dysfunction is beneficial against pathological features of chronic bronchitis in a COPD ferret model.

Biopsy for molecular risk stratification in uveal melanoma: Yields and molecular characteristics in 119 patients.

BACKGROUND: Prognostic cytological and molecular features of uveal melanoma have been well researched and are essential in management. Samples can be obtained in vivo through fine needle aspirate biopsy, vitrector cutter, forceps or post-enucleation for off-site testing. This study aims to examine cytological and chromosome microarray yields of these samples. METHODS: A retrospective cohort analysis of 119 uveal melanoma biopsies submitted to our laboratory. Samples included those taken in vivo (n = 57) and post-enucleation (n = 62). Patient and tumour features were collected including age, sex, primary tumour location, basal diameter and tumour height. Prognostic outcomes measured include cell morphology, chromosomal status and immunohistochemistry. RESULTS: Post-enucleation biopsies accounted for just over half of our samples (52%). Post-enucleation samples had a more successful genetic yield than in vivo biopsies (77% vs. 50%, p = 0.04) though there was no difference for cytological yields. There was no difference in cytological or microarray yields between instruments. The vitrector biopsy group had the smallest tumour thickness (5 mm vs. 10 mm [fine-needle aspirate biopsy], p = 0.003). There was a strong correlation between monosomy 3, BAP1 aberrancy and epithelioid cell type in post-enucleation samples (Tb  = 0.742, p = 0.005). However, epithelioid morphology was not associated with either monosomy 3 (p = 0.07) or BAP1 aberrancy (p = 0.24) for in vivo biopsies. CONCLUSIONS: All three biopsy instruments provide similar cytological yields as post-enucleation sampling, although post-enucleation samples had a more successful chromosome microarray yield. Epithelioid cytomorphology alone is insufficient for prognostication in in vivo biopsies, immunohistochemistry would be a useful surrogate test.

Law and urban governance for health in times of rapid change.

Governance is an important factor in urban health, and law is an important element of healthy governance. Law can be an intervention local government wields to influence behavior and shape environments. Law can also be an important target of health promotion efforts: Law and the enforcement and implementation behaviors it fosters can promote unhealthy behaviors and environmental conditions, and can act as a barrier to healthy interventions or practices. Finally, law is a design and construction tool for the organization of governance. Law is the means through which cities are formally established. Their powers and duties, organizational structure, boundaries and decision-making procedures are all set by law. Regardless of the form of government, cities have legal levers they can manipulate for health promotion. Cities can use tax authority to influence the price of unhealthy products, or to encourage consumption of healthy foods. Cities can use their legal powers to address incidental legal effects of policies that they themselves cannot control. Cities may also have the authority to use law to address deeper determinants of health. The overall level of income or wealth inequality in a country reflects factors well-beyond a local government's control, but city government nonetheless has levers to directly and indirectly reduce economic and social inequality and their effects. A renewed focus on law and urban governance is the key to assuring health and well-being and closing the health equity gap.

Investigating the relative merits of using a mixed reality context for measuring affective response and predicting tea break snack choice.

Sensory evaluation for the investigation of food consumption is often conducted in a controlled laboratory environment, which does not reflect consumption behaviour in real world. Here, we compared the effect of consumption setting (traditional sensory booth, mixed reality projection café, and a café) on consumer affective responses, and to investigate the effectiveness of using Microsoft HoloLens technology, an Augmented Mixed Reality device, as an ecologically valid alternative to natural consumption eating for sensory evaluation. Participant [(n = 120): 86 females/34 males, aged 18-65 years] affective response (overall liking, attribute liking, emotional response, and snack choice) towards two commercially available tea break snacks (caramel slice and chocolate digestive biscuit) was assessed in three different consumption settings using a balanced crossover design. There were no significant differences for most affective ratings between data obtained from the HoloLens evoked café and real café (p ≥ 0.10), suggesting that mixed reality could provide an ecologically valid context for consumer research. However, response differences were observed between these two contexts and the sensory booths. For example, interested, joy, enthusiastic emotion terms were rated slightly higher in the evoked café in comparison to the booth context and slightly higher emotional engagement was observed for joy in the café compared to the booths (all p < .10). This study highlights key considerations for deciding where consumer testing should be conducted and the importance of using a combination of overall liking, attribute liking and emotional response to obtain data representative of real-world environments in consumer studies.

Best case/worst case for the trauma ICU: Development and pilot testing of a communication tool for older adults with traumatic injury.

BACKGROUND: "Best Case/Worst Case" (BC/WC) is a communication tool to support shared decision making in older adults with surgical illness. We aimed to adapt and test BC/WC for use with critically ill older adult trauma patients. METHODS: We conducted focus groups with 48 trauma clinicians in Wisconsin, Texas, and Oregon. We used qualitative content analysis to characterize feedback and adapted the tool to fit this setting. Using rapid sequence iterative design, we developed an implementation tool kit. We pilot tested this intervention at two trauma centers using a pre-post study design with older trauma patients in the intensive care unit (ICU). Main outcome measures included study feasibility, intervention acceptability, quality of communication, and clinician moral distress. RESULTS: BC/WC for trauma patients uses a graphic aid to document major events over time, illustrate plausible scenarios, and convey uncertainty. We enrolled 86 of 116 eligible patients and their surrogates (48 pre/38 postintervention). The median patient age was 72 years (51-95 years) and mean Geriatric Trauma Outcome Score was 126.1 (±30.6). We trained 43 trauma attendings and trauma fellows to use the intervention. Ninety-four percent could perform essential tool elements after training. The median end-of-life communication score (scale 0-10) improved from 4.5 to 6.6 (p = 0.006) after intervention as reported by family and from 4.1 to 6.0 (p = 0.03) as reported by nurses. Moral distress did not change. However, there was improvement (less distress) reported by physicians regarding "witnessing providers giving false hope" from 7.34 to 5.03 (p = 0.022). Surgeons reported the tool put multiple clinicians on the same page and was useful for families, but tedious to incorporate into rounds. CONCLUSION: BC/WC trauma ICU is acceptable to clinicians and may support improved communication in the ICU. Future efficacy testing is threatened by enrollment challenges for severely injured older adults and their family members. LEVEL OF EVIDENCE: Therapeutic, level III.

Development of new therapeutic options for the treatment of uveal melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Important cytogenetic and genetic risk factors for the development of UM include chromosome 3 monosomy, mutations in the guanine nucleotide-binding proteins GNAQ/GNA11, and loss of the BRACA1-associated protein 1 (BAP 1). Most primary UMs are treated conservatively with radiotherapy, but enucleation is necessary for large tumours. Despite the effectiveness of local control, up to 50% of UM patients develop metastasis for which there are no effective therapies. Attempts to utilise the targeted therapies that have been developed for the treatment of other cancers, including a range of signal transduction pathway inhibitors, have rarely produced significant outcomes in UM. Similarly, the application of immunotherapies that are effective in cutaneous melanoma to treat UM have also been disappointing. Other approaches that have been initiated involve proteasomal inhibitors and histone deacetylase inhibitors which are approved for the treatment of other cancers. Nevertheless, there have been occasional positive outcomes from these treatments in UM. Moreover, combination approaches in UM have also yielded some positive developments. It would be valuable to identify how to apply such therapies efficiently in UM, potentially via individualised tumour profiling. It would also be important to characterise UM tumours to differentiate the potential drivers of progression from those in other types of cancers. The recent identification of novel kinases and metastatic genes in UM tumours makes the development of new UM-specific treatments feasible.

Foresight in the time of COVID-19.

Foresight methodologies enable individuals and organizations to envision different future scenarios and plan for greater future resilience. However, foresight is an underused methodology in the Western Pacific region for health policy development that could be extremely beneficial, among other areas, in the context of public health emergency response. We present lessons learned from the application of foresight methodologies through remote, agile think tank sprints to inform the World Health Organization (WHO) Western Pacific Regional Office's (WPRO) response to the COVID-19 pandemic. Four think tanks were set up in topic areas of interest. The think tanks used a six-step foresight methodology to develop scenarios for the pandemic in an 18-month horizon. Backcasting was used to generate recommendations for WHO response and support for countries. This case study demonstrates the value of using foresight methodologies in public health, and specifically in the context of a public health emergency, and its ability to inform more context-appropriate and future-proof responses. FUNDING: Japan.

Interrogating Plant-Microbe Interactions with Chemical Tools: Click Chemistry Reagents for Metabolic Labeling and Activity-Based Probes.

Continued expansion of the chemical biology toolbox presents many new and diverse opportunities to interrogate the fundamental molecular mechanisms driving complex plant-microbe interactions. This review will examine metabolic labeling with click chemistry reagents and activity-based probes for investigating the impacts of plant-associated microbes on plant growth, metabolism, and immune responses. While the majority of the studies reviewed here used chemical biology approaches to examine the effects of pathogens on plants, chemical biology will also be invaluable in future efforts to investigate mutualistic associations between beneficial microbes and their plant hosts.

Governance in health workforce: how do we improve on the concept? A network-based, stakeholder-driven approach.

BACKGROUND: Health workforce governance has been proposed as key to improving health services delivery, yet few studies have examined the conceptualisation of health workforce governance in detail and exploration in literature remains limited. METHODS: A literature review using PubMed, Google Scholar and grey literature search was conducted to map out the current conceptualisation of health workforce governance. We identified all published literature relating to governance in health workforce since 2000 and analysed them on two fronts: the broad definition of governance, and the operationalisation of broad definition into key dimensions of governance. RESULTS: Existing literature adopts governance concepts established in health literature and does not adapt understanding to the health workforce context. Definitions are largely quoted from health literature whilst dimensions are focused around the sub-functions of governance which emphasise operationalising governance practices over further conceptualisation. Two sub-functions are identified as essential to the governance process: stakeholder participation and strategic direction. CONCLUSIONS: Although governance in health systems has gained increasing attention, governance in health workforce remains poorly conceptualised in literature. We propose an improved conceptualisation in the form of a stakeholder-driven network governance model with the national government as a strong steward against vested stakeholder interests. Further research is needed to explore and develop on the conceptual thinking behind health workforce governance.

Ligand- and Structure-Based Analysis of Deep Learning-Generated Potential α2a Adrenoceptor Agonists.

The α2a adrenoceptor is a medically relevant subtype of the G protein-coupled receptor family. Unfortunately, high-throughput techniques aimed at producing novel drug leads for this receptor have been largely unsuccessful because of the complex pharmacology of adrenergic receptors. As such, cutting-edge in silico ligand- and structure-based assessment and de novo deep learning methods are well positioned to provide new insights into protein-ligand interactions and potential active compounds. In this work, we (i) collect a dataset of α2a adrenoceptor agonists and provide it as a resource for the drug design community; (ii) use the dataset as a basis to generate candidate-active structures via deep learning; and (iii) apply computational ligand- and structure-based analysis techniques to gain new insights into α2a adrenoceptor agonists and assess the quality of the computer-generated compounds. We further describe how such assessment techniques can be applied to putative chemical probes with a case study involving proposed medetomidine-based probes.

The Social Determinants of Health: Time to Re-Think?

Twelve years have now passed since the influential WHO Report on the Social Determinants of Health (SDoH) in 2008. A group of senior international public health scholars and decision-makers met in Italy in mid-2019 to review the legacy of the SDoH conceptual framework and its adequacy for the many challenges facing our field as we enter the 2020s. Four major categories of challenges were identified: emerging "exogenous" challenges to global health equity, challenges related to weak policy and practice implementation, more fundamental challenges related to SDoH theory and research, and broader issues around modern research in general. Each of these categories is discussed, and potential solutions offered. We conclude that although the SDoH framework is still a worthy core platform for public health research, policy, and practice, the time is ripe for significant evolution.

Club Cell Heme Oxygenase-1 Deletion: Effects in Hyperoxia-Exposed Adult Mice.

Thioredoxin reductase-1 (TXNRD1) inhibition activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2) responses and prevents acute lung injury (ALI). Heme oxygenase-1 (HO-1) induction following TXNRD1 inhibition is Nrf2-dependent in airway epithelial (club) cells in vitro. The influence of club cell HO-1 on lung development and lung injury responses is poorly understood. The present studies characterized the effects of hyperoxia on club cell-specific HO-1 knockout (KO) mice. These mice were generated by crossing Hmox1 flox mice with transgenic mice expressing cre recombinase under control of the club cell-specific Scgb1a1 promoter. Baseline analyses of lung architecture and function performed in age-matched adult wild-type and KO mice indicated an increased alveolar size and airway resistance in HO-1 KO mice. In subsequent experiments, adult wild-type and HO-1 KO mice were either continuously exposed to >95% hyperoxia or room air for 72 h or exposed to >95 hyperoxia for 48 h followed by recovery in room air for 48 h. Injury was quantitatively assessed by calculating right lung/body weight ratios (g/kg). Analyses indicated an independent effect of hyperoxia but not genotype on right lung/body weight ratios in both wild-type and HO-1 KO mice. The magnitude of increases in right lung/body weight ratios was similar in mice of both genotypes. In the recovery model, an independent effect of hyperoxia but not genotype was also detected. In contrast to the continuous exposure model, right lung/body weight ratio mice were significantly elevated in HO-1 KO but not wild-type mice. Though club cell HO-1 does not alter hyperoxic sensitivity in adult mice, it significantly influences lung development and resolution of lung injury following acute hyperoxic exposure.

A Phase 2, Multicenter Study of Nevanimibe for the Treatment of Congenital Adrenal Hyperplasia.

CONTEXT: Patients with classic congenital adrenal hyperplasia (CAH) often require supraphysiologic glucocorticoid doses to suppress adrenocorticotropic hormone (ACTH) and control androgen excess. Nevanimibe hydrochloride (ATR-101), which selectively inhibits adrenal cortex function, might reduce androgen excess independent of ACTH and thus allow for lower glucocorticoid dosing in CAH. 17-hydroxyprogesterone (17-OHP) and androstenedione are CAH biomarkers used to monitor androgen excess. OBJECTIVE: Evaluate the efficacy and safety of nevanimibe in subjects with uncontrolled classic CAH. DESIGN: This was a multicenter, single-blind, dose-titration study. CAH subjects with baseline 17-OHP ≥4× the upper limit of normal (ULN) received the lowest dose of nevanimibe for 2 weeks followed by a single-blind 2-week placebo washout. Nevanimibe was gradually titrated up if the primary outcome measure (17-OHP ≤2× ULN) was not met. A total of 5 nevanimibe dose levels were possible (125, 250, 500, 750, 1000 mg twice daily). RESULTS: The study enrolled 10 adults: 9 completed the study, and 1 discontinued early due to a related serious adverse event. At baseline, the mean age was 30.3 ±â€…13.8 years, and the maintenance glucocorticoid dose, expressed as hydrocortisone equivalents, was 24.7 ±â€…10.4 mg/day. Two subjects met the primary endpoint, and 5 others experienced 17-OHP decreases ranging from 27% to 72% during nevanimibe treatment. The most common side effects were gastrointestinal (30%). There were no dose-related trends in adverse events. CONCLUSIONS: Nevanimibe decreased 17-OHP levels within 2 weeks of treatment. Larger studies of longer duration are needed to further evaluate its efficacy as add-on therapy for CAH.