Treatment Failures of Direct Oral Anticoagulants Background: Use of direct oral anticoagulants (DOACs) has increased over the years, because they have become a safe and effective alternative to the Vitamin-K antagonists in various clinical scenarios. With their increased use, reports have emerged describing their failure. Study Question: What are the patient characteristics and clinical settings in which DOAC treatment failure manifests? Data Sources: We searched published reports in Google Scholar, PubMed, MEDLINE, and Embase from the introduction of DOACs in any therapy until March 2019. Study Design: Information on patient characteristics, comorbidities, primary anticoagulation indications, pharmacologic treatment, and outcomes were collected. Primary endpoints were new thrombus formation, failure of resolution of an existing thrombus, or discovery of subtherapeutic drug level. Other endpoints were time to treatment failure, manifestations of treatment failure, and new treatment after DOAC failure. Results: Our search yielded 51 manuscripts, describing 79 patients who exhibited DOAC failure. The most common treatment failures were in patients with antiphospholipid syndrome (44.3%), atrial fibrillation (30.4%), and deep venous thrombosis (6.3%). There was a trend toward higher failure rate for rivaroxaban (65.8%) followed by dabigatran (27.8%), apixaban (7.6%), and then edoxaban (1.3%). Each agent had different median failure times. Most common manifestations of treatment failure were stroke/transient ischemic attack (20.3%), pulmonary embolism (19.0%), and deep venous thrombosis (19.0%). More than half of patients were transitioned to a Vitamin-K antagonist after DOAC failure (55.7%). Conclusions: Our analysis illustrates that DOACs may fail in the setting of Food and Drug Administration and non–Food and Drug Administration- approved indications. In clinical practice, it may be best to choose between available anticoagulant drugs on a case-by-case basis. Address for correspondence: Detroit Medical Center, Department of Internal Medicine, Wayne State University School of Medicine, University Health Center, 4201 St. Antoine St, Suite 2E, Detroit, MI 48201. E-mail: mkajy@med.wayne.edu The authors have no conflicts of interest to declare. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.americantherapeutics.com). M. Kajy, A. Mathew and P. Ramappa contributed significantly to the project. All 3 authors were involved in different aspects of data collection, data analysis and manuscript writing. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Pancreatic Extracts for the Treatment of Diabetes (1889–1914): Acomatol Background: Historical review on the early development of organotherapy for diabetes [pancreatic extracts (PE)] and its relationship with the social and political circumstances. Areas of Uncertainty: The diagnosis of diabetes relied only in the presence of glycosuria and cardinal symptoms. Blood glucose determinations were not regularly available, requiring large volumes for sampling. Micromethods for glycemia were developed just in the last years of the investigated period. Hypoglycemia remains undiscovered. Isolation and purification of PE were difficult tasks due to the unknown chemical structure of the antidiabetic hormone. Data Sources: (1) Berliner Medizinhistoriches Museum der Charité (Humboldt University). (2) GeDenKort Charité-Wissenschaft in Verantwortung. (3) Geheim Staatsarchiv Preuβischer Kulturbesitz. (4) Archival Collections, University of Toronto: Thomas Fisher Rare Book Library. Academy of Medicine Collection, F. G. Banting Papers, C. H. Best Papers, J. J. R. Macleod Papers. (5) National Library of Medicine: Pubmed search for the topic of history of insulin. History of Medicine-on syllabus archive. (6) Selected books: The Discovery of Insulin (M. Bliss); Diabetes, Its Medical and Cultural History (D. von Engelhardt); Brown-Séquard (M. J. Aminoff); Diabetes: The Biography (R. Tattersall); The Endocrine Organs (E. Schäfer); The Internal Secretions (E. Gley); Health, race and German politics between national unification and Nazism, 1870–1945 (P. Weindling). Therapeutic Advances: Demonstration that diabetes is a pancreatic disease. The outstanding progress of medical physiology led to the birth of endocrinology and the key concepts of homeostasis. Experimental scientists designed new procedures for complete pancreatectomy and elaboration of PE containing the antidiabetic principle. Organotherapy achieved complete success in the treatment of myxedema and partial success in the treatment of experimental and clinical diabetes. Conclusions: The organotherapy of diabetes was an obliged step to facilitate the identification of the antidiabetic hormone. Organotherapy of diabetes was a paradigm for the integration of basic and applied knowledge about hormone action and development of endocrine pharmacology. Address for correspondence: Fundación DIABEM, c/Cartagena 245; 1°-5a, Barcelona 08025, Spain. E-mail: aleiva@fdiabem.org The authors have no conflicts of interest to declare. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

High-Dose Ketamine Infusion for Neuropathic Pain in Critical Care Settings No abstract available

Insulin Therapy in Type 2 Diabetes Background: Since the discovery of insulin, it was the only drug available for the treatment of diabetes until the development of sulfonylureas and biguanides 50 years later. But even with the availability of oral glucose-lowering drugs, insulin supplementation was often needed to achieve good glucose control in type 2 diabetes. Insulin NPH became the basal insulin therapy of choice and adding NPH to metformin and/or sulfonylureas became the standard of care until basal insulin analogs were developed and new glucose-lowering drugs became available. Areas of Uncertainty: The advantages in cost-benefit of insulin analogs and their combination with new glucose-lowering drugs are still a matter of debate. There is no general agreement on how to avoid inertia by prescribing insulin therapy in type 2 diabetes when really needed, as reflected by the diversity of recommendations in the current clinical practice guidelines. Data Sources: When necessary for this review, a systematic search of the evidence was done in PubMed and Cochrane databases. Therapeutic Advances: Adding new oral glucose-lowering drugs to insulin such as DPP-4 inhibitors lead to a modest HbA1c reduction without weight gain and no increase in hypoglycemia. When SGLT-2 inhibitors are added instead, there is a slightly higher HbA1c reduction, but with body weight and blood pressure reduction. The downside is the increase in genital tract infections. GLP-1 receptor agonists have become the best alternative when basal insulin fails, particularly using fixed ratio combinations. Rapid-acting insulins via the inhaled route may also become an alternative for insulin supplementation and/or intensification. “Smart insulins” are under investigation and may become available for clinical use in the near future. Conclusions: Aggressive weight loss strategies together with the new glucose-lowering drugs which do not cause hypoglycemia nor weight gain should limit the number of patients with type 2 diabetes needing insulin. Nevertheless, because of therapeutic inertia and the progressive nature of the disease, many need at least a basal insulin supplementation and insulin analogs are the best choice as they become more affordable. Fixed ratio combinations with GLP1 receptor agonists are a good choice for intensification of insulin therapy. Address for correspondence: Pontificia Universidad Javeriana, Avenida 15 No. 124-47 Of. 409, Bogotá, Colombia. E-mail: pabloaschner@gmail.com P. Aschner has served on advisory boards for AstraZeneca, Boehringer Ingelheim, Janssen, MSD, Novartis, and Sanofi and on the speaker bureau for AstraZeneca, Lilly, Boehringer Ingelheim, MSD, Novartis, Novo and Sanofi. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Role of Potassium-Sparing Diuretics in the Management of Hypokalemia in Peritoneal Dialysis Background: Patients with kidney disease are at a higher risk of experiencing potassium imbalance. The kidney plays an important role in maintaining potassium homeostasis. A common dyskalemia that peritoneal dialysis (PD) patients experience is hypokalemia. Areas of Uncertainty: Potassium-sparing diuretics such as spironolactone causes increased amounts of sodium and water to be excreted, while potassium is retained. Owing to its potassium-sparing effects, it may correct hypokalemia that PD patients experience. The proper usage of potassium-sparing diuretics in PD patients and data on the efficacy and safety are being explored. Data Sources: Four relevant trials were identified. One randomized double-blind placebo-controlled cross-over study (n = 20), one interventional study without the control group (n = 20), one retrospective single-center chart review (n = 53), and one cross-sectional review (n = 75) trial. The randomized controlled trial did not note a statistically significant change in K levels (P > 0.05); the other 3 trials observed an increase in potassium levels in the potassium-sparing diuretics groups, but trials contained small participants and inadequate statistic rigor. Therapeutic Opinions: The role of potassium-sparing diuretics use for hypokalemia management in PD patients remains unclear. Address for correspondence: Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University (LIU Pharmacy), 75 DeKalb Avenue, Brooklyn, NY 11201-5497. E-mail: timothy.nguyen@liu.edu The authors have no conflicts of interest to declare. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Skin Necrosis Caused by Levamisole-Adulterated Cocaine No abstract available

Ultrasound-Guided Erector Spinae Plane Block Reduces Perioperative Opioid Consumption in Lumbar Spinal Fusion No abstract available

Eltrombopag-Associated Acneiform Rash: A Case Report No abstract available

Automated Insulin Delivery: The Artificial Pancreas Technical Challenges Background: The automation of glucose control has been an important goal of diabetes treatment for many decades. The first artificial pancreas experiences were in-hospital, closely supervised, small-scale, and short-term studies that demonstrated their superiority over continuous subcutaneous insulin infusion therapy. At present, long-term outpatient studies are being conducted in free-living scenarios. Areas of Uncertainty: The integration of multiple devices increases patients' burden and the probability of technical risks. Control algorithms must be robust to manage disturbance variables, such as physical exercise, meal composition, stress, illness, and circadian variations in insulin sensitivity. Extra layers of safety could be achieved through remote supervision. Dual-hormone systems reduce the incidence and duration of hypoglycemia, but the availability of stable pumpable glucagon needs to be solved. Faster insulin analogues are expected to improve all types of artificial pancreas. Therapeutic Advances: Artificial pancreas safety and feasibility are being demonstrated in outpatient studies. Artificial pancreas use increases the time of sensor-measured glucose in near-normoglycemia and reduces the risk of hyperglycemia and hypoglycemia. The benefits are observed both in single- and dual-hormone algorithms and in full- or semi-closed loop control. A recent meta-analysis including 41 randomized controlled trials showed that artificial pancreas use achieves a reduction of time in hyperglycemia (2 hours less than control treatment) and in hypoglycemia (20 minutes less); mean levels of continuous glucose sensor fell by 8.6 mg/dL over 24 hours and by 14.6 mg/dL overnight. The OpenAPS community uses Do It Yourself artificial pancreas in the real world since 2013, and a recent retrospective cross-over study (n = 20) compared continuous glucose sensor readings before and after initiation: mean levels of blood glucose fell by 7.4 mg/dL over 24 hours and time in range increased from 75.8% to 82.2% (92 minutes more). Conclusions: The outpatient use of artificial pancreas is safe and improves glucose control in outpatients with type 1 diabetes compared with the use of any type of insulin-based treatment. The availability of open-source solutions and data sharing is needed to foster the development of new artificial pancreas approaches and to promote the wide use of Big Data tools for knowledge discovery, decision support, and personalization. Address for correspondence: ETSI Telecomunicación, Avda. Complutense 30, 28040 Madrid, Spain. E-mail: mariaelena.hernando@gbt.tfo.upm.es This work was partly supported by a research grant from the Spanish Ministry of Health cofunded by FEDER: FIT-CLOOP (FIS PI14/00109). The authors have no conflicts of interest to declare. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Is Insulin Therapy Safe? Background: After 98 years of insulin therapy, issues of safety remain of concern. Areas of Uncertainty: Uncertainty has been expressed variously in regard of arterial cell wall proliferation, promotion of proliferative retinopathy, promotion of tumor growth, and for pregnancy. Immunological issues have been little studied since the advent of highly purified insulins in the 1970s. A specific topic is whether hypoglycemia, severe or otherwise, might promote cardiac thrombotic or dysrhythmic events. Data Sources: A literature review in these areas is difficult because nearly all clinical trials with insulin refer to adverse events. However, the specific topics aforementioned allow for some informed literature searching supplemented by finger-searching of published articles, notably in connection with the insulin analogues. Therapeutic Understandings: Safety data for pregnancy are weak because of power problems, but there are no signals for added maternal or fetal risk. Clinical-outcome trials that assess insulin against other glucose-lowering therapies or with significantly different insulin preparations in different arms are few and are sometimes conducted at modest dosage but fail to suggest promotion of arterial disease. Concern over growth-promoting activity of insulin glargine turned out to be ill-founded when the circulating moiety after injection was noted to have a lower IGF-1:insulin activity than human insulin, and a direct study of retinopathy progression or meta-analysis of malignancy incidence failed to show signals of concern. It does seem that severe hypoglycemia can cause death in some people with type 1 diabetes, although the tissue mechanism is unknown, but reducing severe hypoglycemia in type 2 diabetes does not protect against arterial events. Both symptomatic and severe hypoglycemia can however be reduced by use of more recently marketed insulin analogues, and this improves tolerability if not safety. Conclusions: In conclusion, although insulin therapy clearly gives health benefits, the evidence for long-term harm is absent or weak. Address for correspondence: Professor, Institute for Cellular Medicine, The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom. E-mail: philip.home@newcastle.ac.uk The authors presented some of the materials discussed to the meeting of the EASD D&CVD Study Group, June 12, 2018, Herzliya, Israel. PDH or institutions with which he is associated have received funding for his advisory, research, or lecturing activities from the manufacturers of all the human insulins and insulin analogues discussed including Antriabio, Biocon, Eli Lilly, Hanmi, Novo Nordisk, and Sanofi. B. Itzhak has received funding for his advisory, research, or lecturing activities from Eli Lilly, NovoNordisk, and Sanofi, and manufacturers of noninsulin glucose-lowering medications. Both authors contributed to the literature identification, synthesis, and writing of this manuscript. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.