Dissociation between the anti-allodynic effects of fingolimod (FTY720) and desensitization of S1P1 receptor-mediated G-protein activation in a mouse model of sciatic nerve injury.

Sphingosine-1-phosphate (S1P) receptor (S1PR) agonists, such as fingolimod (FTY720), alleviate nociception in preclinical pain models by either activation (agonism) or inhibition (functional antagonism) of S1PR type-1 (S1PR1). However, the dose-dependence and temporal relationship between reversal of nociception and modulation of S1PR1 signaling has not been systematically investigated. This study examined the relationship between FTY720-induced antinociception and S1PR1 adaptation using a sciatic nerve chronic constriction injury (CCI) model of neuropathic pain in male and female C57Bl/6J mice. Daily injections of FTY720 for 14 days dose-dependently reversed CCI-induced mechanical allodynia without tolerance development, and concomitantly resulted in a dose-dependent reduction of G-protein activation by the S1PR1-selective agonist SEW2871 in the lumbar spinal cord and brain. These findings indicate FTY720-induced desensitization of S1PR1 signaling coincides with its anti-allodynic effects. Consistent with this finding, a single injection of FTY720 reversed mechanical allodynia while concomitantly producing partial desensitization of S1PR1-stimulated G-protein activation in the CNS. However, mechanical allodynia returned 24-hr post injection, despite S1PR1 desensitization at that time, demonstrating a dissociation between these measures. Furthermore, CCI surgery led to elevations of sphingolipid metabolites, including S1P, which were unaffected by daily FTY720 administration, suggesting FTY720 reversed mechanical allodynia by targeting S1PR1 rather than sphingolipid metabolism. Supporting this hypothesis, acute administration of the S1PR1-selective agonist CYM-5442 mimicked the anti-allodynic effect of FTY720. In contrast, the S1PR1-selective antagonist NIBR-0213 prevented the anti-allodynic effect of FTY720, but NIBR-0213 given alone did not affect nociception. These results indicate that FTY720 alleviates CCI-induced allodynia through a mechanism distinct from functional antagonism.

Public Perceptions of the Australian Health System During COVID-19: Findings From a 2021 Survey Compared to Four Previous Surveys.

BACKGROUND: This study examines the perceptions of the Australian public canvassed in 2021 during the COVID-19 pandemic about their health system compared to four previous surveys (2008, 2010, 2012 and 2018). METHODS: In 2021, a nationwide online survey was conducted with a representative sample of Australians (N = 5100) recruited via market research panels. The results were compared to previous nationwide Australian survey samples from 2018 (N = 1024), 2012 (N = 1200), 2010 (N = 1201) and 2008 (N = 1146). The survey included questions consistent with previous polls regarding self-reported health status and overall opinions of, and confidence in, the Australian health system. RESULTS: There was an increase in the proportion of respondents reporting positive perceptions at each survey between 2008 and 2021, with a significantly higher proportion of respondents expressing a more positive view of the Australian healthcare system in 2021 compared to previous years (χ2(8, N = 9645) = 487.63, p < 0.001). In 2021, over two-thirds of respondents (n = 3949/5100, 77.4%) reported that following the COVID-19 pandemic, their confidence in the Australian healthcare system had either remained the same (n = 2433/5100, 47.7%) or increased (n = 1516/5100, 29.7%). Overall, respondents living in regional or remote regions, younger Australians (< 45 years) and women held less positive views in relation to the system. In 2021, the most frequently identified area for urgent improvement was the need for more healthcare workers (n = 1350/3576, 37.8%), an area of concern particularly for Australians residing in regional or remote areas (n = 590/1385, 42.6%). CONCLUSIONS: Irrespective of disruptions to the Australian healthcare system caused by the COVID-19 pandemic, Australians' perceptions of their healthcare system were positive in 2021. However, concerns were raised about inadequate workforce capacity and the cost of healthcare, with differences identified by age groups and geographical location. PATIENT OR PUBLIC CONTRIBUTION: Health consumer representatives from the Consumers Health Forum of Australia contributed to the co-design, deployment, analysis and interpretation of the results of this survey. J.A. and L.W. from the Consumers Health Forum of Australia contributed to the development of the paper.

Blocking potential metabolic sites on NAT to improve its safety profile while retaining the pharmacological profile.

The number of opioid-related overdose deaths and individuals that have suffered from opioid use disorders have significantly increased over the last 30 years. FDA approved maintenance therapies to treat opioid use disorder may successfully curb drug craving and prevent relapse but harbor adverse effects that reduce patient compliance. This has created a need for new chemical entities with improved patient experience. Previously our group reported a novel lead compound, NAT, a mu-opioid receptor antagonist that potently antagonized the antinociception of morphine and showed significant blood-brain barrier permeability. However, NAT belongs to thiophene containing compounds which are known structural alerts for potential oxidative metabolism. To overcome this, 15 NAT derivatives with various substituents at the 5'-position of the thiophene ring were designed and their structure-activity relationships were studied. These derivatives were characterized for their binding affinity, selectivity, and functional activity at the mu opioid receptor and assessed for their ability to antagonize the antinociceptive effects of morphine in vivo. Compound 12 showed retention of the basic pharmacological attributes of NAT while improving the withdrawal effects that were experienced in opioid-dependent mice. Further studies will be conducted to fully characterize compound 12 to examine whether it would serve as a new lead for opioid use disorder treatment and management.

Effects of Repeated Treatment with the Monoacylglycerol Lipase Inhibitor MJN110 on Pain-Related Depression of Nesting and Cannabinoid 1 Receptor Function in Male and Female Mice.

MJN110 inhibits the enzyme monoacylglycerol lipase (MAGL) to increase levels of the endocannabinoid 2-arachidonoylglycerol , an endogenous high-efficacy agonist of cannabinoid 1 and 2 receptors (CB1/2R). MAGL inhibitors are under consideration as candidate analgesics, and we reported previously that acute MJN110 produced partial antinociception in an assay of pain-related behavioral depression in mice. Given the need for repeated analgesic administration in many pain patients and the potential for analgesic tolerance during repeated treatment, this study examined antinociceptive effects of repeated MJN110 on pain-related behavioral depression and CB1R-mediated G-protein function. Male and female ICR mice were treated daily for 7 days in a 2 × 2 design with (a) 1.0 mg/kg/d MJN110 or its vehicle followed by (b) intraperitoneal injection of dilute lactic acid (IP acid) or its vehicle as a visceral noxious stimulus to depress nesting behavior. After behavioral testing, G-protein activity was assessed in lumbar spinal cord (LSC) and five brain regions using an assay of CP55,940-stimulated [35S]GTPÉ£S activation. As reported previously, acute MJN110 produced partial but significant relief of IP acid-induced nesting depression on day 1. After 7 days, MJN110 continued to produce significant but partial antinociception in males, while antinociceptive tolerance developed in females. Repeated MJN110 also produced modest decreases in maximum levels of CP55,940-induced [35S]GTPÉ£S binding in spinal cord and most brain regions. These results indicate that repeated treatment with a relatively low antinociceptive MJN110 dose produces only partial and sex-dependent transient antinociception associated with the emergence of CB1R desensitization in this model of IP acid-induced nesting depression. SIGNIFICANCE STATEMENT: The drug MJN110 inhibits monoacylglycerol lipase (MAGL) to increase levels of the endogenous cannabinoid 2-arachidonoylglycerol and produce potentially useful therapeutic effects including analgesia. This study used an assay of pain-related behavioral depression in mice to show that repeated MJN110 treatment produced (1) weak but sustained antinociception in male mice, (2) antinociceptive tolerance in females, and (3) modest cannabinoid-receptor desensitization that varied by region and sex. Antinociceptive tolerance may limit the utility of MJN110 for treatment of pain.

Molecular Pharmacology Profiling of Phenylfentanil and Its Analogues to Understand the Putative Involvement of an Adrenergic Mechanism in Fentanyl-Induced Respiratory Depression.

While there are approved therapeutics to treat opioid overdoses, the need for treatments to reverse overdoses due to ultrapotent fentanyls remains unmet. This may be due in part to an adrenergic mechanism of fentanyls in addition to their stereotypical mu-opioid receptor (MOR) effects. Herein, we report our efforts to further understanding of the functions these distinct mechanisms impart. Employing the known MOR neutral antagonist phenylfentanil as a lead, 17 analogues were designed based on the concept of isosteric replacement. To probe mechanisms of action, these analogues were pharmacologically evaluated in vitro and in vivo, while in silico modeling studies were also conducted on phenylfentanil. While it did not indicate MOR involvement in vivo, phenylfentanil yielded respiratory minute volumes similar to those caused by fentanyl. Taken together with molecular modeling studies, these results indicated that respiratory effects of fentanyls may also correlate to inhibition of both α1A- and α1B-adrenergic receptors.

Ortho-Selective amination of arene carboxylic acids via rearrangement of acyl O-hydroxylamines.

Direct amination of arene C-H bonds is an attractive disconnection to form aniline-derived building blocks. This transformation presents significant practical challenges; classical methods for ortho-selective amination require strongly acidic or forcing conditions, while contemporary catalytic processes often require bespoke directing groups and/or precious metal catalysis. We report a mild and procedurally straightforward ortho-selective amination of arene carboxylic acids, arising from a facile rearrangement of acyl O-hydroxylamines without requiring precious metal catalysts. A broad scope of benzoic acid substrates are compatible and the reaction can be applied to longer chain arene carboxylic acids. Mechanistic studies probe the specific requirement for trifluoroacetic acid in generating the active aminating agent, and suggest that two separate mechanisms may be operating in parallel in the presence of an iron catalyst: (i) an iron-nitrenoid intermediate and (ii) a radical chain pathway. Regardless of which mechanism is followed, high ortho selectivity is obtained, proposed to arise from the directivity (first) or attractive interactions (second) arising with the carboxylic acid motif.

Increasing Clinical Trial Participation of Black Women Diagnosed with Breast Cancer.

Despite racial disparities in breast cancer mortality, Black women remain underrepresented in clinical trials. In this mixed methods research, 48 Black women were engaged via focus group discussions and in-depth interviews to better understand the lived experience of women with breast cancer. The results of this qualitative study informed the development of a subsequent online survey to identify barriers, motivators, and other factors that influence decision-making by Black women diagnosed with breast cancer when considering clinical trial participation. Among the 257 Black survey participants, most (95%) were aware of clinical trials; of those, most viewed them as lifesaving (81%) and/or benefiting others (90%). Negative perceptions such as serious side effects (58%), not receiving real treatment (52%), or risk of potential harm (62%) were indicated. Barriers included financial expenses (49%), concerns that their condition could be made worse (29%), that they would receive a placebo (28%), or that treatment was unapproved (28%). Participants were more likely than their health care providers (HCPs) to initiate discussions of clinical trials (53% versus 33%), and 29% of participants indicated a need for more information about risks and benefits, even after having those conversations. The most trustworthy sources of information on clinical trials were HCPs (66%) and breast cancer support groups (64%). These results suggest that trusted communities are key for providing education on clinical trials. However, there is also a need for HCPs to proactively discuss clinical trials with patients to ensure that they are adequately informed about all aspects of participation.

Factors Influencing Continued Wearable Device Use in Older Adult Populations: Quantitative Study.

BACKGROUND: The increased use of wearable sensor technology has highlighted the potential for remote telehealth services such as rehabilitation. Telehealth services incorporating wearable sensors are most likely to appeal to the older adult population in remote and rural areas, who may struggle with long commutes to clinics. However, the usability of such systems often discourages patients from adopting these services. OBJECTIVE: This study aimed to understand the usability factors that most influence whether an older adult will decide to continue using a wearable device. METHODS: Older adults across 4 different regions (Northern Ireland, Ireland, Sweden, and Finland) wore an activity tracker for 7 days under a free-living environment protocol. In total, 4 surveys were administered, and biometrics were measured by the researchers before the trial began. At the end of the trial period, the researchers administered 2 further surveys to gain insights into the perceived usability of the wearable device. These were the standardized System Usability Scale (SUS) and a custom usability questionnaire designed by the research team. Statistical analyses were performed to identify the key factors that affect participants' intention to continue using the wearable device in the future. Machine learning classifiers were used to provide an early prediction of the intention to continue using the wearable device. RESULTS: The study was conducted with older adult volunteers (N=65; mean age 70.52, SD 5.65 years) wearing a Xiaomi Mi Band 3 activity tracker for 7 days in a free-living environment. The results from the SUS survey showed no notable difference in perceived system usability regardless of region, sex, or age, eliminating the notion that usability perception differs based on geographical location, sex, or deviation in participants' age. There was also no statistically significant difference in SUS score between participants who had previously owned a wearable device and those who wore 1 or 2 devices during the trial. The bespoke usability questionnaire determined that the 2 most important factors that influenced an intention to continue device use in an older adult cohort were device comfort (τ=0.34) and whether the device was fit for purpose (τ=0.34). A computational model providing an early identifier of intention to continue device use was developed using these 2 features. Random forest classifiers were shown to provide the highest predictive performance (80% accuracy). After including the top 8 ranked questions from the bespoke questionnaire as features of our model, the accuracy increased to 88%. CONCLUSIONS: This study concludes that comfort and accuracy are the 2 main influencing factors in sustaining wearable device use. This study suggests that the reported factors influencing usability are transferable to other wearable sensor systems. Future work will aim to test this hypothesis using the same methodology on a cohort using other wearable technologies.

Structural Alterations of the "Address" Moiety of NAN Leading to the Discovery of a Novel Opioid Receptor Modulator with Reduced hERG Toxicity.

The search for selective opioid ligands with desired pharmacological potency and improved safety profile has always been an area of interest. Our previous effort yielded a potent opioid modulator, NAN, a 6α-N-7'-indolyl-substituted naltrexamine derivative, which exhibited promising pharmacological activities both in vitro and in vivo. However, significant human ether-a-go-go-related gene (hERG) liability limited its further development. Therefore, a systematic structural modification on NAN was conducted in order to alleviate hERG toxicity while preserving pharmacological properties, which led to the discovery of 2'-methylindolyl derivative compound 21. Compared to NAN, compound 21 manifested overall improved pharmacological profiles. Follow-up hERG channel inhibition evaluation revealed a seven-fold decreased potency of compound 21 compared to NAN. Furthermore, several fundamental drug-like property evaluations suggested a reasonable ADME profile of 21. Collectively, compound 21 appeared to be a promising opioid modulator for further development as a novel therapeutic agent toward opioid use disorder treatments.

Environment, Grain Development, and Harvesting Strategy Effects on Zearalenone Contamination of Grain from Fusarium Head Blight-Affected Wheat Spikes.

Fusarium head blight (FHB), caused by the fungus Fusarium graminearum, is associated with grain contamination with mycotoxins such as deoxynivalenol (DON) and zearalenone (ZEA). Unlike DON, less is known about factors affecting ZEA production during FHB epidemics. The objective of this study was to quantify ZEA contamination of wheat grain as influenced by temperature, relative humidity, FHB index (IND), grain maturation, simulated late-season rainfall, and harvest timing. Mean ZEA concentrations were low (<1.1 ppm) during the early stages of grain development (25 to 31 days after anthesis [DAA]) but rapidly increased 35 to 51 DAA in field experiments, particularly under rainy conditions. Five or ten consecutive days with simulated rainfall shortly before harvest greatly increased ZEA contamination. Similarly, extremely high levels of ZEA (51.8 to 468.6 ppm) were observed in grain from spikes exposed to 100% relative humidity (RH) at all tested temperatures and mean IND levels under controlled conditions. Interestingly, at RH ≤ 90%, ZEA concentrations were very low (0.1 to 3.6 ppm) at all tested temperatures, even at IND above 90%. At 100% RH, mean ZEA contamination was significantly higher at 20 and 25°C (235.1 and 278.2 ppm) than at 30°C (104.7 ppm). Grain harvested early and not exposed to rainfall had lower mean ZEA than grain harvested late and/or subjected to preharvest rainfall. This study was the first to associate ZEA contamination of grain from FHB-affected wheat spikes with temperature and moisture and show through designed experiments that early harvest could be a useful strategy for reducing ZEA contamination.

Environmental Conditions After Fusarium Head Blight Visual Symptom Development Affect Contamination of Wheat Grain with Deoxynivalenol and Deoxynivalenol-3-Glucoside.

Fusarium head blight (FHB) of wheat, caused by the fungus Fusarium graminearum, is associated with grain contamination with mycotoxins such as deoxynivalenol (DON). Although FHB is often positively correlated with DON, this relationship can break down under certain conditions. One possible explanation for this could be the conversion of DON to DON-3-glucoside (D3G), which is typically missed by common DON testing methods. The objective of this study was to quantify the effects of temperature, relative humidity (RH), and preharvest rainfall on DON, D3G, and the D3D/DON relationship. D3G levels were higher in grain from spikes exposed to 100% RH than to 70, 80, or 90% RH at 20 and 25°C across all tested levels of mean FHB index (percentage of diseased spikelets per spike). Mean D3G contamination was higher at 20°C than at 25 or 30°C. There were significantly positive linear relationships between DON and D3G. Rainfall treatments resulted in significantly higher mean D3G than the rain-free check and induced preharvest sprouting, as indicated by low falling numbers (FNs). There were significant positive relationships between the rate of increase in D3G per unit increase in DON (a measure of conversion) and sprouting. As FN decreased, the rate of D3G conversion increased, and this rate of conversion per unit decrease in FN was greater at relatively low than at high mean DON levels. These results provide strong evidence that moisture after FHB visual symptom development was associated with DON-to-D3G conversion and constitute valuable new information for understanding this complex disease-mycotoxin system.

Regional evolution of psychosocial services in Australia before and after the implementation of the National Disability Insurance Scheme.

OBJECTIVES: This paper compares the evolution of the psychosocial sector in two Australian regions pre and post introduction of the National Disability Insurance Scheme - a major reform to the financing, planning and provision of disability services in Australia, intended to create greater competition and efficiency in the market, and more choice for service users. METHODS: We used a standardised service classification instrument based on a health ecosystems approach to assess service availability and diversity of psychosocial services provided by non-government organisations in two Primary Health Network regions. RESULTS: We identified very different evolutionary pathways in the two regions. Service availability increased in Western Sydney but decreased in the Australian Capital Territory. The diversity of services available did not increase in either Primary Health Network 4 years after the reform. Many services were experiencing ongoing funding uncertainty. CONCLUSION: Assumptions of increased efficiency through organisational scaling up, and a greater diversity in range of service availability were not borne out. IMPLICATIONS: This study shows the urgent need for evaluation of the effects of the NDIS on the provision of psychosocial care in Australia. Four years after the implementation of the NDIS at vast expense key objectives not been met for consumers or for the system as a whole, and an environment of uncertainty has been created for providers. It demonstrates the importance of standardised service mapping to monitor the effects of major reforms on mental health care as well as the need for a focus at the local level.

Strategies That Utilize Ion Pairing Interactions to Exert Selectivity Control in the Functionalization of C-H Bonds.

Electrostatic attraction between two groups of opposite charge, typically known as ion-pairing, offers unique opportunities for the design of systems to enable selectivity control in chemical reactions. Catalysis using noncovalent interactions is an established and vibrant research area, but it is noticeable that hydrogen bonding interactions are still the main interaction of choice in system design. Opposite charges experience the powerful force of Coulombic attraction and have the ability to exert fundamental influence on the outcome of reactions that involve charged reagents, intermediates or catalysts. In this Perspective, we will examine how ion-pairing interactions have been used to control selectivity in C-H bond functionalization processes. This broad class of reactions provides an interesting and thought-provoking lens through which to examine the application of ion-pairing design strategies because it is one that encompasses great mechanistic diversity, poses significant selectivity challenges, and perhaps most importantly is of immense interest to synthetic chemists in both industry and academia. We survey reactions that proceed via radical and ionic mechanisms alongside those that involve transition metal catalysis and will deal with control of site-selectivity and enantioselectivity. We anticipate that as this emerging area develops, it will become an ever-more important design strategy for selectivity control.

Australian State and Territory Eclectic Approaches to Obesity Prevention in the Early Years: Policy Mapping and Perspectives of Senior Health Officials.

Background: The international increase in the prevalence of childhood obesity has hastened in recent decades. This rise has coincided with the emergence of comorbidities in childhood-such as type II diabetes, non-alcoholic fatty liver disease, metabolic syndrome, sleep apnoea and hypertension-formerly only described in adulthood. This phenomenon suggests global social and economic trends are impacting on health supportive environments. Obesity prevention is complex and necessitates both long-term and systems approaches. Such an approach considers the determinants of health and how they interrelate to one another. Investment in the early years (from conception to about 5 years of age) is a key life stage to prevent obesity and establish lifelong healthy habits relating to nutrition, physical activity, sedentary behavior and sleep. In Australia, obesity prevention efforts are spread across national and state/territory health departments. It is not known from the literature how, with limited national oversight, state and territory health departments approach obesity prevention in the early years. Methods: We conducted a qualitative study including policy mapping and interviews with senior officials from each Australian state/territory health department. A series of questions were developed from the literature to guide the policy mapping, drawing on the World Health Organisation Ending Childhood Obesity Report, and adapted to the state/territory context. The policy mapping was iterative. Prior to the interviews initial policy mapping was undertaken. During the interviews, these policies were discussed, and participants were asked to supply any additional policies of relevance to obesity prevention. The semi-structured interviews explored the approaches to obesity prevention taken in each jurisdiction and the barriers and enablers faced for policy implementation. Thematic analysis was used to analyse the data, using NVivo software. Results: State and territory approaches to obesity prevention are eclectic and while there are numerous similarities between jurisdictions, no two states are the same. The diversity of approaches between jurisdictions is influenced by the policy culture and unique social, geographic, and funding contexts in each jurisdiction. No Australian state/territory had policies against all the guiding questions. However, there are opportunities for sharing and collaborating within and between Australian jurisdictions to establish what works, where, and for whom, across Australia's complex policy landscape. Conclusions: Even within a single country, obesity prevention policy needs to be adaptable to local contexts. Opportunities for jurisdictions within and between countries to share, learn, and adapt their experiences should be supported and sustained funding provided.

An Aminative Rearrangement of O-(Arenesulfonyl)hydroxylamines: Facile Access to ortho-Sulfonyl Anilines.

Ortho-sulfonyl anilines are important building blocks for a range of applications. We report the discovery of an aromatic rearrangement reaction of O-(arenesulfonyl)hydroxylamines which leads directly to ortho-sulfonyl anilines through formation of a new C-N bond with excellent levels of regiocontrol for the ortho position(s) over all others. We establish that the rearrangement is proceeding through an intermolecular mechanism and propose that the regiocontrol observed is the result of attractive non-covalent interactions occurring during the C-N bond-forming step. Importantly, this method is complementary to classical aniline sulfonation in terms of the variously substituted regioisomers that can be obtained and it is also applicable to O-(benzylsulfonyl) hydroxylamines.

Integrated Care for Multimorbidity Population in Asian Countries: A Scoping Review.

Background: The complex needs of patients with multiple chronic diseases call for integrated care (IC). This scoping review examines several published Asian IC programmes and their relevant components and elements in managing multimorbidity patients. Method: A scoping review was conducted by searching electronic databases encompassing Medline, Embase, Scopus, and Web of Science. Three key concepts - 1) integrated care, 2) multimorbidity, and 3) Asian countries - were used to define searching strategies. Studies were included if an IC programme in Asia for multimorbidity was described or evaluated. Data extraction for IC components and elements was carried out by adopting the SELFIE framework. Results: This review yielded 1,112 articles, of which 156 remained after the title and abstract screening and 27 studies after the full-text screening - with 23 IC programmes identified from seven Asian countries. The top 5 mentioned IC components were service delivery (n = 23), workforce (n = 23), leadership and governance (n = 23), monitoring (n = 15), and environment (n = 14); whist financing (n = 9) was least mentioned. Compared to EU/US countries, technology and medical products (Asia: 40%, EU/US: 43%-100%) and multidisciplinary teams (Asia: 26%, EU/US: 50%-81%) were reported less in Asia. Most programmes involved more micro-level elements that coordinate services at the individual level (n = 20) than meso- and macro-level elements, and programmes generally incorporated horizontal and vertical integration (n = 14). Conclusion: In the IC programmes for patients with multimorbidity in Asia, service delivery, leadership, and workforce were most frequently mentioned, while the financing component was least mentioned. There appears to be considerable scope for development. Highlights: First scoping review to synthesise the key components and elements of integrated care programmes for multimorbidity in Asia.All programmes emphasized 'distinctive service delivery', 'leadership', and 'workforce' components.'Financing' component was least mentioned in identified integrated care programmes.

Intergovernmental policy opportunities for childhood obesity prevention in Australia: Perspectives from senior officials.

BACKGROUND: Early childhood (from conception to five years) is a key life stage for interventions to prevent obesity. In the Australian Federation, policy responsibility for obesity prevention sits across all levels of government and several intergovernmental institutions, rendering a complicated policy space. There is a gap in our understanding of the role of intergovernmentalism in developing obesity prevention policy in Australia. Given the complexity of intergovernmental structures and initiatives influencing childhood obesity prevention policy, it is important to understand the perspectives of senior health officials within the bureaucracy of government who through their roles may be able to influence processes or new strategies. METHODS: Document analysis relating to obesity prevention in the intergovernmental context provided material support to the study. This analysis informed the interview guides for nine interviews with ten senior health department officials (one interview per jurisdiction). FINDINGS: Several opportunities exist to support nutrition and obesity prevention in early childhood including marketing regulation (discretionary choices, breastmilk substitutes, commercial complementary foods and 'toddler milks') and supporting the early childhood education and care sector. This study found a widening structural gap to support national obesity policy in Australia. New public management strategies limit the ability of intergovernmental institutions to support coordination within and between governments to address complex issues such as obesity. Subnational informants perceived a gap in national leadership for obesity prevention, while a Commonwealth informant noted the commitment of the national government to partner with industry under a self-regulation model. In this gap, subnational leaders have pursued nationally consistent action to address obesity, including the development of a national obesity strategy as a bipartisan endeavour across jurisdictions. Public officials calculate the strategic possibilities of pursuing opportunities within state agendas but note the limited chances of structural change in the absence of national leadership and funding.

Rational Design, Chemical Syntheses, and Biological Evaluations of Peripherally Selective Mu Opioid Receptor Ligands as Potential Opioid Induced Constipation Treatment.

Opioid-induced constipation (OIC) is a common adverse effect of opioid analgesics. Peripherally acting µ opioid receptor antagonists (PAMORAs) can be applied in the treatment of OIC without compromising the analgesic effects. NAP, a 6ß-N-4-pyridyl-substituted naltrexamine derivative, was previously identified as a potent and selective MOR antagonist mainly acting peripherally but with some CNS effects. Herein, we introduced a highly polar aromatic moiety, for example, a pyrazolyl or imidazolyl ring to decrease CNS MPO scores in order to reduce passive BBB permeability. Four compounds 2, 5, 17, and 19, when administered orally, were able to increase intestinal motility during morphine-induced constipation in the carmine red dye assays. Among them, compound 19 (p.o.) improved GI tract motility by 75% while orally administered NAP and methylnaltrexone showed no significant effects at the same dose. Thus, this compound seemed a promising agent to be further developed as an oral treatment for OIC.

Design, Synthesis, and Biological Evaluation of NAP Isosteres: A Switch from Peripheral to Central Nervous System Acting Mu-Opioid Receptor Antagonists.

The µ opioid receptor (MOR) has been an intrinsic target to develop treatment of opioid use disorders (OUD). Herein, we report our efforts on developing centrally acting MOR antagonists by structural modifications of 17-cyclopropylmethyl-3,14-dihydroxy-4,5α-epoxy-6ß-[(4'-pyridyl) carboxamido] morphinan (NAP), a peripherally acting MOR-selective antagonist. An isosteric replacement concept was applied and incorporated with physiochemical property predictions in the molecular design. Three analogs, namely, 25, 26, and 31, were identified as potent MOR antagonists in vivo with significantly fewer withdrawal symptoms than naloxone observed at similar doses. Furthermore, brain and plasma drug distribution studies supported the outcomes of our design strategy on these compounds. Taken together, our isosteric replacement of pyridine with pyrrole, furan, and thiophene provided insights into the structure-activity relationships of NAP and aided the understanding of physicochemical requirements of potential CNS acting opioids. These efforts resulted in potent, centrally efficacious MOR antagonists that may be pursued as leads to treat OUD.

Phage-Displayed Mimotopes of SARS-CoV-2 Spike Protein Targeted to Authentic and Alternative Cellular Receptors.

The evolution of the SARS-CoV-2 virus during the COVID-19 pandemic was accompanied by the emergence of new heavily mutated viral variants with increased infectivity and/or resistance to detection by the human immune system. To respond to the urgent need for advanced methods and materials to empower a better understanding of the mechanisms of virus's adaptation to human host cells and to the immuno-resistant human population, we suggested using recombinant filamentous bacteriophages, displaying on their surface foreign peptides termed "mimotopes", which mimic the structure of viral receptor-binding sites on the viral spike protein and can serve as molecular probes in the evaluation of molecular mechanisms of virus infectivity. In opposition to spike-binding antibodies that are commonly used in studying the interaction of the ACE2 receptor with SARS-CoV-2 variants in vitro, phage spike mimotopes targeted to other cellular receptors would allow discovery of their role in viral infection in vivo using cell culture, tissue, organs, or the whole organism. Phage mimotopes of the SARS-CoV-2 Spike S1 protein have been developed using a combination of phage display and molecular mimicry concepts, termed here "phage mimicry", supported by bioinformatics methods. The key elements of the phage mimicry concept include: (1) preparation of a collection of p8-type (landscape) phages, which interact with authentic active receptors of live human cells, presumably mimicking the binding interactions of human coronaviruses such as SARS-CoV-2 and its variants; (2) discovery of closely related amino acid clusters with similar 3D structural motifs on the surface of natural ligands (FGF1 and NRP1), of the model receptor of interest FGFR and the S1 spike protein; and (3) an ELISA analysis of the interaction between candidate phage mimotopes with FGFR3 (a potential alternative receptor) in comparison with ACE2 (the authentic receptor).