Association of Toll like receptor 2 and 9 gene variants with pulmonary tuberculosis: exploration in a northern Indian population.

Tuberculosis (TB) is a disease of global importance. There is an increasing recognition of the role of Toll like receptors, important pattern recognition receptors of host immune system, in determining the susceptibility or resistance to TB in various populations. In an attempt to examine the importance of Toll like receptors in immune response to Mycobacterium tuberculosis infection, we explored two variants each of TLR2 and TLR9 in a population residing in Uttar Pradesh, India. Genotyping was performed to detect -196 to -174 del polymorphism and G2258A SNP (Arg753Gln, rs5743708) in TLR2 gene and -T1237C (rs5743836) and G2848A (rs352140) SNP in TLR9 gene in patients with pulmonary TB and healthy controls. The A allele of G2848A SNP in TLR9 gene was found with a marginally higher frequency among TB patients as compared to healthy controls, suggesting that A allele at position 2848 of TLR9 gene may be associated with susceptibility to TB in North Indian population [p = 0.05, Mantel-Haenszel OR = 1.34, 95% CI (1.0-1.82)].

Preoperative Cardiac Evaluation in Kidney Transplant Patients: Is Coronary Angiography Superior? A Focused Review.

Cardiovascular disease is the major cause of morbidity and mortality in chronic kidney disease patients. Because of a higher occurrence of asymptomatic coronary artery disease and increased perioperative cardiovascular mortality in kidney transplant patients, screening for coronary artery disease before transplant surgery is essential. Various studies have shown that cardiac stress testing is an unreliable screening method in these patients because of significant variability in sensitivity and negative predictive value. We suggest that high-risk candidates such as those with diabetes or a prior history of myocardial infarction, stroke, peripheral vascular disease, or coronary artery disease should perhaps be considered for coronary angiography rather than stress testing as cardiac screening before kidney transplantation.

Almost everyone over 50 should be put on a statin to reduce the risk of cardiovascular disease: A contrarian view.

3-Hydroxy-3-methyl-glutarylCoA reductase inhibitors, or statins, are a mainstay in the treatment of patients with established coronary artery disease (CAD) because of their proven efficacy in reducing cardiovascular death, myocardial infarction, and coronary revascularization procedures in this patient population. Statin therapy has also proven successful in the primary prevention of CAD. However, the absolute reduction in cardiovascular events is lower in primary prevention than in secondary prevention trials, and many of the primary prevention trials enrolled a significant number of patients with established cardiovascular disease and/or other high-risk features, such as diabetes mellitus. For these reasons we do not recommend widespread treatment of the general adult population with a statin. Rather, we advocate a strategy which involves collection of standard clinical data and the use of validated risk-prediction tools to stratify patient risk and limit initiation of a statin to those who are more likely to benefit from such therapy.

Treatment patterns and healthcare costs among patients with psoriasis initiating apremilast or biologics: a retrospective claims database cohort analysis.

OBJECTIVE: This study aimed to compare treatment patterns and healthcare costs for patients with psoriasis who initiate apremilast, tumor necrosis factor inhibitor, or interleukin inhibitor. METHODS: This retrospective cohort study used Optum Clinformatics® Data Mart to identify propensity score-matched patients initiating apremilast, tumor necrosis factor inhibitors, or interleukin inhibitors, with 12-month baseline and 24-month follow-up data. Switch, discontinuation, persistence, healthcare resource utilization, and total healthcare costs were assessed. RESULTS: Twenty-four-month switch rates were highest for tumor necrosis factor inhibitors (32%), followed by apremilast (21%) then interleukin inhibitors (14%). Mean (SD) per-patient-per-month costs for switchers were lowest for apremilast ($4213 [$2304]), higher for tumor necrosis factor inhibitors ($5274 [$2280]), and highest for interleukin inhibitors ($5539 [$2296]; p < .001), primarily attributable to pharmacy costs: $3466 (apremilast), $4432 (tumor necrosis factor inhibitor), and $4721 (interleukin inhibitor). LIMITATIONS: Psoriasis severity is absent from claims data; cost outcomes may be influenced by more severe psoriasis being more costly. CONCLUSION: Switching psoriasis treatment is common and increases over time. Apremilast initiators had lower switch rates and costs compared with tumor necrosis factor inhibitors, despite lower effectiveness reported in previous studies, perhaps indicating patient preference for oral treatment. Additional oral options may be desirable for this population.

MedlinePlus-based health information prescriptions: a comparison of email vs paper delivery.

BACKGROUND: The internet can provide evidence-based patient education to overcome time constraints of busy ambulatory practices. Health information prescriptions (HIPs) can be effectively integrated into clinic workflow, but compliance to visit health information sites such as MedlinePlus is limited. OBJECTIVE: Compare the efficacy of paper (pHIP) and email (eHIP) links to deliver HIPs; evaluate patient satisfaction with the HIP process and MedlinePlus information; assess reasons for noncompliance to HIPs. METHOD: Of 948 patients approached at two internal medicine clinics affiliated with an academic medical centre, 592 gave informed consent after meeting the inclusion criteria. In this randomised controlled trial, subjects were randomised to receive pHIP or eHIP for accessing an intermediate website that provided up to five MedlinePlus links for physician-selected HIP conditions. Patients accessing the intermediate website were surveyed by email to assess satisfaction with the health information. Survey non-responders were contacted by telephone to determine the reasons for no response. RESULTS: One hundred and eighty-one patients accessed the website, with significantly more 'filling' eHIP than pHIP (38% vs 23%; P < 0.001). Most (82%) survey respondents found the website information useful, with 77% favouring email for future HIPs delivery. Lack of time, forgot, lost instructions or changed mind were reasons given for not accessing the websites. CONCLUSIONS: Delivery of MedlinePlus-based HIPs in clinic is more effective using email prescriptions than paper. Satisfaction with the HIP information was high, but overall response was low and deserves further investigation to improve compliance and related outcomes.

Contemporary indications and therapeutic implications for digoxin use.

Heart failure (HF) is a leading cause of morbidity and mortality. Appropriate medical therapy using angiotensin converting enzyme inhibitors and beta-blockers improves outcomes in HF, whereas the role of digoxin is still not clearly defined. Digoxin is currently recommended for patients with HF who are symptomatic despite standard therapy and for controlling the ventricular rate in atrial fibrillation. Digoxin is a time-tested drug that accounts for 20 million drug prescriptions annually in the United States. It has favorable hemodynamic effects for patients with HF and atrial tachyarrhythmias. We conducted a systematic literature search for the current indications for digoxin. Despite extensive research and safety data, the literature suggests that digoxin is underused in clinical settings. Citing the literature where available, our review highlights the various clinical settings where digoxin is indicated. Despite difficulties with designing prospective studies in acute HF settings and lack of outcomes data, we believe that digoxin will continue to serve an important role in optimizing care in certain acute and chronic cardiac conditions.

Exploring the Role of C-C Motif Chemokine Ligand-2 Single Nucleotide Polymorphism in Pulmonary Tuberculosis: A Genetic Association Study from North India.

The C-C motif chemokine ligand-2 (CCL2) was evidenced to be associated with tuberculosis susceptibility in some ethnic groups. In the present study, effort was made to find out the association of CCL2-2518 A>G and -362 G>C variants with susceptibility to TB in a population from North India. The genotyping was carried out in 373 participants with pulmonary TB (PTB) and 248 healthy controls (HCs) for CCL2-2518 A>G and -362 G>C polymorphisms by PCR-RFLP and by melting curve analysis using fluorescence-labeled hybridization fluorescent resonance energy transfer (FRET) probes, respectively, followed by DNA sequencing in a few representative samples. Genotype and allele frequencies were compared by the chi-squared test and crude and Mantel-Haenszel (M-H) odds ratio (OR). OR was calculated using STATA/MP16.1 software. Further, CCL2, IL-12p70, IFN-γ, TNF-α, and TGF-ß levels were measured in serum samples of these participants using commercially available kits. Our analysis indicated that the homozygous mutant in both -2518 GG (OR = 2.07, p = 0.02) and -362 CC (OR = 1.92, p = 0.03) genotypes was associated with susceptibility to pulmonary TB. Further, heterozygous genotypes -2518AG (OR = 0.60, p = 0.003) and -362GC (OR = 0.64, p = 0.013) provide resistance from PTB disease. Haplotype analysis revealed AC haplotype (p = 0.006) to be a risk factor associated with PTB susceptibility. The serum CCL2 level was significantly elevated among participants with -2518 AA genotype compared to -2518 GG genotype. CCL2 level was observed to be positively correlated with IL12p70, IFN-γ and TNF-α, thus suggesting the immunological regulatory role of CCL2 against pulmonary tuberculosis. CCL2-2518 GG and -362 CC genotypes were found to be associated with susceptibility to pulmonary tuberculosis and CCL2-2518AG and CCL2-362GC with resistance from PTB. AC haplotype was found to be a risk factor for PTB in the present study. It may be hypothesized from the findings that -2518G allele could be responsible for lower production of CCL2 which leads to defective Th1 response and makes a host susceptible for pulmonary tuberculosis.

Estimation of efflux mediated multi-drug resistance and its correlation with expression levels of two major efflux pumps in mycobacteria.

Multidrug resistance has been posing an increasing problem in the treatment of tuberculosis. Mutations in the genomic targets of drugs have been identified as the major mechanism behind this resistance. However, high degree of resistance in some isolates towards major drugs like rifampicin, isoniazid, ethambutol and streptomycin can not be explained solely on the basis of mutations. Besides this, certain other mechanisms like efflux pumps have also been considered as alternative mechanisms in the drug resistant isolates where there is no mutation and these mechanisms are specially important for drug resistance in non-tuberculous mycobacteria (NTM). In this study, we have estimated efflux pump mediated drug resistance in different mycobacterial species with the help of efflux pump inhibitors. All major anti-tuberculous drugs have been shown to be extruded by efflux pumps and the degree to which these drugs are extruded, vary in different mycobacterial species and isolates. The correlation of this resistance with functional activity of two major efflux pump genes pstB and Rv1258c was also assessed by reverse transcription PCR. Besides the significant role of these pumps observed, other efflux pumps, present in mycobacteria, may also be involved in drug resistance and need to be investigated.

Role of isolated ultrafiltration in the management of chronic refractory and acute decompensated heart failure.

Chronic congestive heart failure (CHF) and acute decompensated heart failure (ADHF) refractory to medical therapy represent therapeutic challenges. In such patients, attempts to reduce pulmonary and systemic congestion frequently produce deterioration of renal function. In studies of patients with chronic severe CHF refractory to medical therapy (including loop diuretics), isolated ultrafiltration was frequently able to relieve congestive symptoms by precise removal of extracellular water and sodium, and in some cases was able to restore responsiveness to loop diuretics. Randomized controlled trials comparing isolated ultrafiltration and medical therapy (mainly loop diuretics) in patients with ADHF failed to demonstrate the superiority of isolated ultrafiltration over diuretic therapy with respect to renal function and mortality. Isolated ultrafiltration reduced length of hospital stay in several studies. At this time, there is insufficient evidence to support the use of isolated ultrafiltration as initial therapy of ADHF.

Comparison of left ventricular ejection fraction values obtained using invasive contrast left ventriculography, two-dimensional echocardiography, and gated single-photon emission computed tomography.

OBJECTIVES: Left ventricular ejection fraction can be measured by a variety of invasive and non-invasive cardiac techniques. This study assesses the relation of three diagnostic modalities to each other in the measurement of left ventricular ejection fraction: invasive contrast left ventriculography, two-dimensional echocardiography, and quantitative gated single-photon emission computed tomography. METHODS: Retrospective chart review was conducted on 58 patients hospitalized with chest pain, who underwent left ventricular ejection fraction evaluation using each of the aforementioned modalities within a 3-month period not interrupted by myocardial infarction or revascularization. RESULTS: The mean left ventricular ejection fraction values were as follows: invasive contrast left ventriculography (0.44±0.15), two-dimensional echocardiography (0.46±0.13), and gated single-photon emission computed tomography (0.37±0.10). Correlations coefficients and associated p values were as follows: invasive contrast left ventriculography versus two-dimensional echocardiography (r=0.69, p<0.001), invasive contrast left ventriculography versus gated single-photon emission computed tomography (r=0.80, p<0.0001), and gated single-photon emission computed tomography versus two-dimensional echocardiography (r=0.69, p<0.001). CONCLUSION: Our results indicate that strong positive correlations exist among the three techniques studied.

Does pharmacotherapy improve cardiovascular outcomes in hemodialysis patients?

Cardiovascular disease (CVD) occurs commonly in patients with chronic kidney disease (CKD) including those treated with hemodialysis (HD), and is associated with poor outcomes in this population. Pharmacologic management of hypertension, dyslipidemia, acute and chronic coronary artery disease, and atrial fibrillation in the general population is supported by the results of high-quality, randomized, controlled clinical trials. Pharmacotherapy of these disorders in the general population is effective in improving clinical outcomes. In contrast, information concerning the effect of pharmacotherapy on mortality and cardiovascular outcomes in patients with CKD, and particularly in HD patients, is limited. Available data suggest that, in general, pharmacotherapy of hypertension and dyslipidemia, anti-platelet therapy of CVD, and anticoagulant therapy in patients with atrial fibrillation are less effective in HD patients than in the general population or even in patients with early stage of CKD.

Pharmacological and non pharmacological strategies in the management of coronary artery disease and chronic kidney disease.

Patients with advanced chronic kidney disease (CKD), including those treated with dialysis, are at high risk for the development of cardiovascular disease (CVD). CVD accounts for 45-50% of deaths among dialysis patients. Therapy of acute and chronic coronary heart disease (CHD) that is effective in the general population is frequently less effective in patients with advanced CKD. Drug therapy in such patients may require dose modification in some cases. Oral anti-platelet drugs are less effective in those with advanced CKD than in persons with normal or near normal renal function. The intravenous antiplatelet drugs eptifibatide and tirofiban both require dose reductions in patients with advanced CKD. Enoxaparin requires dose reduction in early stage CKD and is contraindicated in hemodialysis patients. Unfractionated heparin and warfarin maybe used without dose adjustment in CKD patients. Atenolol, acetbutolol and nadolol may require dose adjustments in CKD. Metoprolol and carvedilol do not. Calcium channel blockers and nitrates do not require dose adjustment, whereas ranolazine does. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers may safely be used in CKD patients with close observation for hyperkalemia. The safety of spironolactone in such patients is questionable. Statins are less effective in reducing cardiovascular complication in CKD patients and their initiation is not recommended in dialysis patients. Coronary artery bypass grafting is associated with higher shortterm mortality, but better long-term morbidity and mortality than percutaneous coronary interventions in patients with advanced CKD with non-ST segment ACS and chronic CHD.

Antithrombotics in atrial fibrillation and coronary disease.

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia and approximately 18-45% of AF patients have concomitant coronary artery disease (CAD). Several studies have demonstrated that oral anticoagulation is the mainstay of therapy for stroke prevention in AF. Similarly, antiplatelet therapy including aspirin and P2Y12 inhibitor is recommended in the management of acute coronary syndrome and stable CAD. Despite the high prevalence of CAD with AF, practice guidelines are scarce on the appropriate antithrombotic regimen due to lack of large-scale randomized clinical trials. The use of direct thrombin and factor Xa inhibitors for stroke prevention in AF has also complicated the possible combinations of antithrombotic therapies. This review aims to discuss the available evidence regarding aspirin as an antithrombotic strategy, the role of novel anticoagulants and the specific clinical situations where aspirin may be beneficial in patients with AF and CAD.

Toll-like Receptor 1 743 A>G, 1805 T>G & Toll-like Receptor 6 745 C>T gene polymorphism and tuberculosis: a case control study of north Indian population from Agra (India).

Infection with Mycobacteriumtuberculosis possibly depends on host genetic factors and is thought to be the major cause of differential susceptibility to the disease. In the present study, 205 pulmonary tuberculosis cases and 127 healthy controls were studied for the association of Toll-like Receptor (TLR) variants (TLR1 variants 743A>G and 1805T>G, and TLR6 variant 745 C>T) in north Indian population. The frequency of heterozygous genotypes (AG) in TB cases (0.47) and HCs (0.61), differed significantly (p value = 0.02). The association of AG genotypes in HCs was adjusted for gender as gender was observed to be a confounder and M-H OR was found to be 0.62 (p = 0.044). On categorizing the cases basing on AFB smear positivity, the heterozygous genotypes (AG) was found to be associated with low bacillary load (scanty and 1+) (P = 0.002). No association was observed for either TLR1 1805 T>G or TLR6 745 C>T polymorphism. Level of serum IL6 was found to be significantly higher among healthy controls with TLR1 GG genotype compared to healthy controls with AA (p = 0.035) and AG (p = 0.005) genotypes. Thus, it may be suggested that the heterozygous condition for TLR1 743 A>G provide resistance from the disease. However, in depth study is required to understand the mechanism for possible protective responses.

The surgery clerkship: an opportunity for preclinical credentialing in urinary catheterization.

BACKGROUND: At our hospital, medical students lost privileges to perform urinary catheterization because of concern regarding catheter-associated urinary tract infections. We hypothesized that trained medical students could perform urinary catheterization with the same proficiency as licensed practitioners. METHODS: Medical students completed a credentialing program in urinary catheterization. Prospectively, the rate of catheter-associated urinary tract infections after urinary catheterization performed by medical students was compared with the health system-wide rate of catheter-associated urinary tract infections after urinary catheterization performed by non-medical students using an incidence rate ratio (IRR). RESULTS: Over 9 months, a total of 432 and 55,401 catheter days accrued in patients who underwent urinary catheterization by medial students and non-medical students, resulting in 1 and 129 catheter-associated urinary tract infections, respectively. The incidence rate of catheter-associated urinary tract infections per 1,000 catheter days was 2.31 in the medical student-placed catheters and 2.33 in the non-MS-placed catheters (IRR = .99, P = .55). CONCLUSIONS: Preclinical credentialing in urinary catheterization resulted in the reinstatement of urinary catheterization privileges to qualified medical students. Student proficiency in urinary catheterization can match that of licensed practitioners.

Successful implementation of the american college of surgeons/association of program directors in surgery surgical skills curriculum via a 4-week consecutive simulation rotation.

INTRODUCTION: Increased patient awareness, duty hour restrictions, escalating costs, and time constraints in the operating room have revolutionized surgery education. Although simulation and skills laboratories are emerging as promising alternatives for skills training, their integration into graduate surgical education is inconsistent, erratic, and often on a voluntary basis. We hypothesize that, by implementing the American College of Surgeons/Association of Program Directors in Surgery Surgical Skills Curriculum in a structured, inanimate setting, we can address some of these concerns. METHODS: Sixty junior surgery residents were assigned to the Penn Surgical Simulation and Skills Rotation. The National Surgical Skills Curriculum was implemented using multiple educational tools under faculty supervision. Pretraining and posttraining assessments of technical skills were conducted using validated instruments. Trainee and faculty feedbacks were collected using a structured feedback form. RESULTS: Significant global performance improvement was demonstrated using Objective Structured Assessment of Technical Skills score for basic surgical skills (knot tying, wound closure, enterotomy closure, and vascular anastomosis) and Fundamentals of Laparoscopic Surgery skills, P < 0.001. Six trainees were retested on an average of 13.5 months later (range, 8-16 months) and retained more than 75% of their basic surgical skills. DISCUSSION: The American College of Surgeons/Association of Program Directors in Surgery National Surgical Skills Curriculum can be implemented in its totality as a 4-week consecutive surgical simulation rotation in an inanimate setting, leading to global enhancement of junior surgical residents' technical skills and contributing to attainment of Accreditation Council for Graduate Medical Education core competency.

Germ simulation: a novel approach for raising medical students awareness toward asepsis.

INTRODUCTION: Medical student procedural training has become increasingly limited amid concerns for patient safety. Because simulation education has been shown to be effective for early skills training, we used germ simulation for teaching hand hygiene principles and aseptic technique in urinary catheterization (UC). We hypothesized that posttraining, students would demonstrate proficiency comparable to surgery residents. METHODS: Seventy-five clinical clerks, second-year medical students, underwent the simulation training. Sixty-four volunteered to have their asepsis scores compared with 21 residents who were credentialed for UC placement. We used simulated germs to objectively quantify effectiveness of hand washing and maintenance of aseptic technique during UC. A task-specific check list was also used for assessing UC skills. Students completed a posttraining feedback survey. RESULTS: Compared with residents, students after simulation training washed their hands with equal effectiveness at baseline (P = 0.2), maintained better sterility (P = 0.05), and had a higher technical proficiency score during UC (P < 0.001). Students believed that it was a great idea to use simulated germs to highlight effectiveness of hand washing (100%) and they indicated that they would pay extra attention when washing hands (97%). CONCLUSION: We describe a novel approach to germ simulation and a training approach to teach aseptic technique in UC. Students reported a heightened awareness of the importance of hand hygiene and aseptic precautions during UC. Further studies are needed to see if this could lead to a reduction in hospital-acquired infections.

Endothelial progenitor cells as factors in neovascularization and endothelial repair.

Endothelial progenitor cells (EPCs) are a heterogeneous population of cells that are provided by the bone marrow and other adult tissue in both animals and humans. They express both hematopoietic and endothelial surface markers, which challenge the classic dogma that the presumed differentiation of cells into angioblasts and subsequent endothelial and vascular differentiation occurred exclusively in embryonic development. This breakthrough stimulated research to understand the mechanism(s) underlying their physiologic function to allow development of new therapeutic options. One focus has been on their ability to form new vessels in injured tissues, and another has been on their ability to repair endothelial damage and restore both monolayer integrity and endothelial function in denuded vessels. Moreover, measures of their density have been shown to be a better predictor of cardiovascular events, both in healthy and coronary artery disease populations than the classical tools used in the clinic to evaluate the risk stratification. In the present paper we review the effects of EPCs on revascularization and endothelial repair in animal models and human studies, in an attempt to better understand their function, which may lead to potential advancement in clinical management.

Assessment of email communication skills of rheumatology fellows: a pilot study.

Physician-patient email communication is gaining popularity. However, a formal assessment of physicians' email communication skills has not been described. We hypothesized that the email communication skills of rheumatology fellows can be measured in an objective structured clinical examination (OSCE) setting using a novel email content analysis instrument which has 18 items. During an OSCE, we asked 50 rheumatology fellows to respond to a simulated patient email. The content of the responses was assessed using our instrument. The majority of rheumatology fellows wrote appropriate responses scoring a mean (±SD) of 10.6 (±2.6) points (maximum score 18), with high inter-rater reliability (0.86). Most fellows were concise (74%) and courteous (68%) but not formal (22%). Ninety-two percent of fellows acknowledged that the patient's condition required urgent medical attention, but only 30% took active measures to contact the patient. No one encrypted their messages. The objective assessment of email communication skills is possible using simulated emails in an OSCE setting. The variable email communication scores and incidental patient safety gaps identified, suggest a need for further training and defined proficiency standards for physicians' email communication skills.