Lipid-protein interactions drive membrane protein topogenesis in accordance with the positive inside rule.

Transmembrane domain orientation within some membrane proteins is dependent on membrane lipid composition. Initial orientation occurs within the translocon, but final orientation is determined after membrane insertion by interactions within the protein and between lipid headgroups and protein extramembrane domains. Positively and negatively charged amino acids in extramembrane domains represent cytoplasmic retention and membrane translocation forces, respectively, which are determinants of protein orientation. Lipids with no net charge dampen the translocation potential of negative residues working in opposition to cytoplasmic retention of positive residues, thus allowing the functional presence of negative residues in cytoplasmic domains without affecting protein topology.

Determine whether markers of lipid metabolism, inflammation and/or liver function are altered in tuberculosis patients with diabetes

The mechanism for higher susceptibility of diabetes patients to TB is unknown. Chronic hyperglycemia has been shown to be associated with altered immunity to Mycobacterium tuberculosis, and may explain the higher risk of TB among diabetes patients. However, it is possible that other conditions that frequently occur in these patients are also contributing to TB susceptibility. Our goal was to determine whether lipid metabolism, liver function and/or chronic inflammation are altered in tuberculosis (TB) patients with diabetes (DM), compared to non-DM.^ Confirmed TB patients who were 20 years or older (n=159) were selected from a database in the south Texas and northeast Mexico area. Differences between serum values for liver function, lipid metabolism and/or chronic inflammation were compared between TB patients with DM to non-DM.^ We found that CRP was the most frequent alteration, with about 80% having high values suggestive of chronic inflammation. The other frequent abnormalities were high triglycerides in about 40% of the patients and low HDL cholesterol in about 60% of the patients. Otherwise, less than 10% of the TB patients had an abnormal finding for any of the other laboratory tests. The abnormalities were not more frequent among the patients with either DM (versus non-DM) or high HbA1c (versus normal).^ A possible explanation for the high levels or CRP may be that everyone in the study had TB, which in itself causes inflammation and may have masked the increased CRP levels that characterize diabetes patients. There was a mild alteration in lipid metabolism in patients with DM, which is unlikely to explain altered immunity to TB. Otherwise, liver function tests were normal in patients with DM. Therefore the processing of anti-TB medications should be no different between the TB patients with and without diabetes. Our findings, however, do not rule out that other study populations have more remarkable metabolic alterations associated with diabetes. Therefore, it would be interesting to conduct a similar study in patients from different ethnic groups (White, African American, or Native American) in order to see if the same pattern is observed.^

On Bayesian seamless phase I-II designs

Early phase clinical trial designs have long been the focus of interest for clinicians and statisticians working in oncology field. There are several standard phse I and phase II designs that have been widely-implemented in medical practice. For phase I design, the most commonly used methods are 3+3 and CRM. A newly-developed Bayesian model-based mTPI design has now been used by an increasing number of hospitals and pharmaceutical companies. The advantages and disadvantages of these three top phase I designs have been discussed in my work here and their performances were compared using simulated data. It was shown that mTPI design exhibited superior performance in most scenarios in comparison with 3+3 and CRM designs. ^ The next major part of my work is proposing an innovative seamless phase I/II design that allows clinicians to conduct phase I and phase II clinical trials simultaneously. Bayesian framework was implemented throughout the whole design. The phase I portion of the design adopts mTPI method, with the addition of futility rule which monitors the efficacy performance of the tested drugs. Dose graduation rules were proposed in this design to allow doses move forward from phase I portion of the study to phase II portion without interrupting the ongoing phase I dose-finding schema. Once a dose graduated to phase II, adaptive randomization was used to randomly allocated patients into different treatment arms, with the intention of more patients being assigned to receive more promising dose(s). Again simulations were performed to compare the performance of this innovative phase I/II design with a recently published phase I/II design, together with the conventional phase I and phase II designs. The simulation results indicated that the seamless phase I/II design outperform the other two competing methods in most scenarios, with superior trial power and the fact that it requires smaller sample size. It also significantly reduces the overall study time. ^ Similar to other early phase clinical trial designs, the proposed seamless phase I/II design requires that the efficacy and safety outcomes being able to be observed in a short time frame. This limitation can be overcome by using validated surrogate marker for the efficacy and safety endpoints.^

External validation study of a clinical prediction rule for ambulation outcomes after traumatic spinal cord injury

The main objective of this study was to determine the external validity of a clinical prediction rule developed by the European Multicenter Study on Human Spinal Cord Injury (EM-SCI) to predict the ambulation outcomes 12 months after traumatic spinal cord injury. Data from the North American Clinical Trials Network (NACTN) data registry with approximately 500 SCI cases were used for this validity study. The predictive accuracy of the EM-SCI prognostic model was evaluated using calibration and discrimination based on 231 NACTN cases. The area under the receiver-operating-characteristics curve (ROC) curve was 0.927 (95% CI 0.894 – 0.959) for the EM-SCI model when applied to NACTN population. This is lower than the AUC of 0.956 (95% CI 0.936 – 0.976) reported for the EM-SCI population, but suggests that the EM-SCI clinical prediction rule distinguished well between those patients in the NACTN population who were able to achieve independent ambulation and those who did not achieve independent ambulation. The calibration curve suggests that higher the prediction score is, the better the probability of walking with the best prediction for AIS D patients. In conclusion, the EM-SCI clinical prediction rule was determined to be generalizable to the adult NACTN SCI population.^