Hundred Years of Insulin Therapy: Purified Early Insulins Background: The discovery of insulin has changed dramatically the outcome of patients with type 1 diabetes, giving them the possibility to survive. This is of particular concern due to the fact that type 1 diabetes most frequently occurs in children who were destined to die in ketoacidosis coma. Areas of Uncertainty: From insulin discovery to the availability of human insulin and human insulin analogs to be used in diabetes therapy, a series of problems have arisen as the difficulty of insulin purifications, the animal insulin used by the first researches were in fact contaminated by proteins, fats, and other impurities, and the presence of side effects such as allergy, antibodies generation, and lipoatrophy. Data Source Literature: Data strictly related to the argument have been searched in Pub Med and used. Results: Starting from insulin discovery in 1921 to nowadays, significant efforts have been made by a series of researches to purify animal insulin, discover the molecular structure of human insulin, and develop methods to synthetize human insulin and then insulin analogs. Conclusions: The history of insulin discovery here reported is fascinating; insulin is a hormone, a product of biotechnology, a field of research that saved and save the life of many diabetic patients. Address for correspondence: E-mail: annunziata.lapolla@unipd.it The authors have no conflicts of interest to declare. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Examining the Causes and Consequences of Increasing Insulin Costs With Prospective Interventions No abstract available

Paliperidone-Associated Priapism in an Autistic Child No abstract available

Cefepime-Associated Myoclonic Seizures No abstract available

Angioedema in an Immunocompromised Patient No abstract available

Insulin Therapy and Diabetic Pregnancy Background: A good metabolic control before conception and throughout pregnancy with diabetes decreases the risk of short- and long-term adverse outcomes of the mothers and their offsprings. Insulin treatment remains the gold standard treatment recommended for any type of diabetes. New technologies including new insulins and insulin analogues, continuous subcutaneous insulin infusion without and with sensors, the low-glucose predictive suspension function, and closed-loop systems that persistently and automatically self-adjust according to patients' continuous glucose monitoring readings have expanded the offer to clinicians for achieving tight glucose control. Areas of Uncertainty: Unsafe effects of insulin and insulin analogues in pregnancy with diabetes could be linked with changes in insulin immunogenicity, teratogenicity, and mitogenicity. Second-generation insulin analogues need to be tested and proven. Effectiveness and safety of new insulin delivery systems in real life of diabetic women in pregnancy need further confirmations. Sources: MEDLINE, EMBASE, Web of Science, Cochrane Library, randomized controlled trials, systematic review and meta-analysis, observational prospective and retrospective studies, case series reports for the most recent insulin analogues, published in English impacted journals, and consensus statements from scientific societies I excluded 60 from 221 papers as not suitable for the purpose of the subject. Results: Subcutaneous insulin infusion can be safely used during pregnancy and delivery of well-trained women. Sensors are increasingly accurate tools that improve the efficacy and safety of integrated systems' functioning. Continuous glucose monitoring provides metrics (“time in range” time in “hypoglycemia” and in “hyperglycemia,” glucose variability, average glucose levels in different time intervals) used as a guide to diabetes management; these new metrics are object of discussion in special populations. Randomized controlled trials have shown that sensor-augmented pump therapy improves pregnancy outcomes in women with type 1 diabetes. Closed-loop insulin delivery provides better glycemic control than sensor-augmented pump therapy during pregnancy, before, and after delivery. Conclusion: Second-generation insulin analogues and newer insulin infusion systems that automatically self-adjust according to patients continuous glucose monitor readings are important tools improving the treatment and quality of life of these women. Multi-institutional and disciplinary teams are working to develop and evaluate a pregnancy-specific artificial pancreas. Address for correspondence: Professor of Endocrinology, Department of Clinical and Molecular Medicine, Faculty of Medicine and Psycology, “Sapienza” University of Rome, via di Grottarossa, 1035, CAP 00189, Rome, Italy. E-mail: angela.napoli@uniroma1.it Grant from Medtronic to “Clinical and Molecular Department” of “Sapienza” University, Rome. The author has no conflicts of interest to declare. Clinical Trials Identifier: NCT03761615. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Palliative Care in Heart Failure: A Public Health Emergency Background: Palliative care (PC) is the holistic care of patients with life-limiting illnesses focused on relief of suffering and maximizing quality of life for patients and their families. Patients with heart failure (HF) are the largest group eligible for PC services, but only a small percentage of them receive PC. Areas of Uncertainty: The optimal content and method of delivery of PC interventions to HF patients in resource-limited countries remain unknown. The integration of PC into existing HF disease management continues to be a challenge. Data Sources: PUBMED was searched to identify articles on the topic published in the last 5 years (2014–April 2019). One hundred thirty-six articles were identified—14 articles out of were included in the revision. Therapeutic Advances: Research concerning PC in HF is still scarce and comes predominantly from developed countries. PC in HF improves patients' and caregivers' outcomes in terms of dyspnea, sleep, depression, communication, coping, and care-giving burden. Specialized home-based PC services have a positive impact on patients' physical and emotional wellbeing while decreasing utilization of medical services. Fatigue, dyspnea, and pain are frequent symptoms. Evidence concerning use of opioids for dyspnea is increasing. Family caregivers offer a considerable amount of care during the disease trajectory. There is often incongruence between the carer's and the patient's wishes in terms of treatment decisions and preferences. Carers should be assessed for risk and supported in their roles in care management and care coordination. Conclusions: Because of the unpredictability of the disease and difficulty in prognostication, PC should be introduced at the point of diagnosis of HF. Basic education in PC needs to be introduced early in the training of cardiology staff, focused on concept definition, differencing PC and terminal care, symptom management, communication, and decision-making. Address correspondence to: Transilvania University of Brasov, Faculty of Medicine, Nicolae Balcescu Street no 56, Brasov, Romania. E-mail: r_liliana@yahoo.com The authors have no conflicts of interest to declare. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Low Response to Clopidogrel in Coronary Artery Disease Background: In patients with coronary artery disease, cardiovascular mortality and other acute events showed a clear correlation with risk factors and biomarkers including platelet activation. Study Question of This Research: Which was the incidence of low response to clopidogrel and its correlation with risk factors and biomarkers in coronary artery disease? Study Design: Four hundred patients (pts) with coronary artery disease—stable angina (SA) and acute coronary syndrome—were divided into 8 groups of study, consistent with low response to clopidogrel and the type of coronary artery disease. Low response to clopidogrel—defined as adenosine diphosphate test—ADP-test of >46 U by multiple electrode platelet aggregometry was evaluated in correlation with cardiovascular risk factors and biomarkers of oxidative stress, endothelial dysfunction, hypercoagulability, high platelet reactivity. Results: In coronary artery disease, low response to clopidogrel significantly correlated with older than 65 years, smoking, hypertension, diabetes mellitus, body mass index of >25, previous aspirin treatment (P < 0.05), high value of total and low-density lipoprotein cholesterol, low value of high-density lipoprotein cholesterol, low response to aspirin, high mean platelets volume and von Willebrand factor activity, low flow-mediated vasodilatation, total antioxidant status (P < 0.01) and only in patients with SA of male gender (P < 0.01). The incidence of other hypercoagulability biomarkers, such as reduced values of S protein, C protein, antithrombin III, and V Factor Leiden resistance to activated protein C, was very low and not correlated with low response to clopidogrel. Conclusions: In coronary artery disease, low response to clopidogrel significantly correlated with the most of old cardiovascular risk factors, with previous aspirin treatment, low response to aspirin, higher mean platelets volume, higher von Willebrand factor activity, lower flow-mediated vasodilatation, and lower total antioxidant status values and only in patients with SA of male gender. Address for correspondence: Faculty of Medicine, “Transilvania” University Brasov, Str. Nicolae Balcescu Nr. 56, Brasov 500019, Romania. E-mail: alexandru.covaciu92@gmail.com The authors have no conflicts of interest to declare. Elaboration of the research design and protocol: E. Bobescu and L. G. Marceanu; acquisition of data: A. Covaciu and H. Rus; analysis and interpretation of the data: E. Bobescu and L. G. Marceanu; writing of the manuscript: E. Bobescu, A. Covaciu, and L. G. Marceanu; critical revision of the manuscript for intellectual content: L. M. Rogozea and M. Badea. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Granuloma Annulare Induced by Pregabalin No abstract available

Transcatheter Versus Surgical Aortic Valve Replacement in Rheumatic Aortic Valve Disease—A Nationwide Analysis No abstract available