Value-based medicine: concepts and application.
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ABSTRACT:
SUBMITTER: Bae JM
PROVIDER: S-EPMC4398974 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Multivalent interactions are common in biological systems and are also widely deployed for targeting applications in biomedicine. A unique feature of multivalent binding is "superselectivity". Superselectivity refers to the sharp discrimination of surfaces (e.g., on cells or cell compartments) by their comparative surface densities of a given receptor. This feature is different from the conventional "type" selectivity, which discriminates surfaces by their distinct receptor types. In a broader definition, a probe is superselective if it converts a gradual change in any one interaction parameter into a sharp on/off dependency in probe binding.This Account describes our systematic experimental and theoretical efforts over the past decade to analyze the determinants of superselective binding. It aims to offer chemical biologists, biophysicists, biologists, and biomedical scientists a set of guidelines for the interpretation of multivalent binding data, and design rules for tuning superselective targeting. We first provide a basic introduction that identifies multiple low-affinity interactions and combinatorial entropy as the minimal set of conditions required for superselective recognition. We then introduce the main experimental and theoretical tools and analyze how salient features of the multivalent probes (i.e., their concentration, size, ligand valency, and scaffold type), of the surface receptors (i.e., their affinity for ligands, surface density, and mobility), and of competitors and cofactors (i.e., their concentration and affinity for the ligands and/or receptors) influence the sharpness and the position of the threshold for superselective recognition.Emerging from this work are a set of relatively simple yet quantitative data analysis guidelines and superselectivity design rules that apply to a broad range of probe types and interaction systems. The key finding is the scaling variable xS which faithfully predicts the influence of the surface receptor density, probe ligand valency, receptor-ligand affinity, and competitor/cofactor concentrations and affinities on superselective recognition. The scaling variable is a simple yet versatile tool to quantitatively tune the on/off threshold of superselective probes. We exemplify its application by reviewing and reinterpreting literature data for selected biological and biomedical interaction systems where superselectivity clearly is important.Our guidelines can be deployed to generate a new mechanistic understanding of multivalent recognition events inside and outside cells and the downstream physiological/pathological implications. Moreover, the design rules can be harnessed to develop novel superselective probes for analytical purposes in the life sciences and for diagnostic/therapeutic intervention in biomedicine.
| S-EPMC10077582 | biostudies-literature
Project description:Nonalcoholic fatty liver disease (NALFD) is now a leading cause of chronic liver disease worldwide, in part, as a consequence of rapidly rising levels of obesity and metabolic syndrome and is a major risk factor for cirrhosis, hepatocellular carcinoma, and liver-related mortality. From NAFLD stems a myriad of clinical challenges related to both diagnosis and management. A growing body of evidence suggests an intricate linkage between the gut microbiome and the pathogenesis of NAFLD. We highlight how our current knowledge of the gut-liver axis in NAFLD may be leveraged to develop gut microbiome-based personalized approaches for disease management, including its use as a non-invasive biomarker for diagnosis and staging, as a target for therapeutic modulation, and as a marker of drug response. We will also discuss current limitations of these microbiome-based approaches. Ultimately, a better understanding of microbiota-host interactions in NAFLD will inform the development of novel preventative strategies and precise therapeutic targets.
| S-EPMC8414992 | biostudies-literature
Project description:BackgroundThe most effective method of teaching critical appraisal concepts remains unclear. We used simulation scenarios in a Risk-of-Bias (RoB) 2.0 framework to teach the various biases that may affect randomized controlled trials and assessed whether including this interactive session in an evidence-based medicine (EBM) course for third-year preclinical medical students can optimize their understanding of critical appraisal concepts.MethodsThe session had 13 modules, each corresponding to a particular risk of bias in RoB 2.0. Each module included a simulated scenario, followed by data presentation and a generalized conclusion. The students were subsequently asked to use colored vote cards to indicate whether they agreed, had some concern, or disagreed with the conclusion and to justify their answers. On the basis of the students' answers, the facilitator debriefed the scenario and addressed the specific bias. In each module, the students were required to demonstrate critical thinking in analyzing the claims and quality of the supporting evidence and in justifying their decisions, thus conceptualizing their understanding of research biases.ResultsWe included 306 students across two pilot sessions in spring 2020 and 2021, and the response rate was 97.4%. The students were least able to discern the following problems: baseline imbalances when assessing allocation bias (correct answers: 9.06%), missing outcome data when assessing attrition bias (correct answers: 11.65%), and balanced nonprotocol interventions when assessing performance bias (correct answers: 14.88%). The postcourse survey revealed several aspects of the interactive session that the students appreciated or found challenging.ConclusionPreclinical medical students generally appreciated the inclusion of simulation scenarios and vote cards in an EBM course. The use of vote cards facilitated medical students' understanding of critical appraisal concepts, uncovered areas that they found challenging to understand, and encouraged their active participation. Such interactive sessions should be increasingly included in medical education.
| S-EPMC10548740 | biostudies-literature
Project description:Pharmacometabolomics (PMx) studies use information contained in metabolic profiles (or metabolome) to inform about how a subject will respond to drug treatment. Genome, gut microbiome, sex, nutrition, age, stress, health status, and other factors can impact the metabolic profile of an individual. Some of these factors are known to influence the individual response to pharmaceutical compounds. An individual's metabolic profile has been referred to as his or her "metabotype." As such, metabolomic profiles obtained prior to, during, or after drug treatment could provide insights about drug mechanism of action and variation of response to treatment. Furthermore, there are several types of PMx studies that are used to discover and inform patterns associated with varied drug responses (i.e., responders vs. non-responders; slow or fast metabolizers). The PMx efforts could simultaneously provide information related to an individual's pharmacokinetic response during clinical trials and be used to predict patient response to drugs making pharmacometabolomic clinical research valuable for precision medicine. PMx biomarkers can also be discovered and validated during FDA clinical trials. Using biomarkers during medical development is described in US Law under the 21st Century Cures Act. Information on how to submit biomarkers to the FDA and their context of use is defined herein.
| S-EPMC7241083 | biostudies-literature
Project description:Place value concepts were measured longitudinally from kindergarten (2017) to first grade (2018) in a diverse sample (n = 279; Mage = 5.76 years, SD = 0.55; 135 females; 41% Black, 38% White, 8% Asian, 12% Latino). Children completed three syntactic tasks that required an explicit understanding of base-10 symbols and three approximate tasks that could be completed without this explicit understanding. Approximate performance was significantly better in both age groups. A factor analysis confirmed that syntactic and approximate tasks tapped separate latent variables in kindergarten, but not in first grade. Path analyses indicated that only kindergarten approximate performance predicted overall first-grade place value understanding. These findings suggest that explicit understanding of base-10 principles develops from implicit, partial knowledge of multidigit numbers.
| S-EPMC9177579 | biostudies-literature
Project description:CONTEXT:This study assesses if, and how, existing methods for economic evaluation are applicable to the evaluation of personalized medicine (PM) and, if not, where extension to methods may be required. METHODS:A structured workshop was held with a predefined group of experts (n = 47), and was run using a modified nominal group technique. Workshop findings were recorded using extensive note taking, and summarized using thematic data analysis. The workshop was complemented by structured literature searches. RESULTS:The key finding emerging from the workshop, using an economic perspective, was that two distinct, but linked, interpretations of the concept of PM exist (personalization by 'physiology' or 'preferences'). These interpretations involve specific challenges for the design and conduct of economic evaluations. Existing evaluative (extra-welfarist) frameworks were generally considered appropriate for evaluating PM. When 'personalization' is viewed as using physiological biomarkers, challenges include representing complex care pathways; representing spillover effects; meeting data requirements such as evidence on heterogeneity; and choosing appropriate time horizons for the value of further research in uncertainty analysis. When viewed as tailoring medicine to patient preferences, further work is needed regarding revealed preferences, e.g. treatment (non)adherence; stated preferences, e.g. risk interpretation and attitude; consideration of heterogeneity in preferences; and the appropriate framework (welfarism vs. extra-welfarism) to incorporate non-health benefits. CONCLUSIONS:Ideally, economic evaluations should take account of both interpretations of PM and consider physiology and preferences. It is important for decision makers to be cognizant of the issues involved with the economic evaluation of PM to appropriately interpret the evidence and target future research funding.
| S-EPMC4422179 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma is a stroma-rich and highly challenging cancer to treat. Over recent years, it has become increasingly evident that the complex network of soluble cytokines, growth factors, proteases, and components of the extracellular matrix collaboratively interact within the tumor microenvironment, sustaining and driving cancer cell proliferation, invasion, and early metastasis. More recently, the tumor microenvironment has also been appreciated to mediate therapeutic resistance in pancreatic ductal adenocarcinoma, thus opening numerous avenues for novel therapeutic explorations. Inert and soluble components of the tumor stroma have been targeted in order to break down the extracellular matrix scaffold, relieve vessel compression, and increase drug delivery to hypovascular tumors. Moreover, targeting of antiapoptotic, immunosuppressive, and pro-proliferative effects of the tumor stroma provides novel vantage points of attack. This review focuses on current and future developments in pancreatic cancer medicine, with a particular emphasis on biophysical and biochemical approaches that target the tumor microenvironment.
| S-EPMC3872146 | biostudies-literature
Project description:The current state, tools, and applications of personalized medicine with special emphasis on inflammatory skin diseases like psoriasis and atopic dermatitis are discussed. Inflammatory pathways are outlined as well as potential targets for monoclonal antibodies and small-molecule inhibitors.
| S-EPMC6851586 | biostudies-literature
Project description:In the past decade, substantial evidence supports the paradigm that stem cells exert their reparative and regenerative effects, in large part, through the release of biologically active molecules acting in a paracrine fashion on resident cells. The data suggest the existence of a tissue microenvironment where stem cell factors influence cell survival, inflammation, angiogenesis, repair, and regeneration in a temporal and spatial manner.
| S-EPMC4874329 | biostudies-literature
Project description:BACKGROUNDThe stomach-derived hormone ghrelin stimulates appetite, but the ghrelin receptor is also expressed in brain circuits involved in motivation and reward. We examined ghrelin effects on decision making beyond food or drug reward using monetary rewards.METHODSThirty participants (50% women and 50% men) underwent 2 fMRI scans while receiving i.v. ghrelin or saline in a randomized counterbalanced order.RESULTSStriatal representations of reward anticipation were unaffected by ghrelin, while activity during anticipation of losses was attenuated. Temporal discounting rates of monetary reward were lower overall in the ghrelin condition, an effect driven by women. Discounting rates were inversely correlated with neural activity in a large cluster within the left parietal lobule that included the angular gyrus. Activity in an overlapping cluster was related to behavioral choices and was suppressed by ghrelin.CONCLUSIONThis is, to our knowledge, the first human study to extend the understanding of ghrelin's significance beyond the canonical feeding domain or in relation to addictive substances. Contrary to our hypothesis, we found that ghrelin did not affect sensitivity to monetary reward anticipation, but rather resulted in attenuated loss aversion and lower discounting rates for these rewards. Ghrelin may cause a motivational shift toward caloric reward rather than globally promoting the value of reward.TRIAL REGISTRATIONEudraCT 2018-004829-82.FUNDINGSwedish Research Council (2013-07434), Marcus and Marianne Wallenberg foundation (2014.0187) and National Institute on Drug Abuse/National Institute on Alcohol Abuse and Alcoholism Intramural Research Program.
| S-EPMC10266781 | biostudies-literature