Applying metabolomics to cardiometabolic intervention studies and trials: past experiences and a roadmap for the future

Metabolomics and lipidomics are emerging methods for detailed phenotyping of small molecules in samples. It is hoped that such data will: (i) enhance baseline prediction of patient response to pharmacotherapies (beneficial or adverse); (ii) reveal changes in metabolites shortly after initiation of therapy that may predict patient response, including adverse effects, before routine biomarkers are altered; and( iii) give new insights into mechanisms of drug action, particularly where the results of a trial of a new agent were unexpected, and thus help future drug development. In these ways, metabolomics could enhance research findings from intervention studies. This narrative review provides an overview of metabolomics and lipidomics in early clinical intervention studies for investigation of mechanisms of drug action and prediction of drug response (both desired and undesired). We highlight early examples from drug intervention studies associated with cardiometabolic disease. Despite the strengths of such studies, particularly the use of state-of-the-art technologies and advanced statistical methods, currently published studies in the metabolomics arena are largely underpowered and should be considered as hypothesis-generating. In order for metabolomics to meaningfully improve stratified medicine approaches to patient treatment, there is a need for higher quality studies, with better exploitation of biobanks from randomized clinical trials i.e. with large sample size, adjudicated outcomes, standardized procedures, validation cohorts, comparison witth routine biochemistry and both active and control/placebo arms. On the basis of this review, and based on our research experience using clinically established biomarkers, we propose steps to more speedily advance this area of research towards potential clinical impact

The Design, Synthesis, and Controlled Polymerization of Cationic and Zwitterionic Norbornene Derivatives

Ring-opening metathesis polymerization (ROMP) has been exploited for the controlled polymerization of cationic and zwitterionic norbornene-based monomers and employed in the preparation of homo- and block-copolymer systems in homogeneous organic media without the use of post-polymerization modification or protecting group chemistries. Relying on previous knowledge of certain halogenated alcoholic organic solvents capable of solubilizing hydrophilic monomers, the first study, describes the synthesis and controlled polymerization of a series of new permanently cationic ammonium exo-7- oxanorbornene derivatives M31 via ROMP, with the first generation Grubbs catalyst 17, in a novel solvent mixture comprised of 1:1 vol/vol 2,2,2-trifluoroethanol (TFE)/methylene chloride (CH2CI2). This cosolvent mixture was demonstrated to be a convenient reaction medium facilitating the polymerization of hydrophilic substrates by hydrophobic initiators under homogeneous conditions. Homo- and copolymerizations proceed rapidly yielding materials with controlled molecular masses, and narrow molecular mass distributions. It was demonstrated that this protocol is not limited to the use of TFE as a cosolvent and that additional halogenated alcohols, such as 2,2,2- trichloroethanol (TCE) and 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), are also effective cosolvents for the controlled polymerization of such substrates. Finally, we demonstrate that the TFE/CH2CI2 mixture has no apparent detrimental effect on 17. The second study describes results relating to the effect of halide counterion on the ROMP of a permanently cationic exo-7-oxanorbornene derivative whose synthesis we described recently in the presence of the 17. Statistical copolymerizations of exo-benzyl- [2-(3,5-dioxo-10-oxa-4-aza-tricyclo[5.2.1.0 \u27 ]dec-8-en-4-yl)-ethyl]dimethyl ammonium bromide/chloride were conducted at molar ratios of 25:75, 50:50, and 75:25, and the polymerizations evaluated with respect to their kinetic features as well as their molecular mass profiles as a function of conversion and the ability to produce materials with narrow molecular mass distributions. Direct comparison of the statistical copolymerizations with the corresponding bromide/chloride homopolymerizations indicates that their polymerization characteristics are intermediate of that observed for the homopolymerizations. In all instances, the copolymerizations appear controlled. The clearest effect is on the measured polydispersity index which in all instances coincides with that of the bromide homopolymerization and indicates a positive, beneficial effect even with only 25 mol% bromide comonomer. The polymerization characteristics are rationalized in terms of the in situ formation of the mixed Grubbs\u27 derivative RuClBr(PCy3)2CHPh and/or the dibromo analog RuBr2(PCy3)2CHPh formed by halide exchange with the bromide counterions in exo-benzyl-[2-(3,5-dioxo-10-oxa-4-azatricyclo[ 5.2.1.02,6]dec-8-en-4-yl)-ethyl]dimethyl ammonium bromide MON-Bn-Cl. The third study describes the synthesis and controlled ROMP of highly functional zwitterionic sulfopropylbetaine- M32 and carboxyethylbetaine-ejco-7-oxanorbornene derivatives M33 with the first generation Grubbs\u27 initiator 17 in a TFE/CH2CI2 solvent mixture. These are the first examples of such norbornene-based betaine substrates. Both species can be polymerized directly in a controlled manner in organic media as judged from the kinetic profiles and aqueous size exclusion chromatographic analysis. This represents the first time betaine monomers have been polymerized directly in a controlled fashion by a technique other than a controlled free radical polymerization process, and the first time it has have been achieved in organic, as opposed to aqueous, media. Finally, preliminary results demonstrate that water-soluble, salt-responsive AB diblock copolymers can be prepared and that such materials are able to undergo supramolecular self-assembly in aqueous media to yield nano-sized aggregates simply by controlling the aqueous electrolyte concentration

Dissents and Concurrences: Seven Debates in Charter Jurisprudence

The Supreme Court of Canada released seven Charter decisions in 2012 that were not unanimous. When compared to the non-Charter cases released the same year, the Charter dissents represented a higher rate of disagreement between the justices. This should not come as a surprise. The Charter is an open-textured instrument that admits of flexibility and growth. Dissents and differing approaches are expected as Charter jurisprudence continues to develop. This paper argues that the seven Charter dissents/concurrences released in 2012 provide a rich illustration of the various functions of dissenting opinions. As articulated by Justice L’Heureux-Dubé, these are: to prophesize, to stir dialogue, and to safeguard the integrity of the law and judicial institutions. Each of these functions takes on a special dimension in the realm of Charter jurisprudence. In their prophetic function, dissents are intimately connected to the doctrine of the living tree — recognizing, as it does, that there will be a future audience of constitutional opinions that will not necessarily share the constraints of our more dated institutions. The dialogic function of dissents, likewise, takes on additional significance in this context. Charter dissents are a fundamental part of the forward-looking conversation between courts and society, giving the m the potential to shape, over the long term, the societal values they engage. Finally, dissents in Charter cases essentially promote the integrity of our judicial institutions. The “fierce independence” of the justices on constitutional matters necessitates real opportunities to dissent

Dissents and Concurrences: Seven Debates in Charter Jurisprudence

The Supreme Court of Canada released seven Charter decisions in 2012 that were not unanimous. When compared to the non-Charter cases released the same year, the Charter dissents represented a higher rate of disagreement between the justices. This should not come as a surprise. The Charter is an open-textured instrument that admits of flexibility and growth. Dissents and differing approaches are expected as Charter jurisprudence continues to develop. This paper argues that the seven Charter dissents/concurrences released in 2012 provide a rich illustration of the various functions of dissenting opinions. As articulated by Justice L’Heureux-Dubé, these are: to prophesize, to stir dialogue, and to safeguard the integrity of the law and judicial institutions. Each of these functions takes on a special dimension in the realm of Charter jurisprudence. In their prophetic function, dissents are intimately connected to the doctrine of the living tree — recognizing, as it does, that there will be a future audience of constitutional opinions that will not necessarily share the constraints of our more dated institutions. The dialogic function of dissents, likewise, takes on additional significance in this context. Charter dissents are a fundamental part of the forward-looking conversation between courts and society, giving the m the potential to shape, over the long term, the societal values they engage. Finally, dissents in Charter cases essentially promote the integrity of our judicial institutions. The “fierce independence” of the justices on constitutional matters necessitates real opportunities to dissent

Extended Length of Hospital Stay in Orthopaedic Surgery - Frequency, Severity, and Risk Factors Associated with Different Treatment Procedures

Orthopaedic surgical procedures are associated with different outcomes that have both physical and psychological implications for patients. This makes it important to understand the risk factors that drive these outcomes and their impacts to better equip clinicians to prospectively manage patients and forestall Extended Length of Hospital Stay (ELOHS). De-identified data from a private acute teaching hospital obtained between 10/2015 – 12/2020 is used for this retrospective study. Results suggest that careful management of risk factors through perioperative risk adjustment before the various surgeries will help to reduce complications, improve recovery, minimize ELOHS, and the cost of hospitalization

Does the Use of Computer-Generated Slide Presentations in the Classroom Affect Student Performance and Interest?

This paper examines how computer-assisted instruction affects students. The use of computer-generated slide presentations in an introductory economics course is examined for potential effects on student performance, student attitudes, and the evaluations of the instructor. Multiple sections of Introductory Economics are used to determine if the use of computer-generated slide presentations has any effect on students in the areas listed above. Control variables used are student ability, gender, classification, and prior exposure to economics. The results indicate that the use of computer-generated slide presentations has no effect on student performance, attitudes, or evaluation of the instructor.Economics; Introductory Economics

The emergence of proton nuclear magnetic resonance metabolomics in the cardiovascular arena as viewed from a clinical perspective

The ability to phenotype metabolic profiles in serum has increased substantially in recent years with the advent of metabolomics. Metabolomics is the study of the metabolome, defined as those molecules with an atomic mass less than 1.5 kDa. There are two main metabolomics methods: mass spectrometry (MS) and proton nuclear magnetic resonance (1H NMR) spectroscopy, each with its respective benefits and limitations. MS has greater sensitivity and so can detect many more metabolites. However, its cost (especially when heavy labelled internal standards are required for absolute quantitation) and quality control is sub-optimal for large cohorts. 1H NMR is less sensitive but sample preparation is generally faster and analysis times shorter, resulting in markedly lower analysis costs. 1H NMR is robust, reproducible and can provide absolute quantitation of many metabolites. Of particular relevance to cardio-metabolic disease is the ability of 1H NMR to provide detailed quantitative data on amino acids, fatty acids and other metabolites as well as lipoprotein subparticle concentrations and size. Early epidemiological studies suggest promise, however, this is an emerging field and more data is required before we can determine the clinical utility of these measures to improve disease prediction and treatment. This review describes the theoretical basis of 1H NMR; compares MS and 1H NMR and provides a tabular overview of recent 1H NMR-based research findings in the atherosclerosis field, describing the design and scope of studies conducted to date. 1H NMR metabolomics-CVD related research is emerging, however further large, robustly conducted prospective, genetic and intervention studies are needed to advance research on CVD risk prediction and to identify causal pathways amenable to intervention

Sustainability processes in community-level health initiatives: the experiences of Scottish healthy living centres

Background This thesis explores processes involved in stakeholders’ attempts to secure sustainability of three short-term funded community health initiatives known as healthy living centres (HLCs). The overall aim was to identify and examine development of sustainability strategies in Scottish HLC organisations. In contrast to retrospective accounts examining influences on extent of sustainability little is known about how this concept is considered by organisations approaching the end of funding. Organisational development theorising has focused on organisational change, with no attention given to sustainability processes in short-term funded organisations. Building on a concurrent longitudinal evaluation of a larger sample of HLCs, the temporal nature of this PhD study offered scope to explore development of, influences on and changes to stakeholders’ sustainability strategies over time. Methods The study used a qualitative evaluation methodology. A case study approach framed the HLCs, permitting comparison between sites. An ethnographic approach using observations and in-depth interviews was employed. Interviews were undertaken with stakeholders (comprising managers, staff, partners and board members) from each HLC. Managers were interviewed on several occasions. Latterly, interviews were undertaken with respondents holding policy, practice and funding posts. A thematic analysis, informed by grounded theory, was carried out. This used a constant comparative methodology to understand the data against the backdrop of the PhD study aims and wider literature. Findings Findings examine stakeholders’ accounts of the impact of a range of issues on HLC sustainability strategies. These are located in the context of health and community sector restructuring. Especially challenging were: efforts to secure local partners and further lottery funding; consideration of new funding criteria and models of service delivery; and limitations in demonstrating effectiveness. Addressing such challenges, managers’ strategic positioning signified attempts to influence HLCs’ fit within local health structures. Stakeholders’ accounts highlighted attempts to secure continuation of HLCs’ original identity; ensuring continued accessibility of Centres to local communities; and, seeking continuation of developmental methods of work. External respondents’ perspectives illuminated how policy-driven changes restricted system-wide attention to HLC sustainability. Latterly, Government-provided funding offered a short-term fix, enabling continuation of attempts to secure sustainability. Conclusions and implications This study offers new perspectives on the temporal exploration of sustainability of shortterm funded health initiatives. Analysis of stakeholders’ accounts over time provides insight into the effects of restructuring and ways in which system-wide flux impacted on influences known to enhance the likelihood of sustainability. Recommendations address programme design and wider responsibilities of health system actors in positioning and considering a future for such organisations after short-term funding ends

Predictors of Success for High School Students Enrolled in Online Courses in a Single District Program

The rapid growth in online learning opportunities and online courses in K-12 education is well documented in the literature. Studies conducted by various researchers that have focused on the K-12 population of online learners demonstrate that certain online learner characteristics and online learning environment characteristics may impact the likelihood of students passing or failing online courses. Research has produced models that predict online course success with measurable degrees of accuracy. This descriptive study examines characteristics of students enrolled in online high school courses provided by a virtual learning program administered by a single Virginia public school district. The study determined that students’ prior academic success; confidence in their technology skills and access to technology; confidence in their ability to achieve; and strong beliefs in their organizational skills proved to have a significant statistical relationship with online course success. The study developed a model with these factors that predicted success in online courses with a high degree of accuracy and predicted failure with a moderate degree of accuracy.The study has policy implications for public school leaders in Virginia as they implement recent state legislation requiring students to successfully complete a virtual course to graduate from public high school. The study indicates that additional research is warranted to further delineate learner and learning environment characteristics producing a model that more accurately predicts failure in online courses. Additional research is warranted with larger samples from single district virtual programs