Diagnosis and Management of Adrenal Insufficiency in Hospitalized Patients Background: Plasma cortisol is commonly obtained in hospitalized hypotensive patients, and adrenocorticotropic hormone (ACTH) challenge is typically conducted to further workup hypocortisolemia. It is important to recognize that relative adrenal insufficiency (AI) is the most common cause of low cortisol levels and failed ACTH challenge in ill patients. Both cortisol and synthetic ACTH challenge assays are unreliable in critically ill patients. In clinical practice, corticosteroid therapy in septic shock patients results in immediate hemodynamic benefits with less vasopressor and ventilator dependence. Areas of Uncertainty: There is no consensus about the diagnostic criteria of relative AI, appropriate cortisol level, and the dose used for synthetic ACTH challenge in patients with septic shock. There is controversy about the mortality benefits of supplemental steroid therapy and about the use of adjunctive fludrocortisone. Data Sources: PubMed search of randomized control trials and meta-analyses. Therapeutic Opinion: Despite all the controversies, hospital physicians frequently use steroids in patients with septic shock with hypocortisolemia. Hydrocortisone should be the choice of steroid for most relative AI patients, and fludrocortisone can be added on a case-by-case basis in refractory shock. Most of the adverse effects induced by a short course of steroids are easily managed in the inpatient setting. Address for correspondence: Associate Professors of Medicine, Division of General Internal Medicine, UF Health Jacksonville, 653-1 West Eight St 3rd Floor, Faculty Clinic Jacksonville, FL 32209. E-mail; pramod.reddy@jax.ufl.edu The author has no conflicts of interest to declare. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Potential Association of Doxycycline With the Onset of Primary Sclerosing Cholangitis: A Case Series Background: Primary sclerosing cholangitis (PSC) is linked to inflammatory bowel diseases (IBD). Evidence suggests an association between the gut microbiome and PSC. However, the putative relationship between exposure to antibiotics and onset of PSC has never been reported. We observed 3 cases in which patients without antecedent liver or bowel issues developed symptoms leading to diagnosis of IBD and subsequently PSC after being exposed to doxycycline. We aimed to identify, through the PSC Partners national patient registry, additional cases of PSC in which there is a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD. Areas of Uncertainty: The etiopathogenesis of PSC remains an enigma. Data Sources: We collected data from patients with PSC and PSC-IBD in which there seemed to be a temporal relationship between exposure to doxycycline and PSC. Time from doxycycline exposure to: (1) onset of PSC or PSC-IBD symptoms and (2) diagnosis of PSC were documented for each patient. Descriptive statistical analyses were performed. Results: We identified 6 additional patients with PSC or PSC-IBD in whom there was a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD. The median age of these 9 patients was 20 years, 6 were female, and 7 had ulcerative colitis. The median time from doxycycline exposure to onset of first symptoms was 3 months, and median time from doxycycline exposure to diagnosis of PSC was 15 months. Therapeutic Hypothesis: We describe 9 cases of PSC and PSC-IBD in which there seem to be a temporal relationship between exposure to doxycycline and onset of PSC. Address for correspondence: Professor of Medicine, Senior Advisor to the University Provost, Professor of Medicine, Office of the University Provost, College of Health Solutions, Arizona State University, 502 E. Monroe St, Phoenix, AZ 85004. E-mail: keith.lindor@asu.edu The authors have no conflicts of interest to declare. K. D. Lindor, J. G. Buness, C. W. Buness, and A. H. Ali designed the study. A. H. Ali performed the statistics and calculations. K. D. Lindor, J. G. Buness, C. W. Buness, A. H. Ali, J. H. Tabibian, and K. L. Cox drafted and edited the manuscript. A. H. Ali created the table. J. G. Buness and A. H. Ali are cofirst authors. The Mayo Clinic IRB waived the requirement for IRB review of this study. Patients were not required to provide informed consent to the study because the analysis used anonymous clinical data that were obtained from each patient after their agreement to participate in this study. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Nitrofurantoin Induced Antineutrophil Cytoplasmic Antibodies–Associated Vasculitis No abstract available

Insulin Therapy: Future Perspectives Background: Insufficient insulin secretion is a core pathogenetic mechanism of diabetes mellitus and therefore, insulin therapy remains the cornerstone of management. Over the past 100 years, much progress has been made in the development of insulin therapy, including elaboration of novel insulin formulations and delivery methods. Areas of Uncertainty: Despite significant advances, there are still many barriers, challenges, and uncertainties involving insulin therapy. With newer pharmacological and technological approaches, there are many potential drawbacks to be addressed, such as immunogenicity, biocompatibility, degradation/clearance of delivery materials, stability, precision of dosing, reproducibility, predictability of performance, and safety over time, etc. In addition, the new formulations/delivery systems should be cost-effective and accessible. Data Sources: A literature search of original and review articles, editorials, and meta-analyses in Medline/PubMed and Google Scholar has been performed. ClinicalTrials.gov website was searched for ongoing relevant clinical trials. Therapeutic Advances: New insulin formulations (ultralong basal and ultrarapid analogues) were designed to obtain a prolonged, flatter profile, with less hypoglycemia and improvement of postprandial glucose control, respectively. The next generation of insulin therapy is probably best represented by the “smart” (glucose-responsive) insulins, which deliver it according to an endogenous glucose-sensing feedback mechanism. Another area of continuous advances includes insulin delivery systems with new jet injectors, smart pens, patch pumps, and other needle-free devices for subcutaneous administrations. Many alternative routes of insulin delivery (pulmonary, nasal, buccal, oral, and transdermal) have also been explored, with some reaching clinical use. The digitalization of diabetes care has made considerable progress in the past several years and will most probably make even more so in the near future. Conclusions: The improved insulin formulations, newer delivery methods/routes, and digital technologies are rapidly becoming effective and have great potential to improve metabolic control as well as other outcomes, including quality of life of persons living with diabetes mellitus. Address for correspondence: Department M3/Internal Medicine IV, University of Medicine, Pharmacy, Science and Technology of Târgu Mureş, 38 Gheorghe Marinescu Str, Târgu Mureş, Romania 540139. E-mail: simonacernea@yahoo.com S. Cernea discloses the following: Payment for lectures from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Sanofi, Novo Nordisk, Merck Sharp & Dohme, Berlin-Chemie Menarini, Servier Pharma and for Steering Committee meetings as National Lead Investigator for DECLARE-TIMI58 from TIMI Study Group. Consultant fees for Advisory Board from AstraZeneca. Support for travel to meetings from AstraZeneca, Eli Lilly, Sanofi, Boehringer Ingelheim, Merck Sharp & Dohme, Novo Nordisk, Worwag Pharma. I. Raz discloses the following: Advisory Board: AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk, Inc, Sano+ Consultant: AstraZeneca, Insuline Medical, Medial EarlySign Ltd, CamerEyes Ltd, Exscopia, Orgenesis Ltd, BOL, Glucome Ltd, DarioHealth, Diabot Speaker's Bureau: AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk, Inc., Sano+ Stock/Shareholder: Glucome Ltd, Orgenesis Ltd, DarioHealth, CamerEyes Ltd, Diabot, BOL. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Afatinib Achieved Remarkable Disease Control in a Chinese Patient With Lung Adenocarcinoma Harboring Rare EGFR Exon 18–25 Kinase Domain Duplication No abstract available

Methylphenidate for Comorbid Epilepsy and Attention-Deficit/Hyperactivity Disorder No abstract available

Add-on Milnacipran Boosts Methylphenidate Response in an Adolescent With Attention-Deficit/Hyperactivity Disorder With Comorbid Anxiety and Enuresis No abstract available

Dose-Dependent Escitalopram-Associated Ventricular Bigeminy No abstract available

Prevention and Management of Supine Hypertension in Patients With Orthostatic Hypotension Background: Orthostatic hypotension (OH) is a potentially debilitating condition caused by dysfunction of the autonomic nervous system, which is essential for the physiologic response to orthostatic posture. In addition to OH, autonomic dysfunction may also be associated with the development of concurrent supine hypertension (SH). Areas of Uncertainty: This paradoxical effect speaks to the complexity of the pathogenesis of autonomic disease and greatly complicates management of these patients. Clinicians are faced with a dilemma because aggressive treatment of orthostatic intolerance can worsen supine hypertension and attempts to control supine hypertension can worsen orthostatic intolerance. Data Sources: Systematic review of the published literature. Prevention of Supine Hypertension: Patients should aim to avoid known stressors, perform physical maneuvers (eg, slowly getting up from bed, sleeping with head of bed elevated), manage underlying related conditions (eg, diabetes mellitus), and exercise. Management of Supine Hypertension: With failure of conservative management, patients may advance to pharmacologic therapy. It is important to understand the underlying suspected etiology of the syndrome of supine hypertension and OH (SH-OH) to select promising pharmacologic agents. This article reviews medical treatment options to work toward achieving a better quality of life for patients afflicted with this disease. Although clonidine and beta-blockers can be used to treat hypertension without causing significant hypotension, midodrine, pyridostigmine, and droxidopa may be helpful in preventing OH. Conclusion: The etiology and severity of autonomic dysfunction vary widely between patients, suggesting a need for an individualized treatment approach. Achieving perfect blood pressure control is not a realistic goal. Rather, treatment should be aimed at improving the patient's quality of life and decreasing their risk of injury and organ damage. Address for correspondence: Clinical Assistant Professor of Medicine, Michigan State University, McLaren Greater Lansing Hospital, Lansing, MI 48910. E-mail: Khalilkanjwal@yahoo.com The authors have no conflicts of interest to declare. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Direct Oral Anticoagulants Versus Warfarin and Enoxaparin in Ovarian Vein Thrombosis No abstract available