Research Design and Methods. Patients Patients were recruited from the departments of internal medicine at two nonacademic teaching hospitals, the Leyenburg Hospital and the Red Cross Hospital, the Hague, the Neth- erlands. Subjects were eligible for the study if they had been diagnosed with type 2 diabetes for at least 1 year, were aged 30–80 years, and were without a history of CVD (defined as CAD, electrocardiographic criteria for a past myocardial infarction, ischemic stroke, peripheral artery bypass surgery, percutaneous transluminal angioplasty, or amputation because of atherosclerotic disease). At a screening visit, fasting blood samples were drawn and a resting electrocardiogram performed. Patients with fasting total cholesterol > 6.9 mmol/l or < 4.0 mmol/l, triglycerides > 6.0 mmol/l, creatinine kinase values more than three times and alanine aminotransferase (ALT) more than two times the upper limit of normal, or creatinine clearance < 30 ml/min were excluded. Any lipid-lowering therapy had to be discontinued 8 weeks before the screening visit. The study was approved by the medical ethics committees of both hospitals and performed in accordance with the Declaration of Helsinki.
Research Design and Methods. Subjects and design The study design and baseline characteristics of the original patient population have been described elsewhere 27. Briefly, 250 patients with DM2 for at least one year, aged 30-80 years, without CVD were included in this randomized, double-blind, clinical trial. Patients were given 0.4 mg cerivastatin (Bayer B.V., Mijdrecht , The Netherlands) or placebo daily for 2 years. After the withdrawal of cerivastatin from the market, 0.4 mg cerivastatin was replaced by 20 mg simvastatin (Merck Sharp & Dome, Haarlem, the Netherlands), without deblinding the study. Only patients who completed the study were included in the present analysis. There were no significant differences in demographic or lipid parameters between the full cohort (n=250) and the patients in this study (n=182), except for race, as more Caucasians than non-Caucasians completed the study (data not shown). Eligible patients gave their written informed consent. The study was performed at the Leyenburg Hospital, The Hague. The study was approved by the hospital’s Medical Ethics Committee.
Research Design and Methods. A randomized, placebo-controlled double-blind trial was performed in 250 patients with DM2 without manifest cardiovascular disease. Patients were given 0.4 mg cerivastatin or placebo daily. The primary endpoint was the change in high sensitivity CRP after 2 years. Results CRP in the statin group was 1.58 mg/L at baseline and 1.69 mg/L at 2 years (p= 0.413), in the placebo group it increased from 2.03 mg/L at baseline to 2.54 mg/L at 2 years (p = 0.058) (p= 0.269 for comparison between the groups). In a high-risk subgroup with the metabolic syndrome and LDL levels > 2.6 mmol/L (40 % of the cohort) CRP levels increased significantly in the placebo group (from 2.97 mg/L at baseline to 3.99 mg/L at 2 years, p=0.036) in com- parison to the statin group (from 2.13 mg/L at baseline to 2.10 mg/L at 2 years, p=0.885) (p=0.042 for comparison between the groups) Conclusions There was no effect of two year statin therapy on CRP in patients with DM2 without manifest cardiovascular disease, except in a subgroup with the metabolic syndrome and LDL > 2.6 mmol/L. Studies supporting risk stratified therapy in primary prevention in DM2 are needed. INTRODUCTION Cardiovascular disease (CVD) is the most important cause of mortality in patients with type 2 diabetes mellitus (DM2)1. C-reactive protein (CRP) is a marker for the chronic inflammatory process in atherosclerotic plaques, and probably has pro-atherogenic properties of its own2-4. When measured with high sensitivity assays, CRP levels are highly reproducible, unaffected by food intake and with no circadian variation. CRP is a strong predictor of future cardiovas- cular events, independent of traditional risk factors such as LDL cholesterol5-7. CRP levels are associated with components of the metabolic syndrome (MS) such as triglycerides, obesity and insulin sensitivity8,9. Finally, CRP might be predictive of incident DM210-12. In DM2 without coronary artery disease, levels of CRP are higher than in non-diabetic controls13. CRP levels independently predict future cardiovascular events in DM2 in some studies14,15. Importantly, in the Hoorn study16, the association of CRP with future CVD events in DM2 was not independent of classical risk factors. A meta-analysis of intervention studies with statins in the setting of secondary prevention after a cardiovascular event has shown a correlation between reduced cardiovascular events and reduction in CRP, independent of LDL cholesterol lowering17. Results from intervention studie...
Research Design and Methods. Subjects and design The study design and baseline characteristics of the original patient population have been described elsewhere24. Briefly, 250 patients with DM2 for at least one year, aged 30-80 years, without CVD were included between August 1999 and February 2001 in this randomized, double-blind, clinical trial. Patients were given 0.4 mg cerivastatin (Bayer B.V., Mijdrecht , The Netherlands) or placebo daily for 2 years. After the withdrawal of cerivastatin from the mar- ket, 0.4 mg cerivastatin was replaced by 20 mg simvastatin (Merck Sharp & Dome, Haarlem, the Netherlands), without unblinding the study. At that moment, all the patients had been randomized with a mean follow-up of 15 months (range 6-23 months). Eligible patients gave their written informed consent. The study was performed at the HAGA Hospital, The Hague. The study was approved by the hospital’s Medical Ethics Committee.
Research Design and Methods. Study design This study was a single-center sub-study of the previously reported DALI study15. The study was carried out in accordance with the principles of the Declaration of Helsinki. The local medical ethics committee approved the study and all patients gave informed consent. Patients Male and female patients aged 45–75 years with DM2 (according to the American Diabetes Association classification) of at least 1-year duration were included in the study. Inclusion criteria were: fasting triglycerides between 1.5 and 6.0 mmol/L, total cholesterol between 4.0 and 8.0 mmol/L, and HbA1c < 10%. Patients were assessed after a washout period of lipid- lowering medication of at least 8 weeks. Patients with manifest or previous cardiovascular disease were excluded from the study. Pre-menopausal women and patients with acute liver disease, hepatic dysfunction, or impaired renal function (plasma creatinine > 150 μmol/L) were excluded. Patients consuming more than four alcoholic drinks per day or on systemic steroids, androgens, cyclosporine, other immunosuppressive drugs, erythromycin, or mibe- fradil were also excluded. Definition of MS criteria cut-off values and low-grade chronic systemic inflammation The WHO cut-off values were used for the assessment of MS load16. The criteria were defined as follows: hypertension: systolic/diastolic ≥ 140/90 (mm Hg); triglyceride levels ≥ 1.7 mmol/L; and HDL cholesterol < 1.0 mmol/L (women) and < 0.9 mmol/L (men). Furthermore, waist circumference was used as a measure for obesity with a cut-off value of ≥ 94 cm in men and ≥ 80 cm in women. MS load was defined by the number of factors present exceeding the thresholds defined above, in addition to DM2. Five groups with respectively 0, 1, 2, 3, or 4 additional MS criteria could be defined. As for CRP, patients with levels over 15 mg/L were excluded from the evaluations on the suspicion of being a temporary outlier not represent- ing the continuous habitual level17.
Research Design and Methods. Using baseline data from a clinical trial we provide an initial description of vascular param- eters in AI-DM2 compared to Europid Caucasian controls (ECs) matched for age and gender. Endpoints of the study were endothelial function, low-grade systemic inflammation (CRP) and carotid intima-media thickness (CIMT). Results AIs had longer duration of diabetes, worse glycemic control and more microangiopathy. Both groups demonstrated marked endothelial dysfunction. CRP levels were similar: 1.7 (4.9) mg/L in AIs and 2.8 (3.6) mg/L in ECs. CIMT values were significantly lower in AI-DM2 than EC-DM2 (0.655 mm (0.12) versus 0.711 mm (0.15), p = 0.03). Multiple regression analysis showed that variability in CRP was mainly determined by waist circumference, not by ethnicity. In contrast, ethnicity was a significantly explanatory variable for CIMT.
Research Design and Methods. [***] In the past, we have successfully overexpressed functional human synthetases in E. coli. In order to enhance protein expression and solubility, all 6 human genes have been codon-optimized for translation in E. coli using the proprietary algorithms developed by CODA Genomics, Inc (xxxx://xxx.xxxxxxxxxxxx.xxx/). We have cloned the genes into pBAD vectors. Five out of the 6 genes have been expressed, and of these, two have good solubility. Aminoacyl-tRNA synthetases have modular structures with distinct domains that are joined together (Xxxxx, Xxxxx et al. 1983). Each domain is responsible for a specific task—for example, the catalytic domain for aminoacylation, anti-codon recognition domain for recognition of the triplet anti-codon embedded in the tRNA, and editing domain for clearance of the misactivated non-cognate amino acids or the mischarged tRNAs. Mammalian tRNA synthetases usually have acquired additional domains, each of which belongs to one of 3 types of structures; glutathione S-transferase (GST), helix-turn-helix (HTH), and endothelial monocyte activating peptide II (EMAP II). The extra domains often are dispensable for aminoacylation, and may provide a regulatory mechanism for non-canonical functions, as demonstrated for TyrRS and TrpRS. In addition, the extra domains may be involved with specific interactions between members of the multi-synthetase complex. With these considerations, we have also cloned domain fragments from the above 6 genes. As an additional benefit, most of the fragments have better expressions and improved solubility relative to the full-length proteins. Gene Fragment Tag MW (KD) Expression Solubility [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] * Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***]
Research Design and Methods. The research program outlined herein builds upon the combined experience of the collaborators to develop technologies to accelerate the completion of the human genome sequence as well as to enable more routine genome sequencing. As outlined before, the HGP has evolved to the point where its completion is tractable. This project plans to hasten that timeline in stages:
Research Design and Methods. This study used a qualitative design to describe and understand how the unit culture that evolved during the Magnet journey influenced nurses’ cognitive beliefs and behavior concerning the three dimensions of EBP. Qualitative methods were used to uncover the role of the unit culture, and at the same time, to explore the process by which nurses engaged in EBP and how the interplay between the unit culture and individual behavior was demonstrated (Xxxxxxxx, 2007; Xxxxxxxx & Xxxxxxx, 1989; Xxxxx & Xxxxxxxx, 1994; Xxxxx-Xxxxxx & Xxxxxxxxxx, 2004; Xxxxxx, 2004). In-depth semi-structured interviews were used to uncover the processes by which nurses understood and implemented EBP. This method provided the ability to explore concepts within the theoretical framework detailed above. Semi-structured in- depth interviews provided rich data on individuals’ perception and their experiences. This technique also provided flexibility to the researcher to adapt questioning to the participant’s understanding of the topic under discussion and to elicit participant’s beliefs, opinions, and values (Xxxxxxxx, 2007; Xxxxx & Xxxxxxxx, 1994; Price, 2002; Xxxxx, 1994). In-depth interviewing provided a way to access participant’s cognitive models, which informed their perspective of their environment and guided their behavior. Potential limitations to in-depth interviewing include the participants’ reluctance to respond or to provide an inaccurate or incomplete recollection of the situation. Most experts agree that in-depth interviewing is a more than adequate method for exploratory research (Xxxxxxxx & Xxxxxxx, 1989; Xxxxx, 1994). The principles of analytic ethnography (Xxxxxxx, 1995; Xxxxxxx, Xxxx, Xxxxxxxx, & Xxxxxxx, 2006; Xxxx, Xxxxxxx, & Xxxxxxxx, 2003) were used to clarify concepts, to elucidate their relationships to each other, and to explore the theoretical constructs of the theory of planned behavior integrated with organizational culture concepts. Analytic ethnography incorporates both a deductive and inductive process that seeks to refine or extend an existing theoretical framework and is open to the possibility of theory discovery. Analytic ethnography was pertinent for this study because it allowed the testing of the core features of the integrated theories as well as revising those existing theories in light of new data. Data were analyzed using a multistep process to identify common themes that were informed by the theoretical framework, as well as themes which aros...
Research Design and Methods. This study used an explanatory cross-sectional sequential mixed methods design, which consisted of first collecting quantitative data (that provide a general picture of the research problem) and then collecting qualitative data to help explain or elaborate on the quantitative results, which will refine and extend the general picture (Xxxxxxxx, 2014, p. 572). Quantitative data were collected via an online survey and qualitative data were collected through semi-structured interviews. This research design aligned with the research questions as a way to understand the general picture regarding the support for play in the state kindergartens in Nur-Sultan, but also to explore the deeper explanations from individual practitioners to clarify the broader picture. In the field of educational research, both quantitative and qualitative methods have been used to understand play and playful learning. In this study, for example, conducting a quantitative survey was necessary to see the situation in general, but also to identify potential candidates for further qualitative study. As Xxxxxxxx (2013) noted: We conduct qualitative research because a problem or issue needs to be explored. This exploration is needed, in turn, because of a need to study a group or population, identify variables which cannot be easily measured, or hear silenced voices … We also conduct qualitative research because we need a complex, detailed understanding of the issue. (pp. 47-48) Thus, qualitative research is one of the tools that helps to explore and understand in depth the issues that cannot be easily measured and hear the voices that are not often heard. Therefore, a qualitative approach is also appropriate for the exploration of complex situations where individuals can offer their perspectives. In this research, a qualitative approach was used since the study focused on early childhood educators’ perceptions of play and learning and their support for play in a natural setting—the state kindergarten. This study adapted Xxxxxx’x (2017) doctoral study where a multiple case study approach was used to understand the support of play in US kindergartens. However, apart from a survey and face-to-face interviews, Xxxxxx’x study (2017) also included classroom observations, which could not be replicated due to both time constraints and the COVID-19 pandemic restrictions in early childhood education (ECE) organisations. Data Collection Instruments and Procedures Both quantitative and qualitative data...
