Rohan Khera

Complement Receptor 1: disease associations and therapeutic implications.

Abstract Exaggerated complement activation is a key event in the pathogenesis of a range of autoimmune and inflammatory diseases. Complement Receptor 1 (CR1) has emerged as a molecule of immense interest in gaining insight to the susceptibility, pathophysiology, diagnosis, prognosis and therapy of such diseases. This review brings forth a composite view of the current understanding on the structure, functions, genetics, disease associations and therapeutic implications of CR1.

Association of Pharmacological Treatments for Obesity With Weight Loss and Adverse Events: A Systematic Review and Meta-analysis

IMPORTANCE Five medications have been approved for the management of obesity, but data on comparative effectiveness are limited. OBJECTIVE To compare weight loss and adverse events among drug treatments for obesity using a systematic review and network meta-analysis. DATA SOURCES MEDLINE, EMBASE, Web of Science, Scopus, and Cochrane Central from inception to March 23, 2016; clinical trial registries. STUDY SELECTION Randomized clinical trials conducted among overweight and obese adults treated with US Food and Drug Administration-approved long-term weight loss agents (orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, or liraglutide) for at least 1 year compared with another active agent or placebo. DATA EXTRACTION AND SYNTHESIS Two investigators identified studies and independently abstracted data using a predefined protocol. A Bayesian network meta-analysis was performed and relative ranking of agents was assessed using surface under the cumulative ranking (SUCRA) probabilities. Quality of evidence was assessed using GRADE criteria. MAIN OUTCOMES AND MEASURES Proportions of patients with at least 5% weight loss and at least 10% weight loss, magnitude of decrease in weight, and discontinuation of therapy because of adverse events at 1 year. RESULTS Twenty-eight randomized clinical trials with 29 018 patients (median age, 46 years; 74% women; median baseline body weight, 100.5 kg; median baseline body mass index, 36.1) were included. A median 23% of placebo participants had at least 5% weight loss vs 75% of participants taking phentermine-topiramate (odds ratio [OR], 9.22; 95% credible interval [CrI], 6.63-12.85; SUCRA, 0.95), 63% of participants taking liraglutide (OR, 5.54; 95% CrI, 4.16-7.78; SUCRA, 0.83), 55% taking naltrexone-bupropion (OR, 3.96; 95% CrI, 3.03-5.11; SUCRA, 0.60), 49% taking lorcaserin (OR, 3.10; 95% CrI, 2.38-4.05; SUCRA, 0.39), and 44% taking orlistat (OR, 2.70; 95% CrI, 2.34-3.09; SUCRA, 0.22). All active agents were associated with significant excess weight loss compared with placebo at 1 year-phentermine-topiramate, 8.8 kg (95% CrI, -10.20 to -7.42 kg); liraglutide, 5.3 kg (95% CrI, -6.06 to -4.52 kg); naltrexone-bupropion, 5.0 kg (95% CrI, -5.94 to -3.96 kg); lorcaserin, 3.2 kg (95% CrI, -3.97 to -2.46 kg); and orlistat, 2.6 kg (95% CrI, -3.04 to -2.16 kg). Compared with placebo, liraglutide (OR, 2.95; 95% CrI, 2.11-4.23) and naltrexone-bupropion (OR, 2.64; 95% CrI, 2.10-3.35) were associated with the highest odds of adverse event-related treatment discontinuation. High attrition rates (30%-45% in all trials) were associated with lower confidence in estimates. CONCLUSIONS AND RELEVANCE Among overweight or obese adults, orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, and liraglutide, compared with placebo, were each associated with achieving at least 5% weight loss at 52 weeks. Phentermine-topiramate and liraglutide were associated with the highest odds of achieving at least 5% weight loss.

Inflammation and arterial stiffness in humans

Arterial stiffness is an established marker of cardiovascular morbidity and mortality and a potential therapeutic target. While hypertension and aging are established factors contributing to arterial stiffness, the role of inflammation in stiffening of the arteries is less well understood. We summarize existing literature regarding inflammation and arterial stiffness, including a discussion of the potential mechanisms by which inflammation may lead to arterial stiffening and studies assessing: (1) The association between subclinical inflammation and arterial stiffness in the general population; (2) The presence of increased arterial stiffness in primary inflammatory diseases; (3) The effect of anti-inflammatory therapy on arterial stiffness in primary inflammatory disease including the effect of statins; (4) Experimental evidence of immunization-induced arterial stiffening in normal adults. We discuss potential opportunities to assess the impact of anti-inflammatory interventions on arterial stiffness in subjects without primary inflammatory conditions. We also review the effect of inflammation on wave reflections.

Comparative effectiveness of pharmacological interventions for nonalcoholic steatohepatitis: A systematic review and network meta‐analysis

We performed a Bayesian network meta‐analysis combining direct and indirect treatment comparisons to assess the comparative effectiveness of pharmacological agents for the treatment of nonalcoholic steatohepatitis (NASH). Through systematic literature review, we identified nine randomized, controlled trials (RCTs) including 964 patients with biopsy‐proven NASH, comparing vitamin E, thiazolidinediones (TZDs), pentoxifylline, or obeticholic acid to one another or placebo. The primary outcome was improvement in fibrosis stage; secondary outcomes were improvement in ballooning degeneration, lobular inflammation, and steatosis. We reported relative risks (RRs) and 95% confidence intervals (CIs) from direct meta‐analysis and 95% credible intervals (CrIs) from Bayesian network meta‐analysis, and used Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria to appraise quality of evidence. Moderate‐quality evidence supports the use of pentoxifylline (RR, 0.26; 95% CrI: 0.05‐1.00) and obeticholic acid (RR, 0.81; 95% CI: 0.70‐0.95) over placebo in improving fibrosis. High‐quality evidence supports the effect of vitamin E, TZDs, and obeticholic acid over placebo in improving ballooning degeneration. All four interventions seemed to have at least moderate‐quality evidence over placebo to improve steatosis. Moderate‐quality evidence supports that TZDs, pentoxifylline, and obeticholic acid decrease lobular inflammation. All the head‐to‐head comparisons were supported by very‐low‐quality evidence except for superiority of TZDs over vitamin E on improving steatosis and lobular inflammation, which had moderate‐quality evidence. Conclusions: Based on direct and network meta‐analysis, pentoxifylline and obeticholic acid improve fibrosis, and vitamin E, TZDs, and obeticholic acid improve ballooning degeneration in patients with NASH. Future comparative trials of combination therapies targeting distinct histological features are warranted. (Hepatology 2015;62:1417–1432)

Trends in the Use of Percutaneous Ventricular Assist Devices: Analysis of National Inpatient Sample Data, 2007 Through 2012

IMPORTANCE Percutaneous ventricular assist devices (PVADs) provide robust hemodynamic support compared with intra-aortic balloon pumps (IABPs), but clinical use patterns are unknown. OBJECTIVE To examine contemporary patterns in PVAD use in the United States and compare them with use of IABPs. DESIGN, SETTING, AND PARTICIPANTS Retrospective study of adults older than 18 years who received a PVAD or IABP while hospitalized in the United States (2007-2012). MAIN OUTCOMES AND MEASURES Temporal trends in utilization, patient and hospital characteristics, in-hospital mortality, and cost of PVAD use compared with IABP. RESULTS During 2007 through 2012, utilization of PVADs increased 30-fold (4.6 per million discharges in 2007 to 138 per million discharges in 2012; P for trend < .001) while utilization of IABPs decreased from 1738 per million discharges in 2008 to 1608 per million discharges in 2012 (P for trend = .02). In 2007, an estimated 72 hospitals used PVADs, increasing to 477 in 2011 (P for trend < .001). The number of hospitals with an annual volume of 10 or more PVAD procedures per year increased from 0 in 2007 to 102 in 2011 (21.4% of PVAD-using hospitals; P for trend < .001). Among PVAD recipients, 67.3% had a diagnosis of cardiogenic shock or acute myocardial infarction (AMI). There was a temporal increase in the use of PVADs in older patients and patients with AMI, hypertension, diabetes mellitus, and chronic kidney disease (P for trend < .001 for all). Overall, mortality in PVAD recipients was 28.8%, and mean (SE) hospitalization cost was

Gender differences in the utilisation of surgery for congenital heart disease in India

85,580 (

Adherence to Methodological Standards in Research Using the National Inpatient Sample

4165); both were significantly higher in PVAD recipients with cardiogenic shock (mortality, 47.5%; mean [SE] cost,

With Great Power Comes Great Responsibility: Big Data Research From the National Inpatient Sample

113,695 [

Trends in hospitalization for takotsubo cardiomyopathy in the United States.

6260]; P < .001 for both). The PVAD recipients were less likely than IABP recipients to have cardiogenic shock (34.3% vs 41.2%; P = .001), AMI (48.0% vs 68.6%; P < .001), and undergo coronary artery bypass graft surgery (6.2% vs 43.2%; P < .001), but more likely to undergo percutaneous coronary intervention (70.9% vs 40.4%; P < .001). In propensity-matched analysis, PVADs were associated with higher mortality compared with IABP (odds ratio, 1.23 [95% CI, 1.06-1.43]; P = .007). CONCLUSIONS AND RELEVANCE There has been a substantial increase in the use of PVADs in recent years with an accompanying decrease in the use of IABPs. Given the high mortality, associated cost, and uncertain evidence for a clear benefit, randomized clinical trials are needed to determine whether use of PVADs leads to improved patient outcomes.

Updated Cost-effectiveness Assessments of PCSK9 Inhibitors From the Perspectives of the Health System and Private Payers: Insights Derived From the FOURIER Trial

Background Corrective surgery for congenital heart disease may be life-saving, but its utilisation depends upon several social and economic factors. Girls with cardiac defects may not receive equitable care in India, but this has not been systematically studied. Methods In this prospective study, parents or guardians of 405 consecutive children aged up to 12 years (mean±SD age 3.43±3.44 years; 271 boys) who had been advised to undergo elective paediatric cardiac surgery were interviewed using a validated questionnaire. The status of the patients was reviewed after a year and the factors associated with non-compliance with treatment were analysed. In a qualitative sub-study the parents of 20 children who had not undergone surgery were interviewed. Qualitative data were analysed using an inductive analytical approach. Results Of the 405 patients studied, 44% (59/134) of girls had undergone surgery at 1 year compared with 70% (189/271) of boys (χ2=24.97; p<0.001). Independent predictors for non-compliance with surgery included female gender (OR 3.46, 95% CI −2.06 to 5.80; p<0.0001), lower socioeconomic classes (lower-middle: OR 18.62, 95% CI −2.14 to 161.8, p=0.008; upper-lower: OR 34.27, 95% CI −3.72 to 316.0, p=0.002) and higher cost of surgery (OR 1.92, 95% CI −1.06 to 3.47, p=0.03). In the in-depth interviews, apprehensions about future matrimonial prospects of girls and lack of social support emerged as the major factors responsible for delays in undergoing surgery. Conclusions Female gender is an important determinant of non-compliance with paediatric cardiac surgery. Deep-seated social factors underlie this gender bias.