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1.  Tailored case management for diabetes and hypertension (TEACH-DM) in a community population: Study design and baseline sample characteristics 
Contemporary clinical trials  2013;36(1):10.1016/j.cct.2013.07.010.
Despite recognition of the benefits associated with well-controlled diabetes and hypertension, control remains suboptimal. Effective interventions for these conditions have been studied within academic settings, but interventions targeting both conditions have rarely been tested in community settings. We describe the design and baseline results of a trial evaluating a behavioral intervention among community patients with poorly-controlled diabetes and comorbid hypertension.
Tailored Case Management for Diabetes and Hypertension (TEACH-DM) is a 24-month randomized, controlled trial evaluating a telephone-delivered behavioral intervention for diabetes and hypertension versus attention control. The study recruited from nine community practices. The nurse-administered intervention targets 3 areas: 1) cultivation of healthful behaviors for diabetes and hypertension control; 2) provision of fundamentals to support attainment of healthful behaviors; and 3) identification and correction of patient-specific barriers to adopting healthful behaviors. Hemoglobin A1c and blood pressure measured at 6, 12, and 24 months are co-primary outcomes. Secondary outcomes include self-efficacy, self-reported medication adherence, exercise, and cost-effectiveness.
Of 377 randomized patients, 193 were allocated to the intervention and 184 to attention control. The cohort is balanced in terms of gender, race, education level, and income. The cohort’s mean baseline hemoglobin A1c and blood pressure are above goal, and mean baseline body mass index falls in the obese range. Baseline self-reported non-adherence is high for diabetes and hypertension medications. Trial results are pending.
If effective, the TEACH-DM intervention’s telephone-based delivery strategy and nurse administration make it well-suited for rapid implementation and broad dissemination in community settings.
PMCID: PMC3828629  PMID: 23916915
Diabetes; Hypertension; Behavioral Intervention; Telemedicine; Self-management; Case Management
2.  Holt-Oram Syndrome in Adult Presenting with Heart Failure: A Rare Presentation 
Case Reports in Cardiology  2014;2014:130617.
Holt-Oram syndrome is a rare inherited disorder involving the hands, arms, and the heart. The defects involve carpal bones of the wrist and the thumb and the associated cardiac anomalies like atrial or ventricular septal defects. Congenital cardiac and upper-limb malformations frequently occur together and are classified as heart-hand syndromes. The most common amongst the heart-hand disorders is the Holt-Oram syndrome, which is characterized by septal defects of the heart and preaxial radial ray abnormalities. Its incidence is one in 100,000 live births. Approximately three out of four patients have some cardiac abnormality with common associations being either an atrial septal defect or ventricular septal defect. Herein, we report a rare sporadic case of Holt-Oram syndrome with atrial septal defect with symptoms of heart failure in a forty-five-year-old lady who underwent emergency cardiac surgery for the symptoms.
PMCID: PMC4006581  PMID: 24826304
3.  Effect of Store and Forward Teledermatology on Quality of Life 
JAMA dermatology (Chicago, Ill.)  2013;149(5):584-591.
Although research on quality of life and dermatologic conditions is well represented in the literature, information on teledermatology’s effect on quality of life is virtually absent.
To determine the effect of store and forward teledermatology on quality of life.
Two-site, parallel-group, superiority randomized controlled trial.
Dermatology clinics and affiliated sites of primary care at 2 US Department of Veterans Affairs medical facilities.
Patients being referred to a dermatology clinic were randomly assigned, stratified by site, to teledermatology or the conventional consultation process. Among the 392 patients who met the inclusion criteria and were randomized, 326 completed the allocated intervention and were included in the analysis.
Store and forward teledermatology (digital images and a standardized history) or conventional text-based consultation processes were used to manage the dermatology consultations. Patients were followed up for 9 months.
Main Outcome Measures
The primary end point was change in Skindex-16 scores, a skin-specific quality-of-life instrument, between baseline and 9 months. A secondary end point was change in Skindex-16 scores between baseline and 3 months.
Patients in both randomization groups demonstrated a clinically significant improvement in Skindex-16 scores between baseline and 9 months with no significant difference by randomization group (P=.66, composite score). No significant difference in Skindex-16 scores by randomization group between baseline and 3 months was found (P=.39, composite score).
Compared with the conventional consultation process, store and forward teledermatology did not result in a statistically significant difference in skin-related quality of life at 3 or 9 months after referral.
Trial Registration Identifier: NCT00488293
PMCID: PMC3726199  PMID: 23426111
4.  Genetic and chemical knockdown: a complementary strategy for evaluating an anti-infective target 
The equity of a drug target is principally evaluated by its genetic vulnerability with tools ranging from antisense- and microRNA-driven knockdowns to induced expression of the target protein. In order to upgrade the process of antibacterial target identification and discern its most effective type of inhibition, an in silico toolbox that evaluates its genetic and chemical vulnerability leading either to stasis or cidal outcome was constructed and validated. By precise simulation and careful experimentation using enolpyruvyl shikimate-3-phosphate synthase and its specific inhibitor glyphosate, it was shown that genetic knockdown is distinct from chemical knockdown. It was also observed that depending on the particular mechanism of inhibition, viz competitive, uncompetitive, and noncompetitive, the antimicrobial potency of an inhibitor could be orders of magnitude different. Susceptibility of Escherichia coli to glyphosate and the lack of it in Mycobacterium tuberculosis could be predicted by the in silico platform. Finally, as predicted and simulated in the in silico platform, the translation of growth inhibition to a cidal effect was able to be demonstrated experimentally by altering the carbon source from sorbitol to glucose.
PMCID: PMC3572760  PMID: 23413046
knockdown; inhibition; in silico; vulnerability
5.  Demand for Weight Loss Counseling After Copayment Elimination 
Overweight and obesity are public health issues in the United States, and veterans have a higher rate of overweight and obesity than the general population. Our objective was to examine whether copayment elimination increased use of a weight loss clinic by veterans.
We examined clinic use by 44,411 new patients seen in a Veterans Affairs (VA) MOVE! weight management clinic before the copayment elimination and clinic use by 64,398 new patients seen in the year after copayment elimination. We examined clinic use via mixed-effects models for patients who were already exempt from copayment and patients who were newly exempt from copayment. We used 2 outcomes before and after copayment elimination: 1) the ratio of number of clinic visits by new users with the mean number of MOVE! clinic visits by all users, and 2) the number of clinic visits by each new user in the 6 months after their first visit. All models were adjusted for patient and clinic factors.
Among newly exempt patients, the clinic-standardized rate of new use increased by 2.2% after the copayment was eliminated but increased 12% among already exempt veterans. This finding was confirmed in adjusted analyses. Analysis of number of clinic visits adjusted for patient and clinic factors also found that exempt and nonexempt veterans had similar numbers of repeat clinic visits.
We saw an unexpected larger increase in demand among veterans who receive all VA care for free. These results suggest that VA should not assume that copayment reductions for selective preventive services will motivate patient change and achieve intended system-level outcomes.
PMCID: PMC3617989  PMID: 23557640
6.  Accurate Estimation of Nucleic Acids by Amplification Efficiency Dependent PCR 
PLoS ONE  2012;7(8):e42063.
Accurate estimation of template - DNA or RNA by real time PCR is dependent on the amplification efficiency (F) of the reaction. The analytical equation describing the kinetics of PCR that is influenced by template re-annealing is formulated. It predicts the gradual reduction of F - from its initial value of 2, leading to template saturation. From an experimental standpoint, due to the exponential nature of the reaction a minute change in F can lead to a large error in the estimation of the initial template concentration. On the basis of individual variation in the amplification efficiency we have formulated a simple mathematical model and an MS Excel based data analysis software that allows accurate and automated quantification of initial template concentration. This method which does not require any normalisation with housekeeping genes was validated by transcript profiling of the genes in the TCA/glyoxylate cycle of E. coli. Consistent with published reports, we observed a precise and specific induction of the glyoxylate shunt genes when the bacteria was shifted from a six carbon glucose media to a two carbon source like acetate.
PMCID: PMC3422235  PMID: 22912684
7.  Patient and provider interventions for managing osteoarthritis in primary care: protocols for two randomized controlled trials 
Osteoarthritis (OA) of the hip and knee are among the most common chronic conditions, resulting in substantial pain and functional limitations. Adequate management of OA requires a combination of medical and behavioral strategies. However, some recommended therapies are under-utilized in clinical settings, and the majority of patients with hip and knee OA are overweight and physically inactive. Consequently, interventions at the provider-level and patient-level both have potential for improving outcomes. This manuscript describes two ongoing randomized clinical trials being conducted in two different health care systems, examining patient-based and provider-based interventions for managing hip and knee OA in primary care.
Methods / Design
One study is being conducted within the Department of Veterans Affairs (VA) health care system and will compare a Combined Patient and Provider intervention relative to usual care among n = 300 patients (10 from each of 30 primary care providers). Another study is being conducted within the Duke Primary Care Research Consortium and will compare Patient Only, Provider Only, and Combined (Patient + Provider) interventions relative to usual care among n = 560 patients across 10 clinics. Participants in these studies have clinical and / or radiographic evidence of hip or knee osteoarthritis, are overweight, and do not meet current physical activity guidelines. The 12-month, telephone-based patient intervention focuses on physical activity, weight management, and cognitive behavioral pain management. The provider intervention involves provision of patient-specific recommendations for care (e.g., referral to physical therapy, knee brace, joint injection), based on evidence-based guidelines. Outcomes are collected at baseline, 6-months, and 12-months. The primary outcome is the Western Ontario and McMasters Universities Osteoarthritis Index (self-reported pain, stiffness, and function), and secondary outcomes are the Short Physical Performance Test Protocol (objective physical function) and the Patient Health Questionnaire-8 (depressive symptoms). Cost effectiveness of the interventions will also be assessed.
Results of these two studies will further our understanding of the most effective strategies for improving hip and knee OA outcomes in primary care settings.
Trial registration
NCT01130740 (VA); NCT 01435109 (NIH)
PMCID: PMC3433311  PMID: 22530979
Osteoarthritis; Physical activity; Weight reduction program; Pain management; Intervention study
8.  Polyphosphate Kinase from M. tuberculosis: An Interconnect between the Genetic and Biochemical Role 
PLoS ONE  2010;5(12):e14336.
The enzyme Polyphosphate Kinase (PPK) catalyses the reversible transfer of the terminal γ-Pi of ATP to form a long chain Polyphosphate (PolyP). Using an IPTG inducible mycobacterial vector, the vulnerability of this gene has been evaluated by antisense knockdown experiments in M. tuberculosis. Expression profiling studies point to the fact that down regulation of PPK caused cidality during the late phase in contrast to its bacteriostatic mode immediately following antisense expression. PPK thus seems to be a suitable anti-tubercular drug target. The enzyme which is a tetramer has been cloned in E. coli and purified to homogeneity. An enzyme assay suitable for High Throughput Screening was optimized by using the statistical Taguchi protocol and the kinetic parameters determined. The enzyme displayed a strong product inhibition by ADP. In order to accurately estimate the product inhibition, progress curve analysis of the enzyme reaction was monitored. The kinetic equation describing the progress curve was suitably modified by taking into account the product inhibition. The reversible nature of the enzyme indicated a possibility of a two way ATP↔ADP switch operating in the bacteria as a response to its growth requirement.
PMCID: PMC3002279  PMID: 21179463
9.  A kinetic platform for in silico modeling of the metabolic dynamics in Escherichia coli 
A prerequisite for a successful design and discovery of an antibacterial drug is the identification of essential targets as well as potent inhibitors that adversely affect the survival of bacteria. In order to understand how intracellular perturbations occur due to inhibition of essential metabolic pathways, we have built, through the use of ordinary differential equations, a mathematical model of 8 major Escherichia coli pathways.
Individual in vitro enzyme kinetic parameters published in the literature were used to build the network of pathways in such a way that the flux distribution matched that reported from whole cells. Gene regulation at the transcription level as well as feedback regulation of enzyme activity was incorporated as reported in the literature. The unknown kinetic parameters were estimated by trial and error through simulations by observing network stability. Metabolites, whose biosynthetic pathways were not represented in this platform, were provided at a fixed concentration. Unutilized products were maintained at a fixed concentration by removing excess quantities from the platform. This approach enabled us to achieve steady state levels of all the metabolites in the cell. The output of various simulations correlated well with those previously published.
Such a virtual platform can be exploited for target identification through assessment of their vulnerability, desirable mode of target enzyme inhibition, and metabolite profiling to ascribe mechanism of action following a specific target inhibition. Vulnerability of targets in the biosynthetic pathway of coenzyme A was evaluated using this platform. In addition, we also report the utility of this platform in understanding the impact of a physiologically relevant carbon source, glucose versus acetate, on metabolite profiles of bacterial pathogens.
PMCID: PMC3170011  PMID: 21918631
antibacterial drug; mathematical model; kinetic platform; metabolic dynamics; Escherichia coli
10.  Delineating Bacteriostatic and Bactericidal Targets in Mycobacteria Using IPTG Inducible Antisense Expression 
PLoS ONE  2009;4(6):e5923.
In order to identify novel high value antibacterial targets it is desirable to delineate whether the inactivation of the target enzyme will lead to bacterial death or stasis. This knowledge is particularly important in slow growing organisms, like mycobacteria, where most of the viable anti-tubercular agents are bactericidal. A bactericidal target can be identified through the conditional deletion or inactivation of the target gene at a relatively high cell number and subsequently following the time course of survival for the bacteria. A simple protocol to execute conditional inactivation of a gene is by antisense expression. We have developed a mycobacteria specific IPTG inducible vector system and monitored the effect of antisense inhibition of several known essential genes in mycobacteria by following their survival kinetics. By this method, we could differentiate between genes whose down regulation lead to bacteriostatic or bactericidal effect. Targets for standard anti-tubercular drugs like inhA for isoniazid, rpoB and C for rifampicin, and gyr A/B for flouroquinolones were shown to be bactericidal. In contrast targets like FtsZ behaved in a bacteriostatic manner. Induction of antisense expression in embB and ribosomal RNA genes, viz., rplJ and rpsL showed only a marginal growth inhibition. The specificity of the antisense inhibition was conclusively shown in the case of auxotrophic gene ilvB. The bactericidal activity following antisense expression of ilvB was completely reversed when the growth media was supplemented with the isoleucine, leucine, valine and pantothenate. Additionally, under these conditions the expression of several genes in branched chain amino acid pathway was severely suppressed indicating targeted gene inactivation.
PMCID: PMC2691988  PMID: 19526063
11.  Study protocol: Couples Partnering for Lipid Enhancing Strategies (CouPLES) – a randomized, controlled trial 
Trials  2009;10:10.
Almost 50% of Americans have elevated low-density lipoprotein cholesterol (LDL-C). The behaviors required to lower LDL-C levels may be difficult to adhere to if they are inconsistent with spouses' health practices, and, alternatively, may be enhanced by enlisting support from the spouse. This trial extends previous trials by requiring spouse enrollment, teaching spouses how to provide emotional and instrumental support, allowing patients to decide which component of the intervention they would like to receive, and having patients determine their own goals and action plans.
Veteran outpatients with above-goal LDL-C (N = 250) and their spouses are randomized, as a couple, to receive printed education materials only or the materials plus an 11-month, nurse-delivered, telephone-based intervention. The intervention contains four modules: medication adherence, diet, exercise, and patient-physician communication. Patients decide which modules they complete and in which order; modules may be repeated or omitted. Telephone calls are to patients and spouses separately and occur monthly. During each patient telephone call, patients' progress is reviewed, and patients create goals and action plans for the upcoming month. During spouse telephone calls, which occur within one week of patient calls, spouses are informed of patients' goals and action plans and devise strategies to increase emotional and instrumental support.
The primary outcome is patients' LDL-C, measured at baseline, 6 months, and 11 months. Linear mixed models will be used to test the primary hypothesis that an 11-month, telephone-based patient-spouse intervention will result in a greater reduction in LDL-C as compared to printed education materials. Various process measures, including social support, self-efficacy, medication adherence, dietary behavior, and exercise, are also assessed to explain any change, or lack thereof, in LDL-C.
Given the social context in which self-management occurs, interventions that teach spouses to provide instrumental and emotional support may help patients initiate and adhere to behaviors that lower their LDL-C levels. Moreover, allowing patients to retain autonomy by deciding which behaviors they would like to change and how may improve adherence and clinical outcomes.
Trial Registration
The registration number is NCT00321789.
PMCID: PMC2652451  PMID: 19200384
12.  Identification of Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) as the Rosetting Ligand of the Malaria Parasite P. falciparum  
Severe Plasmodium falciparum malaria is characterized by excessive sequestration of infected and uninfected erythrocytes in the microvasculature of the affected organ. Rosetting, the adhesion of P. falciparum–infected erythrocytes to uninfected erythrocytes is a virulent parasite phenotype associated with the occurrence of severe malaria. Here we report on the identification by single-cell reverse transcriptase PCR and cDNA cloning of the adhesive ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1). Rosetting PfEMP1 contains clusters of glycosaminoglycan-binding motifs. A recombinant fusion protein (Duffy binding-like 1–glutathione S transferase; Duffy binding-like-1–GST) was found to adhere directly to normal erythrocytes, disrupt naturally formed rosettes, block rosette reformation, and bind to a heparin-Sepharose matrix. The adhesive interactions could be inhibited with heparan sulfate or enzymes that remove heparan sulfate from the cell surface whereas other enzymes or similar glycosaminoglycans of a like negative charge did not affect the binding. PfEMP1 is suggested to be the rosetting ligand and heparan sulfate, or a heparan sulfate–like molecule, the receptor both for PfEMP1 binding and naturally formed erythrocyte rosettes.
PMCID: PMC2199182  PMID: 9419207

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