Research Spotlight

Roberts, W. C. (2017). “Cholesterol is the cause of atherosclerosis.” Am J Cardiol 120(9): 1696.

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Although some investigators have considered cholesterol the cause of atherosclerosis for several decades,1–15 26 authors, mainly from Europe, in April 2017, published an article titled “Low-density lipoproteins cause atherosclerotic cardiovascular disease…,” a consensus statement from the European Atherosclerosis Society Consensus Panel.16 I was glad to see the article that soundly supports the view that cholesterol is the cause of atherosclerosis. Although I found the article unnecessarily difficult, the message is loud and clear. So when your physician recommends a statin drug or ezetimibe or one of the PCSK-9 inhibitors, take it. These drugs are safer than almost any drug one can put in his/her mouth.

Trotter, J. F. (2017). “Pro: Direct-acting agents are associated with occurrence and recurrence of hepatocellular carcinoma.” Liver Transpl: 2017 Oct [Epub ahead of print].

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The advent of direct-acting oral agents (DAA’s) for the treatment of hepatitis C (HCV) is perhaps the most important therapeutic development in the modern practice of hepatology. These drugs cure HCV, the most common indication for liver transplantation. Their efficacy approaches 100 %, requiring as little as 8 weeks of therapy without clinically relevant side effects. Consequently, HCV can be eradicated in almost any treated patient, even those with decompensation, albeit at a slightly lower rate. Clinicians have enthusiastically treated large numbers of infected patients including those with advanced fibrosis to ultimately prevent longterm complications including hepatocellular carcinoma (HCC) and hepatic decompensation either of which may lead to transplantation or death.

Tolia, V. N., K. Murthy, M. M. Bennett, E. S. Miller, D. K. Benjamin, P. B. Smith and R. H. Clark (2017). “Antenatal methadone vs buprenorphine exposure and length of hospital stay in infants admitted to the intensive care unit with neonatal abstinence syndrome.” J Perinatol: 2017 Oct [Epub ahead of print].

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OBJECTIVE: Antenatal exposure to methadone or buprenorphine often causes neonatal abstinence syndrome (NAS) in newborns. However, comparative effects on affected infants’ hospital courses are inconclusive. We sought to estimate the relationship of antenatal exposure with methadone or buprenorphine and infants’ length of stay among hospitalized infants with NAS. STUDY DESIGN: This was a retrospective cohort study of hospitalized infants with NAS with either maternal exposure. Eligible infants were singleton infants born 36 weeks’ gestation and diagnosed with NAS<7 days of age between 2011 and 2014 in the Pediatrix Clinical Data Warehouse. Infant with congenital anomalies and those of multiple gestation were excluded. RESULTS: Of 3364 eligible infants, 2202 (65%) were exposed to methadone and 1162 (34%) to buprenorphine. Infants exposed to buprenorphine had a lower rate of pharmacologic treatment for NAS (88 vs 91%, P<0.001). Median length of hospital stay was shorter among infants exposed to buprenorphine (21 days (inter-quartile range; 13-31) vs methadone (24 days (15-38), P<0.0001)). On multivariable Cox proportional hazard analyses, buprenorphine was associated with a shorter length of stay (hazard ratio (HR)=1.47 (95% confidence interval (CI): 1.32-1.62, P<0.001) after controlling for maternal age, parity, race or ethnicity, prenatal care, smoking status, use of antidepressants, use of benzodiazepines, and infant gestational age, small for gestational age status, cesarean delivery, sex, out born status, type of pharmacotherapy, breast milk use, year and center. We observed similar results in model using infants matched 1:1 with propensity scores for antenatal medication exposure (HR 1.39 for buprenorphine, CI 1.32-1.62, P<0.001). CONCLUSION: Among infants born 36 weeks' gestation with NAS, antenatal buprenorphine exposure was associated with a decreased length of stay relative to antenatal methadone exposure.

Testa, G., E. C. Koon, L. Johannesson, G. J. McKenna, T. Anthony, G. B. Klintmalm, R. T. Gunby, A. M. Warren, J. M. Putman, G. dePrisco, J. M. Mitchell, K. Wallis and M. Olausson (2017). “Living donor uterus transplantation: A single center’s observations and lessons learned from early setbacks to technical success.” Am J Transplant 17(11): 2901-2910.

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Uterus transplantation is a vascularized composite allograft transplantation. It allows women who do not have a uterus to become pregnant and deliver a baby. In this paper, we analyze the first five cases of living donor uterus transplantation performed in the United States. The first three recipients lost their uterus grafts at days 14, 12, and 6, respectively, after transplant. Vascular complications, related to both inflow and outflow problems, were identified as the primary reason for the graft losses. Two recipients, at 6 and 3 mo, respectively, after transplant, have functioning grafts with regular menstrual cycles. Ultimate success will be claimed only after a live birth. This paper is an in-depth analysis of evaluation, surgical technique, and follow-up of these five living donor uterus transplants. The lessons learned were instrumental in allowing us to evolve from failure to technical and functional success. We aim to share our conclusions and build on knowledge in the evolving field of uterus transplantation.

Packer, M. (2017). “Activation and inhibition of sodium-hydrogen exchanger is a mechanism that links the pathophysiology and treatment of diabetes mellitus with that of heart failure.” Circulation 136(16): 1548-1559.

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The mechanisms underlying the progression of diabetes mellitus and heart failure are closely intertwined, such that worsening of one condition is frequently accompanied by worsening of the other; the degree of clinical acceleration is marked when the 2 coexist. Activation of the sodium-hydrogen exchanger in the heart and vasculature (NHE1 isoform) and the kidneys (NHE3 isoform) may serve as a common mechanism that links both disorders and may underlie their interplay. Insulin insensitivity and adipokine abnormalities (the hallmarks of type 2 diabetes mellitus) are characteristic features of heart failure; conversely, neurohormonal systems activated in heart failure (norepinephrine, angiotensin II, aldosterone, and neprilysin) impair insulin sensitivity and contribute to microvascular disease in diabetes mellitus. Each of these neurohormonal derangements may act through increased activity of both NHE1 and NHE3. Drugs used to treat diabetes mellitus may favorably affect the pathophysiological mechanisms of heart failure by inhibiting either or both NHE isoforms, and drugs used to treat heart failure may have beneficial effects on glucose tolerance and the complications of diabetes mellitus by interfering with the actions of NHE1 and NHE3. The efficacy of NHE inhibitors on the risk of cardiovascular events may be enhanced when heart failure and glucose intolerance coexist and may be attenuated when drugs with NHE inhibitory actions are given concomitantly. Therefore, the sodium-hydrogen exchanger may play a central role in the interplay of diabetes mellitus and heart failure, contribute to the physiological and clinical progression of both diseases, and explain certain drug-drug and drug-disease interactions that have been reported in large-scale randomized clinical trials.