An expedient strategy for the diversity-oriented synthesis of macrocyclic compounds with natural product-like characteristics

Naturally-derived macrocyclic compounds are associated with a diverse range of biological activities, including antibacterial effects, and there are over 100 marketed macrocycle drugs derived from natural products. However, synthetic macrocycles are widely considered to be poorly explored in antibiotic development (indeed, within drug discovery in general). This has been attributed to challenges associated with the generation of such compounds. Whilst there are synthetic methods that can produce large collections of structurally similar macrocycles (i.e., compounds with varying appendages based around similar core macrocyclic ring architectures) there is a relative dearth of strategies for the efficient generation of more structurally diverse macrocycle collections in which there is greater variation in the nature of macrocyclic scaffolds present. Such macrocycle collections should contain compounds with a broad range of biological activities (including antibacterial activities) and the requisite robust synthetic methodology useful for analogue synthesis and lead optimization once an active compound has been identified in a biological screen. Herein, we describe a new and expedient diversity-oriented synthesis (DOS) strategy for the generation of a library of novel structurally diverse macrocyclic compounds with a high level of scaffold diversity. The strategy is concise, proceeds from readily-available starting materials, is modular in nature and features a variety of macrocyclisation techniques. In this proof-of-concept study, the synthesis of several previously unreported macrocyclic compounds was achieved. Each of these macrocycles was based around a distinct molecular scaffold and contained natural product-like structural features (e.g., three-dimensionality and multiple hydrogen bond donors and acceptors) as well as synthetic handles for potential further elaboration. The successful generation of these macrocycles demonstrates the feasibility of the new DOS strategy as a synthetic platform for library generation.The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no [279337/DOS]. In addition, the group research was supported by grants from the Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Medical Research Council and Welcome Trust

Dual equipoise shared decision making: definitions for decision and behaviour support interventions

Contains fulltext : 80919.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: There is increasing interest in interventions that can support patients who face difficult decisions and individuals who need to modify their behaviour to achieve better outcomes. Evidence for effectiveness is used to categorise patients care. Effective care is where evidence of benefit outweighs harm: patients should always receive this type of care, where indicated. Preference-sensitive care describes a situation where the evidence for the superiority of one treatment over another is either not available or does not allow differentiation; in this situation, there are two or more valid approaches, and the best choice depends on how individuals value the risks and benefits of treatments. DISCUSSION: Preference-sensitive decisions are defined by equipoise: situations where options need to be deliberated. Moreover, where both healthcare professionals and patients agree that equipoise exists, situations may be regarded as having 'dual equipoise'. Such conditions are ideal for shared decision making. However, there are many situations in medicine where dual equipoise does not exist, where health professionals hold the view that scientific evidence for benefit strongly outweighs harm. This is often the case where people suffer from chronic conditions, and where behaviour change is recommended to improve outcomes. However, some patients, are either ambivalent or find it difficult to sustain optimal behaviours, i.e., patients will be in varying degrees of equipoise. Therefore, situations where dual equipoise exists (or not) help to clarify the definitions of two classes of support, namely, decision and behaviour change support interventions. Decision support interventions help people think about choices they face; they describe where and why choice exists, in short, conditions of dual equipoise; they provide information about options, including, where reasonable, the option of taking no action. These interventions help people to deliberate, independently or in collaboration with others, about options by considering relevant attributes; they support people to forecast how they might feel about short, intermediate, and long-term outcomes that have relevant consequences, in ways that help the process of constructing preferences and eventual decision making appropriate to their individual situation. Whereas, behavioural support interventions describe, justify, and recommend actions that, over time, lead to predictable outcomes over short, intermediate, and long-term timeframes, and that have relevant and important consequences for those who are considering behaviour change. SUMMARY: Decision and behaviour support interventions have divergent aims, different relationships to equipoise, and form two classes of interventions

Variation in diabetes care by age: opportunities for customization of care

BACKGROUND: The quality of diabetes care provided to older adults has usually been judged to be poor, but few data provide direct comparison to other age groups. In this study, we hypothesized that adults age 65 and over receive lower quality diabetes care than adults age 45–64 years old. METHODS: We conducted a cohort study of members of a health plan cared for by multiple medical groups in Minnesota. Study subjects were a random sample of 1109 adults age 45 and over with an established diagnosis of diabetes using a diabetes identification method with estimated sensitivity 0.91 and positive predictive value 0.94. Survey data (response rate 86.2%) and administrative databases were used to assess diabetes severity, glycemic control, quality of life, microvascular and macrovascular risks and complications, preventive care, utilization, and perceptions of diabetes. RESULTS: Compared to those aged 45–64 years (N = 627), those 65 and older (N = 482) had better glycemic control, better health-related behaviors, and perceived less adverse impacts of diabetes on their quality of life despite longer duration of diabetes and a prevalence of cardiovascular disease twice that of younger patients. Older patients did not ascribe heart disease to their diabetes. Younger adults often had explanatory models of diabetes that interfere with effective and aggressive care, and accessed care less frequently. Overall, only 37% of patients were simultaneously up-to-date on eye exams, foot exams, and glycated hemoglobin (A1c) tests within one year. CONCLUSION: These data demonstrate the need for further improvement in diabetes care for all patients, and suggest that customisation of care based on age and explanatory models of diabetes may be an improvement strategy that merits further evaluation

Evidence-based care of older people with suspected cognitive impairment in general practice: protocol for the IRIS cluster randomised trial

Background: Dementia is a common and complex condition. Evidence-based guidelines for the management of people with dementia in general practice exist; however, detection, diagnosis and disclosure of dementia have been identified as potential evidence-practice gaps. Interventions to implement guidelines into practice have had varying success. The use of theory in designing implementation interventions has been limited, but is advocated because of its potential to yield more effective interventions and aid understanding of factors modifying the magnitude of intervention effects across trials. This protocol describes methods of a randomised trial that tests a theory-informed implementation intervention that, if effective, may provide benefits for patients with dementia and their carers. Aims: This trial aims to estimate the effectiveness of a theory-informed intervention to increase GPs’ (in Victoria, Australia) adherence to a clinical guideline for the detection, diagnosis, and management of dementia in general practice, compared with providing GPs with a printed copy of the guideline. Primary objectives include testing if the intervention is effective in increasing the percentage of patients with suspected cognitive impairment who receive care consistent with two key guideline recommendations: receipt of a i) formal cognitive assessment, and ii) depression assessment using a validated scale (primary outcomes for the trial). Methods: The design is a parallel cluster randomised trial, with clusters being general practices. We aim to recruit 60 practices per group. Practices will be randomised to the intervention and control groups using restricted randomisation. Patients meeting the inclusion criteria, and GPs’ detection and diagnosis behaviours directed toward these patients, will be identified and measured via an electronic search of the medical records nine months after the start of the intervention. Practitioners in the control group will receive a printed copy of the guideline. In addition to receipt of the printed guideline, practitioners in the intervention group will be invited to participate in an interactive, opinion leader-led, educational face-to-face workshop. The theory-informed intervention aims to address identified barriers to and enablers of implementation of recommendations. Researchers responsible for identifying the cohort of patients with suspected cognitive impairment, and their detection and diagnosis outcomes, will be blind to group allocation. Trial registration: Australian New Zealand Clinical Trials Registry: ACTRN12611001032943 (date registered 28 September, 2011)

Review of epidemiologic data on the debate over smokeless tobacco's role in harm reduction

Some tobacco researchers have argued that the European Union should remove its ban on a form of low-nitrosamine smokeless tobacco referred to as Swedish 'snus'. This argument has developed in to an international debate over the use of smokeless tobacco as a measure of harm reduction for smokers. Leading authorities in the USA have firmly stated that there is no safe tobacco - a message which does not allow for any discussion of comparative tobacco risks. This commentary is intended to review the origin of the controversy over Swedish 'snus', to examine briefly the meta-analysis on cancer risks by Peter Lee and Jan Hamling (published in July in BMC Medicine) and to discuss the anticipated direction of the debate on tobacco-harm reduction in the USA. We anticipate that much of the debate will shift from the discussion of epidemiologic data to the discussion of the marketing, health communication and economics of smokeless tobacco. While the Food and Drug Administration's newly approved authority over tobacco will undoubtedly affect the smokeless products, it may not be the sole determinant of harm reduction's fate in the USA

State based model of long-term potentiation and synaptic tagging and capture

Recent data indicate that plasticity protocols have not only synapse-specific but also more widespread effects. In particular, in synaptic tagging and capture (STC), tagged synapses can capture plasticity-related proteins, synthesized in response to strong stimulation of other synapses. This leads to long-lasting modification of only weakly stimulated synapses. Here we present a biophysical model of synaptic plasticity in the hippocampus that incorporates several key results from experiments on STC. The model specifies a set of physical states in which a synapse can exist, together with transition rates that are affected by high- and low-frequency stimulation protocols. In contrast to most standard plasticity models, the model exhibits both early- and late-phase LTP/D, de-potentiation, and STC. As such, it provides a useful starting point for further theoretical work on the role of STC in learning and memory

Identifying patient preferences for communicating risk estimates: A descriptive pilot study

BACKGROUND: Patients increasingly seek more active involvement in health care decisions, but little is known about how to communicate complex risk information to patients. The objective of this study was to elicit patient preferences for the presentation and framing of complex risk information. METHOD: To accomplish this, eight focus group discussions and 15 one-on-one interviews were conducted, where women were presented with risk data in a variety of different graphical formats, metrics, and time horizons. Risk data were based on a hypothetical woman's risk for coronary heart disease, hip fracture, and breast cancer, with and without hormone replacement therapy. Participants' preferences were assessed using likert scales, ranking, and abstractions of focus group discussions. RESULTS: Forty peri- and postmenopausal women were recruited through hospital fliers (n = 25) and a community health fair (n = 15). Mean age was 51 years, 50% were non-Caucasian, and all had completed high school. Bar graphs were preferred by 83% of participants over line graphs, thermometer graphs, 100 representative faces, and survival curves. Lifetime risk estimates were preferred over 10 or 20-year horizons, and absolute risks were preferred over relative risks and number needed to treat. CONCLUSION: Although there are many different formats for presenting and framing risk information, simple bar charts depicting absolute lifetime risk were rated and ranked highest overall for patient preferences for format