Research Spotlight

Posted December 15th 2017

A Panel of Methylated MicroRNA Biomarkers for Identifying High-Risk Patients With Ulcerative Colitis-Associated Colorectal Cancer.

Ajay Goel Ph.D.

Ajay Goel Ph.D.

Toiyama, Y., Y. Okugawa, K. Tanaka, T. Araki, K. Uchida, A. Hishida, M. Uchino, H. Ikeuchi, S. Hirota, M. Kusunoki, C. R. Boland and A. Goel (2017). “A panel of methylated microrna biomarkers for identifying high-risk patients with ulcerative colitis-associated colorectal cancer.” Gastroenterology 153(6): 1634-1646.e1638.

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BACKGROUND & AIMS: Methylation of specific microRNAs (miRNAs) often occurs in an age-dependent manner, as a field defect in some instances, and may be an early event in colitis-associated carcinogenesis. We aimed to determine whether specific mRNA signature patterns (MIR1, MIR9, MIR124, MIR137, MIR34B/C) could be used to identify patients with ulcerative colitis (UC) who are at increased risk for colorectal neoplasia. CONCLUSIONS: In evaluation and validation cohorts, we found specific miRNAs to be methylated in rectal mucosal samples from patients with UC with dysplasia or CRC compared with patients without neoplasms. This pattern also associated with patient age and might be used to identify patients with UC at greatest risk for developing UC-CRC. Our findings provide evidence for a field defect in rectal mucosa from patients with UC-CRC.


Posted December 15th 2017

Outcomes With Transcatheter Mitral Valve Repair in the United States: An STS/ACC TVT Registry Report.

Michael J. Mack M.D.

Michael J. Mack M.D.

Sorajja, P., S. Vemulapalli, T. Feldman, M. Mack, D. R. Holmes, Jr., A. Stebbins, S. Kar, V. Thourani and G. Ailawadi (2017). “Outcomes with transcatheter mitral valve repair in the united states: An sts/acc tvt registry report.” J Am Coll Cardiol 70(19): 2315-2327.

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BACKGROUND: Post-market surveillance is needed to evaluate the real-world clinical effectiveness and safety of U.S. Food and Drug Administration-approved devices. OBJECTIVES: The authors examined the commercial experience with transcatheter mitral valve repair for the treatment of mitral regurgitation. METHODS: Data from the Society of Thoracic Surgery/American College of Cardiology Transcatheter Valve Therapy Registry on patients commercially treated with transcatheter mitral valve repair were analyzed. The study population consisted of 2,952 patients treated at 145 hospitals between November 2013 and September 2015. In 1,867 patients, data were linked to patient-specific Centers for Medicare and Medicaid Services administrative claims for analyses. RESULTS: The median age was 82 years (55.8% men), with a median Society of Thoracic Surgery predicted risk of mortality of 6.1% (interquartile range: 3.7% to 9.9%) and 9.2% (interquartile range: 6.0% to 14.1%) for mitral repair and replacement, respectively. Overall, in-hospital mortality was 2.7%. Acute procedure success occurred in 91.8%. Among the patients with Centers for Medicare and Medicaid Services linkage data, the mortality at 30 days and at 1 year was 5.2% and 25.8%, respectively, and repeat hospitalization for heart failure at 1 year occurred in 20.2%. Variables associated with mortality or rehospitalization for heart failure after multivariate adjustment were increasing age, lower baseline left ventricular ejection fraction, worse post-procedural mitral regurgitation, moderate or severe lung disease, dialysis, and severe tricuspid regurgitation. CONCLUSIONS: Our findings demonstrate that commercial transcatheter mitral valve repair is being performed in the United States with acute effectiveness and safety. Our findings may help determine which patients have favorable long-term outcomes with this therapy.


Posted December 15th 2017

The kidney allocation system claims equity: It is time to review utility and fairness.

Göran Klintmalm M.D.

Göran Klintmalm M.D.

Klintmalm, G. B. and B. Kaplan (2017). “The kidney allocation system claims equity: It is time to review utility and fairness.” Am J Transplant 17(12): 2999-3000.

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The current kidney allocation system (KAS) implemented by the United Network for Organ Sharing in December 2014 was intended to balance inequities in kidney allocation while increasing utility by trans‐planting kidneys expected to last the longest in patients expected to live the longest. In its first iteration, termed Life Years from Transplant (LYFT), a fairly simple system of allocation was proposed to allocate kidneys based on this principle. LYFT, as opposed to our current pro‐cess, also addressed the need to have a codified system to allocate kidneys unsuitable for younger patients to older recipients, such that utility could be maximized across the spectrum of potential recipients. Due to political pressures, LYFT was not instituted and our current KAS was implemented as a compromise solution.1 As with many compromise solutions, much of the original clarity of mission was lost. This lack of clarity has led to a system that, in our opinion, has not achieved true equity; in addition, it has decreased utility and lacks fairness.


Posted December 15th 2017

On the antibacterial and sterilizing effect of benzylpenicillin in tuberculosis.

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Deshpande, D., S. Srivastava, P. Bendet, K. R. Martin, K. N. Cirrincione, P. S. Lee, J. G. Pasipanodya, K. Dheda and T. Gumbo (2017). “On the antibacterial and sterilizing effect of benzylpenicillin in tuberculosis.” Antimicrob Agents Chemother: 2017 Nov [Epub ahead of print].

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The modern chemotherapy era started with Fleming’s discovery of benzylpenicillin. He demonstrated that benzylpenicillin did not kill Mycobacterium tuberculosis (Mtb) Here, we found that >64 mg/L of static benzylpenicillin concentrations killed 1.16-1.43 log10 CFU/mL below starting inoculum of extracellular and intracellular Mtb over 7 days. When we added the beta-lactamase-inhibitor avibactam, benzylpenicillin maximal kill (Emax) of either extracellular log-phase growth Mtb was 6.80+/-0.45 log10 CFU/mL at an EC50 of 15.11+/-5.2.32 mg/L, while for intracellular Mtb was 2.42+/-0.14 log10 CFU/mL at an EC50 of 6.70+/-0.56 mg/L. The median penicillin (plus avibactam) MIC against South African clinical Mtb strains (80% either multi- or extensively drug-resistant) was 2 mg/L. We mimicked human-like benzylpenicillin and avibactam concentration-time profiles in the hollow fiber model of tuberculosis (HFS-TB). The percentage time above MIC was linked to effect, with an optimal exposure of >/=65%. At optimal exposure in the HFS-TB, the bactericidal activity in log-phase growth Mtb was 1.44 log10 CFU/mL/day, while 3.28 log10 CFU/mL of intracellular Mtb was killed over 3 weeks. In an 8 week HFS-TB study of non-replicating persistent Mtb, penicillin-avibactam alone versus the drug combination of isoniazid, rifampin, and pyrazinamide, both killed >7.0 log10 CFU/mL. Monte Carlo simulations of 10,000 pre-term infants with disseminated disease identified an optimal dose of 10,000 U/kg/hr, while for pregnant women or non-pregnant adults with pulmonary tuberculosis optima dose was 25,000 U/kg/hr, by continuous intravenous infusion. Penicillin-avibactam should be examined for effect in pregnant women and infants with drug-resistant tuberculosis, to replace injectable ototoxic and teratogenic second-line drugs.


Posted December 15th 2017

The impact of biologic agents on health-related quality of life outcomes in patients with psoriasis.

Alan M. Menter M.D.

Alan M. Menter M.D.

Frieder, J., D. Kivelevitch, C. T. Fiore, S. Saad and A. Menter (2017). “The impact of biologic agents on health-related quality of life outcomes in patients with psoriasis.” Expert Rev Clin Immunol: 1-19.

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INTRODUCTION: Psoriasis is a common, immune-mediated skin disease often associated with significant physical and psychosocial impairment. Antipsoriatic biologic agents offer patients unparalleled treatment potential in regard to greater skin clearance and overall improved quality of life. Evaluation of the therapeutic efficacy of biologic agents on the full psoriasis disease burden must account for their impact on both physical symptoms, as well as patient-reported, health-related quality of life (HRQoL) measurements. Areas covered: Results from numerous clinical trials demonstrate the significant clinical efficacy of biological agents targeting tumor necrosis factor-alpha (TNF-alpha) and the interleukin (IL)-12/23 and IL-17 immune pathways. However, relatively limited data is available evaluating their full effect on quality of life outcomes. This review will discuss the most relevant and up-to-date clinical data on HRQoL measurements related to treatment with these aforementioned biologic agents. Expert commentary: Patient-reported outcomes (i.e. Dermatology Life Quality Index) are being used with increasing frequency in clinical trials, and provide valuable information on the impact of psoriasis on numerous aspects of day-to-day living. These outcomes must also be incorporated in clinical practice, in addition to physical assessment of disease severity, treatment decisions, and therapeutic response in the psoriasis patient population.