Investigating the role of triglycerides and triglyceride-containing lipoproteins in cardiovascular disease, using observational and genetic epidemiological methods

Despite effective low-density lipoprotein cholesterol (LDL-C) lowering by statins, there remains a residual risk of CVD in individuals, which may in part be due to elevated triglyceride (TG) levels. Existing research evaluating the relationship between triglycerides and CVD has so far been mixed, and therapeutic agents to reduce triglycerides for CVD prevention are not routinely prescribed. Previous studies investigate total serum TG, which represents the summation of TG carried across all lipoproteins. It is possible that certain TG containing lipoproteins are more atherogenic than others, and thus using total serum TG measurement may be insufficiently precise to delineate any causal effect. 1H-nuclear magnetic resonance (NMR) spectroscopy classifies lipoproteins into 14 different lipoprotein subfractions based on size and lipid composition, offering a more detailed interrogation to help confirm or refute the possible causal relationship between TG and CVD. This thesis assesses the distribution of cholesterol and triglyceride content in 14 lipoprotein subfractions and establishes reference interval ranges based on the 2.5th and 97.5th percentiles. The largest interval range for TG content was observed in the medium VLDL subfraction (2.5th 97.5th percentile; 0.08 to 0.68 mmol/L), and for cholesterol content in the large LDL subfraction (0.47-1.45 mmol/L). TG concentrations in all sub-classes increased with increasing age and BMI. Increases in cholesterol concentrations were largely comparable between men and women by age, smoking status, and between fasting and nonfasting states. TG subfraction concentrations were significantly higher in ever smokers compared to never smokers, among subjects with CVD and type 2 diabetes as compared to disease-free subjects. The TG content in the 14 lipoprotein subfractions is evaluated for association with CVD, and the extent to which the effect is independent of LDL-C and HDL-C is explored in observational analysis in Chapter 5. The results in this chapter demonstrate TG in 13 lipoprotein subfractions were positively associated with CHD (OR in the range 1.12 to 1.22). The positive effect estimates attenuated after adjustment for HDL-C and LDL-C. There was an absence of evidence demonstrating any association TG lipoprotein subfraction with stroke. Next, to elucidate potential causal relationships, observational and Mendelian randomisation (MR) approaches are used to investigate the total and direct effects of triglyceride and cholesterol content on CHD. There was a total causal association of TG content in five lipoprotein subfractions, and total association of cholesterol content in 10 lipoprotein subfractions with CHD. Multivariable MR analysis was used to explore the direct effects of TG content of the 14 lipoprotein subfractions conditioning on the cholesterol content, and vice versa for cholesterol associations. Here we found that there was a direct association of CHD for TG in four lipoprotein subfractions and cholesterol in 10 lipoprotein subfractions. Cholesterol content in triglyceride-rich lipoproteins (TRL) displayed the largest effects (MVMR OR in the range 2.73 to 14.31), an association that was not observed for TG in TRL. The observational and MR associations between TG content in lipoprotein subfractions and CHD presented here may be relevant in the context of ongoing drug development targeting TG-mediated pathways for disease reduction. An emerging approach to lower TG concentrations and lower risk of CHD is through inhibition of LPL function. Angiopoietinlike proteins 3 and 4 (ANGPLT3/4) are negative regulators of LPL and have recently emerged as novel drug targets to manage dyslipidaemia. The final section of this thesis discusses the contribution of the results to the current understanding of role of TG in CVD and translational applications to clinical care

HUMAN RIGHTS ISSUES IN INDIA - A MAPPING OF DIFFERENT GROUPS

Human rights are rights inherent to all human beings, whatever our nationality, place of residence, sex, national or ethnic origin, colour, religion, language, or any other status. We are all equally entitled to our human rights without discrimination. These rights are all interrelated, interdependent and indivisible. Human rights are moral principles that set out certain standards of human behaviour and are regularly protected as legal rights in national and international law. They are "commonly understood as inalienable fundamental rights to which a person is inherently entitled simply because she or he is a human being." The doctrine of human rights has been highly influential within international law, global and regional institutions. In India, too, these rights along with Fundamental Rights have been provided to citizens. The concept of ‘human rights' is not of recent origin. Many of the basic ideas that animated the human rights movement developed in the aftermath of the Second World War and the atrocities of The Holocaust, culminating in the adoption of the Universal Declaration of Human Rights in Paris by the United Nations General Assembly in 1948. The ancient world did not possess the concept of universal human rights. So, the expression was first employed in the Declaration of United Nations signed by the Allied Powers on January 1, 1942. India, the world's most populous democracy, continues to have significant human rights problems despite making commitments to tackle some of the most prevalent abuses. The country has a thriving civil society, free media, and an independent judiciary. But longstanding abusive practices, corruption, and lack of accountability for perpetrators foster human rights violations. The rights of the citizens are the pillar of Democracy. Without rights, the citizens cannot develop their full potential. Laski has rightly remarked that the rights are those conditions of life without which no man can develop his best self. That is why all democratic countries make provisions for the enjoyment of certain fundamental rights by citizens. But the scope of Human Rights is much broader than Fundamental Rights. In this article we are going to study the various vulnerable groups of India which require their human rights because these rights are not available to them being vulnerable sections of society. Keywords: Human rights, UN's Human Rights Council, Universal Declaration of Human                                                       Rights, custodial violence, gender sensitizationÂ

Modes of Termination of Principal -Agent Relationship under the Indian Contract Act, 1872

Abstract Agency may be brought to an end either by the act of the parties, or by operation of law. Where the agency was created by agreement, it will be determinable in the same way. A continuing agency may also be determined by giving such period of notice as is specified in any agreement, or failing that, reasonable notice. Finally, if either party acts in a way which is inconsistent with the continuation of the agency then it will be terminated though of course this may well give rise to rights of action for breach of contract. As regards termination by operation of law, if an agency is for a particular transaction, the relationship will terminate when that transaction is completed. If it is for a specified period, it will cease at the end of that period

Triglyceride-containing lipoprotein sub-fractions and risk of coronary heart disease and stroke: A prospective analysis in 11,560 adults.

AIMS:Elevated low-density lipoprotein cholesterol (LDL-C) is a risk factor for cardiovascular disease; however, there is uncertainty about the role of total triglycerides and the individual triglyceride-containing lipoprotein sub-fractions. We measured 14 triglyceride-containing lipoprotein sub-fractions using nuclear magnetic resonance and examined associations with coronary heart disease and stroke. METHODS:Triglyceride-containing sub-fraction measures were available in 11,560 participants from the three UK cohorts free of coronary heart disease and stroke at baseline. Multivariable logistic regression was used to estimate the association of each sub-fraction with coronary heart disease and stroke expressed as the odds ratio per standard deviation increment in the corresponding measure. RESULTS:The 14 triglyceride-containing sub-fractions were positively correlated with one another and with total triglycerides, and inversely correlated with high-density lipoprotein cholesterol (HDL-C). Thirteen sub-fractions were positively associated with coronary heart disease (odds ratio in the range 1.12 to 1.22), with the effect estimates for coronary heart disease being comparable in subgroup analysis of participants with and without type 2 diabetes, and were attenuated after adjustment for HDL-C and LDL-C. There was no evidence for a clear association of any triglyceride lipoprotein sub-fraction with stroke. CONCLUSIONS:Triglyceride sub-fractions are associated with increased risk of coronary heart disease but not stroke, with attenuation of effects on adjustment for HDL-C and LDL-C

Establishing reference intervals for triglyceride containing lipoprotein sub-fraction metabolites measured using Nuclear Magnetic Resonance Spectroscopy in a UK population

Background Nuclear magnetic resonance (NMR) spectroscopy allows triglycerides to be subclassified into 14 different classes based on particle size and lipid content. We recently showed that these subfractions have differential associations with cardiovascular disease events. Here we report the distributions and define reference interval ranges for 14 triglyceride-containing lipoprotein subfraction metabolites. Methods Lipoprotein subfractions using the Nightingale NMR platform were measured in 9073 participants from four cohort studies contributing to the UCL-Edinburgh-Bristol consortium. The distribution of each metabolite was assessed, and reference interval ranges were calculated for a disease-free population, by sex and age group (65 years), and in a subgroup population of participants with cardiovascular disease or type 2 diabetes. We also determined the distribution across body mass index and smoking status. Results The largest reference interval range was observed in the medium very-low density lipoprotein subclass (2.5th 97.5th percentile; 0.08 to 0.68 mmol/L). The reference intervals were comparable among male and female participants, with the exception of triglyceride in high-density lipoprotein. Triglyceride subfraction concentrations in very-low density lipoprotein, intermediate-density lipoprotein, low-density lipoprotein and high-density lipoprotein subclasses increased with increasing age and increasing body mass index. Triglyceride subfraction concentrations were significantly higher in ever smokers compared to never smokers, among those with clinical chemistry measured total triglyceride greater than 1.7 mmol/L, and in those with cardiovascular disease, and type 2 diabetes as compared to disease-free subjects. Conclusion This is the first study to establish reference interval ranges for 14 triglyceride-containing lipoprotein subfractions in samples from the general population measured using the nuclear magnetic resonance platform. The utility of nuclear magnetic resonance lipid measures may lead to greater insights for the role of triglyceride in cardiovascular disease, emphasizing the importance of appropriate reference interval ranges for future clinical decision making

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Spelar representativ demokrati någon roll? : En fallstudie av nätverket Leader Linné

It has become popular for political scientists to discuss the transformation from government to governance and the networks’ greater influence on public policymaking. However, this debate lacks methodological, empirical and theoretical research about the relationship between governance networks and representative democracy. The main objective of this essay is to understand the relationship between governance networks and representative democracy through a case study of the governance network Leader Linné. The theoretical framework includes four analysis models about the relationship between governance networks and representative democracy that are analysed by five factors connected to representative democracy. Each model has a specific approach to the public policymaking in networks e. g. were the power lies, how the general interest is understood and the role of politicians. The essay is designed as a case study combined with interviews of participants from the network’s national, regional and local level. The result of the essay is that the relationship between the governance network and representative democracy is complemental, meaning that representative democracy makes the central decisions in society where secondary decisions are made through a combination of representative- and participate democracy introduced by Leader. In Leader Linné the general interest is formed at EU level and politicians have a managerial role

Design of Topical Moxifloxacin Mucoadhesive Nanoemulsion for the Management of Ocular Bacterial Infections

Ocular bacterial infections can lead to serious visual disability without proper treatment. Moxifloxacin (MOX) has been approved by the US Food and Drug Administration as a monotherapy for ocular bacterial infections and is available commercially as an ophthalmic solution (0.5% w/v). However, precorneal retention, drainage, and low bioavailability remain the foremost challenges associated with current commercial eyedrops. With this study, we aimed to design a MOX-loaded nanoemulsion (NE; MOX-NE) with mucoadhesive agents (MOX-NEM) to sustain MOX release, as well as to overcome the potential drawbacks of the current commercial ophthalmic formulation. MOX-NE and MOX-NEM formulations were prepared by hot homogenization coupled with probe sonication technique and subsequently characterized. The lead formulations were further evaluated for in vitro release, ex vivo transcorneal permeation, sterilization, and antimicrobial efficacy studies. Commercial MOX ophthalmic solution was used as a control. The lead formulations showed the desired physicochemical properties and viscosity. All lead formulations showed sustained release profiles a period of more than 12 h. Filtered and autoclaved lead formulations were stable for one month (the last time point tested) under refrigeration and at room temperature. Ex vivo transcorneal permeation studies revealed a 2.1-fold improvement in MOX permeation of the lead MOX-NE formulation compared with Vigamox&reg; eyedrops. However, MOX-NEM formulations showed similar flux and permeability coefficients to those of Vigamox&reg; eyedrops. The lead formulations showed similar in vitro antibacterial activity as the commercial eyedrops and crude drug solution. Therefore, MOX-NE and MOX-NEM formulations could serve as effective delivery vehicles for MOX and could improve treatment outcomes in different ocular bacterial infections