Design and Synthesis of Novel 3-Nitro-1H-1,2,4-triazole-1,2,3-triazole-1,4-disubstituted Analogs as Promising Antitrypanosomatid Agents: Evaluation of In Vitro Activity against Chagas Disease and Leishmaniasis.

A series of 28 compounds, 3-nitro-1H-1,2,4-triazole, were synthesized by click-chemistry with diverse substitution patterns using medicinal chemistry approaches, such as bioisosterism, Craig-plot, and the Topliss set with excellent yields. Overall, the analogs demonstrated relevant in vitro antitrypanosomatid activity. Analog 15g (R1 = 4-OCF3-Ph, IC50 = 0.09 µM, SI = >555.5) exhibited an outstanding antichagasic activity (Trypanosoma cruzi, Tulahuen LacZ strain) 68-fold more active than benznidazole (BZN, IC50 = 6.15 µM, SI = >8.13) with relevant selectivity index, and suitable LipE = 5.31. 15g was considered an appropriate substrate for the type I nitro reductases (TcNTR I), contributing to a likely potential mechanism of action for antichagasic activity. Finally, 15g showed nonmutagenic potential against Salmonella typhimurium strains (TA98, TA100, and TA102). Therefore, 3-nitro-1H-1,2,4-triazole 15g is a promising antitrypanosomatid candidate for in vivo studies.

Structure-Activity Relationship Study to Develop Peptide Amphiphiles as Species-Specific Antimicrobials.

Antimicrobial peptide amphiphiles (PAs) are a promising class of molecules that can disrupt the bacterial membrane or act as drug nanocarriers. In this study, we prepared 33 PAs to establish supramolecular structure-activity relationships. We studied the morphology and activity of the nanostructures against different Gram-positive and Gram-negative bacterial strains (such as Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii). Next, we used principal component analysis (PCA) to determine the key contributors to activity. We found that for S. aureus, the zeta potential was the major contributor to the activity while Gram-negative bacteria were more influenced by the partition coefficient (LogP) with the following order P. aeruginosa>E. coli>A. baumannii. We also performed a study of the mechanism of action of selected PAs on the bacterial membrane assessing the membrane permeability and depolarization, changes in zeta potential and overall integrity. We studied the toxicity of the nanostructures against mammalian cells. Finally, we performed an in vivo study using the wax moth larvae to determine the therapeutic efficacy of the active PAs. This study shows cationic PA nanostructures can be an intriguing platform for the development of nanoantibacterials.

Mediating pathways that link adverse childhood experiences with cardiovascular disease.

OBJECTIVES: There is uncertainty about which factors mediate the association between adverse childhood experiences (ACEs) and cardiovascular disease (CVD). This could inform secondary prevention targets. STUDY DESIGN: Mediation analysis of a prospective cohort study. METHODS: English Longitudinal Study of Ageing (ELSA) wave 3 data (2006/7) were used to measure retrospective exposure to 12 individual ACEs and waves 2 to 4 (2004/5 to 2008/9) data to measure current exposure to potential mediators [smoking, physical activity, alcohol consumption, body mass index, depression, and C-reactive protein (CRP)]. Waves 4 to 9 ELSA data (2008/9 to 2018/19) were used to measure incident CVD. Cumulative ACE exposure was categorised into experiencing 0, 1 to 3, or ≥4 individual ACEs. Associations were tested between ACE categories, potential mediators, and incident CVD, to inform which variables were analysed in causal mediation models. RESULTS: The analytical cohort consisted of 4547 participants (56% women), with a mean age of 64 years (standard deviation = 9 years). At least one ACE had been experienced by 45% of the cohort, and 24% developed incident CVD over a median follow-up period of 9.7 years (interquartile range: 5.3-11.4 years). After adjusting for potential confounders, experiencing ≥4 ACEs compared with none was associated with incident CVD [odds ratio (OR): 1.55; 95% confidence interval (CI): 1.10, 2.17], and the association of one to three ACEs compared with none was non-significant (OR: 1.08; 95% CI: 0.93, 1.24). There were two statistically significant mediators of the association between ≥4 ACEs and incident CVD: CRP and depression, which accounted for 10.7% and 10.8% of the association, respectively. CONCLUSIONS: Inflammation and depression partially mediated the association between ACEs and CVD. Targeting these factors may reduce the future incidence of CVD.

Exploring views of members of the public and policymakers on the acceptability of population level dietary and active-travel policies: a qualitative study.

BACKGROUND: There is limited evidence on what shapes the acceptability of population level dietary and active-travel policies in England. This information would be useful in the decision-making process about which policies should be implemented and how to increase their effectiveness and sustainability. To fill this gap, we explored public and policymakers' views about factors that influence public acceptability of dietary and active-travel policies and how to increase public acceptability for these policies. METHODS: We conducted online, semi-structured interviews with 20 members of the public and 20 policymakers in England. A purposive sampling frame was used to recruit members of the public via a recruitment agency, based on age, sex, socioeconomic status and ethnicity. Policymakers were recruited from existing contacts within our research collaborations and via snowball sampling. We explored different dietary and active-travel policies that varied in their scope and focus. Interviews were transcribed verbatim and analysed using thematic reflexive analysis with both inductive and deductive coding. RESULTS: We identified four themes that informed public acceptability of dietary and active-travel policies: (1) perceived policy effectiveness, i.e., policies that included believable mechanisms of action, addressed valued co-benefits and barriers to engage in the behaviour; (2) perceived policy fairness, i.e., policies that provided everyone with an opportunity to benefit (mentioned only by the public), equally considered the needs of various population subgroups and rewarded 'healthy' behaviours rather than only penalising 'unhealthy' behaviours; (3) communication of policies, i.e., policies that were visible and had consistent and positive messages from the media (mentioned only by policymakers) and (4) how to improve policy support, with the main suggestion being an integrated strategy addressing multiple aspects of these behaviours, inclusive policies that consider everyone's needs and use of appropriate channels and messages in policy communication. CONCLUSIONS: Our findings highlight that members' of the public and policymakers' support for dietary and active-travel policies can be shaped by the perceived effectiveness, fairness and communication of policies and provide suggestions on how to improve policy support. This information can inform the design of acceptable policies but can also be used to help communicate existing and future policies to maximise their adoption and sustainability.

In Vivo Antileishmanial Effect of 3,5-Diaryl-isoxazole Analogues Based on Veraguensin, Grandisin, and Machilin G: A Glance at a Preclinical Study.

New treatment approaches targeting cutaneous leishmaniasis (CL) are required since conventional drugs exhibit limitations due to their several adverse effects and toxicity. In this study, we aimed to evaluate the in vivo intralesional treatment efficacy of five isoxazole derivatives previously synthesized and effective in vitro against intracellular amastigote forms of Leishmania (L.) amazonensis. Among the tested analogues, 7 exhibited relevant in vivo therapeutic effects. The in silico predictions provided interesting information about the toxicity, suggesting the safety of analogue 7. Experiments performed with Salmonella typhimurium strains (TA98, TA100, and TA102) showed a non-mutagenicity profile of 7. The treatment of Leishmania-infected BALB/c mice with isoxazole 7 showed remarkably smaller CL lesions and decreased the parasitism (by 98.4%) compared to the control group. Hence, analogue 7 is a promising drug candidate and alternative treatment for CL caused by L. amazonensis.

The relation between the social and the biological and COVID-19.

Social factors have been linked to disease severity and mortality in COVID-19. These social factors are ethnicity, social disadvantage, age, gender and occupation. Pre-existing medical conditions have also been identified as an increasing risk. This paper explores the relationship between these social and biological factors using a syndemic frame of reference. The paper argues that although the associations have been very well documented, the mechanisms linking the social factors and disease outcomes are not well understood. An approach that seeks to find commensurability between the social and the biological, is suggested.

How can we achieve impact from public health research? A meta-ethnography of case studies.

BACKGROUND: Generation of public health impact from research is challenging. Research of similar quality often has differential uptake and there is considerable lag time between initiation and uptake of research. Improving understanding of how research impact can be achieved may identify areas stakeholders could target. METHODS: This work uses meta-ethnography to synthesize 21 case studies exploring how researchers have generated public health policy impact. RESULTS: Eight constructs were identified: expertise; motivation; practical solutions to important problems; support structure and funding; collaboration; wide dissemination and use of media to contribute ideas to the wider narrative; understanding the policy realm; and models of impact. The constructs were combined in a lines-of-argument synthesis, producing a model that seeks to illustrate the diffuse, complex and dynamic nature of the process of generating impact from research. CONCLUSION: Achieving research impact involves seeking to shape wider debates, building relationships with policy makers, becoming a trusted collaborator and being available to provide relevant and practical solutions to questions of concern to policy makers at the appropriate time.

Why is translating research into policy so hard? How theory can help public health researchers achieve impact?

OBJECTIVE: To describe how overly simple conceptualisations of how research is translated into public health policy impact impair effective translation. To suggest how alternative approaches to conceptualising impact, which incorporate recent developments in social and political sciences, can help stakeholders improve translation of high-quality public health research into policy impact. STUDY DESIGN: Researchers often describe generating impact in terms of linear or cyclical models, in which the production of scientific findings alone compels action and leads to impact. However, such conceptualisations do not appear to have supported improved translation of research into policy and practice. Improving understanding of how research impact is achieved may identify areas stakeholders seeking to achieve impact could target. METHODS: Overview of theoretical and practical approaches to achieving public health policy impact from research. RESULTS: Despite much evidence that translating research into public health policy is more complex than linear and cyclical models suggest, stakeholders often revert to these heuristics, that is shorthand ways of thinking that allow simple but inaccurate answers to complex problems. This leads to potentially missing opportunities for impact, such as conducting research in collaboration with local policy makers and contributing ideas to the wider narrative through the media and public engagement. CONCLUSION: The process of translating research into impact appears more complex than that suggested by linear and cyclical models. Success involves a planned approach targeting multiple routes to impact, sustained over time.

From the National Health Service to local government: perceptions of public health transition in England.

OBJECTIVES: In England, in 2013, responsibility for some public health (PH) functions transferred from the National Health Service (NHS) to local government. This moved PH from a health-focussed into a broader and more politically oriented context. This article reports on the perceptions of those involved in this transition about how the PH function was changing as it transited to local government. STUDY DESIGN: This is a cross-sectional interview study. METHODS: The study included semi-structured interviews with 31 local government councillors, directors and deputy directors of PH, PH team members and members of clinical commissioning groups. Interviews and data analysis were informed by a theoretical framework, COM-B and an inductive and deductive approach was taken to identify relevant themes. RESULTS: There was a mixed picture of perceived gains and losses for PH. The transition from NHS to local government was seen by some as a 'homecoming', providing the opportunity for PH to have further reach through influence and collaboration with departments like housing, transport and planning. The opportunity to promote evidence-based practice across local government was also seen as a positive aspect of the transition. However, professional roles of PH and individual PH practitioners were perceived to have less influence and autonomy than in the NHS, with some uncertainty about roles within local government. PH practitioners perceived the need to develop other skills to fulfil their roles in local government. Shorter timescales for action and pressure for faster responses were reported to be the reason for less emphasis on using PH evidence to inform policy and decision-making than hitherto in the NHS. CONCLUSION: This study illustrates a variety of consequences of transitioning from NHS to local government. There were perceived benefits afforded by proximity to related local government departments but at the costs of reduction in status for PH practitioners and working to a timescale which in some cases reduced drawing on scientific evidence.

Cognitive biases in public health and how economics and sociology can help overcome them.

OBJECTIVES: The objective of this study was to identify important gaps in the public health evidence base and consider the implications of these for public health and public health economics. STUDY DESIGN: This was a review and critique of public health policy in the UK. METHODS: Using two key psychological concepts relating to cognitive biases, viz. cognitive dissonance and heuristics, the shortcomings in public health approaches to confronting the prevalence of non-communicable diseases are described. The implications are drawn out. RESULTS: Two cognitive biases in public health thinking are identified. (i) A dissonance between what is known and what is done, resulting in the repetition of solutions that have previously been shown to have had little or no effect. (ii) The habitual use of set of heuristics which mean that simple solutions to complex problems are preferred to undertaking the detailed assessment of how to bring about change. These biases mean that the evidence about the dynamics of populations and the ways that the mechanisms of prevention actually operate seldom feature in the way interventions, policy and practice are undertaken. The evidence base is consequently highly skewed. CONCLUSIONS: Health economics combined with sociological reasoning has potentially an important role to play in developing the ideas that will overcome the problems attaching to the cognitive biases.

Control of Cryptococcus Gattii Biofilms by an Ethanolic Extract of Cochlospermum Regium (Schrank) Pilger Leaves.

Cryptococcus gattii is an etiologic agent of cryptococcosis and a serious disease that affects immunocompromised and immunocompetent patients worldwide. The therapeutic arsenal used to treat cryptococcosis is limited to a few antifungal agents, and the ability of C. gattii to form biofilms may hinder treatment and decrease its susceptibility to antifungal agents. The objective of this study was to evaluate the antifungal and antibiofilm activities of an ethanolic extract of Cochlospermum regium (Schrank) Pilger leaves against C. gattii. The antifungal activity was assessed by measuring the minimum inhibitory concentration (MIC) using the broth microdilution technique and interaction of the extract with fluconazole was performed of checkerboard assay. The antibiofilm activity of the extract was evaluated in 96-well polystyrene microplates, and the biofilms were quantified by counting colony forming units. The extract showed antifungal activity at concentrations of 62.5 to 250 µg/mL and when the extract was evaluated in combination with fluconazole, C. gattii was inhibited at sub-MIC levels. The antibiofilm activity of the extract against C. gattii was observed both during biofilm formation and on an already established biofilm. The results showed that the ethanolic extract of the leaves of C. regium shows promise for the development of antifungal drugs to treat cryptococcosis and to combat C. gattii biofilms.

Moving beyond individual choice in policies to reduce health inequalities: the integration of dynamic with individual explanations.

Background: A strong focus on individual choice and behaviour informs interventions designed to reduce health inequalities in the UK. We review evidence for wider mechanisms from a range of disciplines, demonstrate that they are not yet impacting on programmes, and argue for their systematic inclusion in policy and research. Methods: We identified potential mechanisms relevant to health inequalities and their amelioration from different disciplines and analysed six policy documents published between 1976 and 2010 using Bacchi's 'What's the problem represented to be?' framework for policy analysis. Results: We found substantial evidence of supra-individualistic and relational mechanisms relevant to health inequalities from sociology, history, biology, neuroscience, philosophy and psychology. Policy documents sometimes expressed these mechanisms in policy rhetoric but rarely in policy recommendations, which continue to focus on individual behaviour. Discussion: Current evidence points to the potential of systematically applying broader thinking about causal mechanisms, beyond individual choice and responsibility, to the design, implementation and evaluation of policies to reduce health inequalities. We provide a set of questions designed to enable critique of policy discussions and programmes to ensure that these wider mechanisms are considered.

In vitro antifungal activity of Myracrodruon urundeuva Allemão against human vaginal Candida species.

Myracrodruon urundeuva is a plant native to Brazil, which is used by the indigenous population for the treatment of candidiasis. The aims of this study were to evaluate the antifungal activity of extract against human vaginal Candida species and evaluate the possible toxicological activities of M. urundeuva. Initially, ethanol extracts, ethyl acetate fractions, and hydroalcoholic fractions of the bark and leaf of M. urundeuva were used to determine the minimum inhibitory concentration. The extracts that showed antifungal activity were characterized by liquid chromatography and subjected to toxicity assessment. Toxic, cytotoxic, genotoxic, and mutagenic testing were performed using Allium cepa and Ames assays with the ethanol extracts of the bark and leaves. Hemolytic activity was evaluated in erythrocytes and acute toxicity in rats. The ethanol bark extracts showed best activity against Candida albicans, C. krusei, and C. tropicalis ATCC (4-512 µg/mL). Chemical characterization indicated the presence of flavonoids and tannins in the extracts. Hemolytic activity, genotoxicity, and mutagenicity were not observed. The results of the Ames and A. cepa tests were also in agreement, ethanol bark extracts and ethanol leaf extracts of M. urundeuva showed absence of mutagenic activity. Similar results were observed in the A. cepa assay and acute toxicity test in rats. M. urundeuva bark extracts showed potential for the treatment of vaginal infections caused Candida species, as a topical.

Evidence-based medicine meets democracy: the role of evidence-based public health guidelines in local government.

Background: In 2013, many public health functions transferred from the National Health Service to local government in England. From 2006 NICE had produced public health guidelines based on the principles of evidence-based medicine. This study explores how the guidelines were received in the new environment in local government and related issues raised relating to the use of evidence in local authoritites. Methods: In depth, interviews with 31 elected members and officers, including Directors of Public Health, from four very different local government organizations ('local authorities'). Results: Participants reported that (i) there were tensions between evidence-based, and political decision-making; (ii) there were differences in views about what constituted 'good' evidence and (iii) that organizational life is an important mediator in the way evidence is used. Conclusions: Democratic political decision-making does not necessarily naturally align with decision-making based on evidence from the international scientific literature, and local knowledge and local evidence are very important in the ways that public health decisions are made.

PDE11A negatively regulates lithium responsivity.

Lithium responsivity in patients with bipolar disorder has been genetically associated with Phosphodiesterase 11A (PDE11A), and lithium decreases PDE11A mRNA in induced pluripotent stem cell-derived hippocampal neurons originating from lithium-responsive patients. PDE11 is an enzyme uniquely enriched in the hippocampus that breaks down cyclic AMP and cyclic GMP. Here we determined whether decreasing PDE11A expression is sufficient to increase lithium responsivity in mice. In dorsal hippocampus and ventral hippocampus (VHIPP), lithium-responsive C57BL/6J and 129S6/SvEvTac mice show decreased PDE11A4 protein expression relative to lithium-unresponsive BALB/cJ mice. In VHIPP, C57BL/6J mice also show differences in PDE11A4 compartmentalization relative to BALB/cJ mice. In contrast, neither PDE2A nor PDE10A expression differ among the strains. The compartment-specific differences in PDE11A4 protein expression are explained by a coding single-nucleotide polymorphism (SNP) at amino acid 499, which falls within the GAF-B homodimerization domain. Relative to the BALB/cJ 499T, the C57BL/6J 499A decreases PDE11A4 homodimerization, which removes PDE11A4 from the membrane. Consistent with the observation that lower PDE11A4 expression correlates with better lithium responsiveness, we found that Pde11a knockout mice (KO) given 0.4% lithium chow for 3+ weeks exhibit greater lithium responsivity relative to wild-type (WT) littermates in tail suspension, an antidepressant-predictive assay, and amphetamine hyperlocomotion, an anti-manic predictive assay. Reduced PDE11A4 expression may represent a lithium-sensitive pathophysiology, because both C57BL/6J and Pde11a KO mice show increased expression of the pro-inflammatory cytokine interleukin-6 (IL-6) relative to BALB/cJ and PDE11A WT mice, respectively. Our finding that PDE11A4 negatively regulates lithium responsivity in mice suggests that the PDE11A SNPs identified in patients may be functionally relevant.

In vitro antifungal activity of Myracrodruon urundeuva Allemão against human vaginal Candida species

ABSTRACT Myracrodruon urundeuva is a plant native to Brazil, which is used by the indigenous population for the treatment of candidiasis. The aims of this study were to evaluate the antifungal activity of extract against human vaginal Candida species and evaluate the possible toxicological activities of M. urundeuva. Initially, ethanol extracts, ethyl acetate fractions, and hydroalcoholic fractions of the bark and leaf of M. urundeuva were used to determine the minimum inhibitory concentration. The extracts that showed antifungal activity were characterized by liquid chromatography and subjected to toxicity assessment. Toxic, cytotoxic, genotoxic, and mutagenic testing were performed using Allium cepa and Ames assays with the ethanol extracts of the bark and leaves. Hemolytic activity was evaluated in erythrocytes and acute toxicity in rats. The ethanol bark extracts showed best activity against Candida albicans, C. krusei, and C. tropicalis ATCC (4-512 µg/mL). Chemical characterization indicated the presence of flavonoids and tannins in the extracts. Hemolytic activity, genotoxicity, and mutagenicity were not observed. The results of the Ames and A. cepa tests were also in agreement, ethanol bark extracts and ethanol leaf extracts of M. urundeuva showed absence of mutagenic activity. Similar results were observed in the A. cepa assay and acute toxicity test in rats. M. urundeuva bark extracts showed potential for the treatment of vaginal infections caused Candida species, as a topical.

Critique of the review of 'Water fluoridation for the prevention of dental caries' published by the Cochrane Collaboration in 2015.

The Cochrane Review on water fluoridation for the prevention of dental caries was published in 2015 and attracted considerable interest and comment, especially in countries with extensive water fluoridation programmes. The Review had two objectives: (i) to evaluate the effects of water fluoridation (artificial or natural) on the prevention of dental caries, and (ii) to evaluate the effects of water fluoridation (artificial or natural) on dental fluorosis. The authors concluded, inter alia, that there was very little contemporary evidence, meeting the Review's inclusion criteria, that evaluated the effectiveness of water fluoridation for the prevention of dental caries. The purpose of this critique is to examine the conduct of the above Review, and to put it into context in the wider body of evidence regarding the effectiveness of water fluoridation. While the overall conclusion that water fluoridation is effective in caries prevention agrees with previous reviews, many important public health questions could not be answered by the Review because of the restrictive criteria used to judge adequacy of study design and risk of bias. The potential benefits of using wider criteria in order to achieve a fuller understanding of the effectiveness of water fluoridation are discussed.

Comparison of spinal deformity in children with Chiari I malformation with and without syringomyelia: matched cohort study.

PURPOSE: To describe curve patterns in patients with Chiari malformation I (CIM) without syringomyelia, and compare to patients with Chiari malformation with syringomyelia (CIM + SM). METHODS: Review of medical records from 2000 to 2013 at a single institution was performed to identify CIM patients with scoliosis. Patients with CIM were matched (1:1) by age and gender to CIM + SM. Radiographic curve patterns, MRI-based craniovertebral junction parameters, and associated neurological signs were compared between the two cohorts. RESULTS: Eighteen patients with CIM-associated scoliosis in the absence of syringomyelia were identified; 14 (78 %) were female, with mean age of 11.5 ± 4.5 years. Mean tonsillar descent was 9.9 ± 4.1 mm in the CIM group and 9.1 ± 3.0 mm in the CIM + SM group (p = 0.57). Average syrinx diameter in the CIM + SM group was 9.0 ± 2.7 mm. CIM patients demonstrated less severe scoliotic curves (32.1° vs. 46.1°, p = 0.04), despite comparable thoracic kyphosis (43.7° vs. 49.6°, p = 0.85). Two (11 %) patients with CIM demonstrated thoracic apex left deformities compared to 9/18 (50 %) in the CIM + SM cohort (p = 0.01). Neurological abnormalities were only observed in the group with syringomyelia (6/18, or 33 %; p = 0.007). CONCLUSION: In the largest series specifically evaluating CIM and scoliosis, we found that these patients appear to present with fewer atypical curve features, with less severe scoliotic curves, fewer apex left curves, and fewer related neurological abnormalities than CIM + SM. Notably, equivalent thoracic kyphosis was observed in both groups. Future studies are needed to better understand pathogenesis of spinal deformity in CIM with and without SM.

Amphetamine sensitization in mice is sufficient to produce both manic- and depressive-related behaviors as well as changes in the functional connectivity of corticolimbic structures.

It has been suggested that amphetamine abuse and withdrawal mimics the diverse nature of bipolar disorder symptomatology in humans. Here, we determined if a single paradigm of amphetamine sensitization would be sufficient to produce both manic- and depressive-related behaviors in mice. CD-1 mice were subcutaneously dosed for 5 days with 1.8 mg/kg d-amphetamine or vehicle. On days 6-31 of withdrawal, amphetamine-sensitized (AS) mice were compared to vehicle-treated (VT) mice on a range of behavioral and biochemical endpoints. AS mice demonstrated reliable mania- and depression-related behaviors from day 7 to day 28 of withdrawal. Relative to VT mice, AS mice exhibited long-lasting mania-like hyperactivity following either an acute 30-min restraint stress or a low-dose 1 mg/kg d-amphetamine challenge, which was attenuated by the mood-stabilizers lithium and quetiapine. In absence of any challenge, AS mice showed anhedonia-like decreases in sucrose preference and depression-like impairments in the off-line consolidation of motor memory, as reflected by the lack of spontaneous improvement across days of training on the rotarod. AS mice also demonstrated a functional impairment in nest building, an ethologically-relevant activity of daily living. Western blot analyses revealed a significant increase in methylation of histone 3 at lysine 9 (H3K9), but not lysine 4 (H3K4), in hippocampus of AS mice relative to VT mice. In situ hybridization for the immediate-early gene activity-regulated cytoskeleton-associated protein (Arc) further revealed heightened activation of corticolimbic structures, decreased functional connectivity between frontal cortex and striatum, and increased functional connectivity between the amygdala and hippocampus of AS mice. The effects of amphetamine sensitization were blunted in C57BL/6J mice relative to CD-1 mice. These results show that a single amphetamine sensitization protocol is sufficient to produce behavioral, functional, and biochemical phenotypes in mice that are relevant to bipolar disorder.

Prioritising public health guidance topics in the National Institute for Health and Care Excellence using the Analytic Hierarchy Process.

OBJECTIVES: The Centre for Public Health (CPH), at the United Kingdom's National Institute for Health and Care Excellence (NICE) is responsible for producing national guidance relating to the promotion of good health and the prevention and treatment of disease. Given the challenges of developing guidance in this area, choosing the most appropriate topics for further study is of fundamental importance. This paper explores the current prioritisation process and describes how the Analytic Hierarchy Process (AHP), a multi criteria decision analysis (MCDA) technique, might be used to do so. STUDY DESIGN: A proposed approach is outlined, which was tested in a proof of concept pilot. This consisted of eight participants with experience of related NICE committees building scores for each topic together in a 'decision conference' setting. METHODS: Criteria were identified and subsequently weighted to indicate the relative importance of each. Participants then collaboratively estimated the performance of each topic on each criterion. RESULTS: Total scores for each topic were calculated, which could be ranked and used as the basis for better informed discussion for prioritising topics to recommend to the Minister for future guidance. Sensitivity analyses of the dataset found it to be robust. CONCLUSIONS: Choosing the right topics for guidance at the earliest possible time is of fundamental importance to public health guidance, and judgement is likely to play an important part in doing so. MCDA techniques offer a potentially useful approach to structuring the problem in a rational and transparent way. NICE should consider carefully whether such an approach might be worth pursuing in the future.