Prothrombin Complex Concentrates are Superior to Fresh Frozen Plasma for Emergency Reversal of Vitamin K Antagonists: A Meta-Analysis in 2606 Subjects Abstract Background Urgent reversal of vitamin K antagonists (VKAs) is required for major bleeding or urgent surgery by intravenous vitamin K with either prothrombin complex concentrates (PCCs) or fresh frozen plasma (FFP). However, there is lack of consensus regarding the superiority of either reversal agent. We sought to compare the performance of PCC and FFP in urgent reversal of VKA. Methods A meta-analysis was conducted up to November 2018. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random effects model. Results Seventeen studies comprising 2606 participants met the inclusion criteria. Compared with FFP treatment, PCC treatment led to a reduction in 90-day all-cause mortality (OR 0.60, 95% CI 0.40–0.90, p = 0.01), better reversal of INR (OR 7.36, 95% CI 4.18–12.98; p < 0.00001) and lower risk of at least one treatment-related adverse event (OR 0.45, 95% CI 0.26–0.80, p = 0.006). Among patients with VKA-associated intracranial haemorrhage, PCC treatment led to a reduction in 90-day all-cause mortality (OR 0.58, 95% CI 0.35–0.94, p = 0.03) and better reversal of INR (OR 6.52, 95% CI 1.66–25.59, p = 0.007). There were no differences between these two agents in thrombogenicity, requirement for and quantity of red blood cell transfusions, all adverse events, fluid overload or disability on discharge or at 90 days. Conclusions As an agent for urgent reversal of VKA, PCC outperforms FFP in 90-day all-cause mortality including those with VKA-related intracranial haemorrhage, INR reversal and treatment-related adverse events.

Current and Emerging Drug Therapies for Connective Tissue Disease-Interstitial Lung Disease (CTD-ILD) Abstract Interstitial lung disease (ILD) can be associated with all connective tissue diseases and is an important cause of morbidity and mortality. The management of connective tissue disease-interstitial lung disease (CTD-ILD) is challenging due substantial heterogeneity in disease behaviour and paucity of controlled clinical trials to guide treating clinicians. Not all patients require treatment, and the decision to treat needs to be individualised based on a patient’s observed disease behaviour, baseline and longitudinal lung function measurements, extent of lung involvement on radiology and patient factors including age, co-morbidities and personal preference. If indicated, treatment of the CTD-ILD is largely with immunomodulation, with the aim to prevent progression of the ILD before further irreversible lung injury and disability occurs. Corticosteroids, cyclophosphamide, mycophenolate mofetil and azathioprine are the most common immunosuppressive agents currently used to treat CTD-ILD, demonstrating stability of lung function in case series and a small number of randomised controlled trials in ILD associated with systemic sclerosis. Biological and non-biological disease-modifying anti-rheumatic drugs, and the anti-fibrotics nintedanib and pirfenidone, have revolutionised the treatment of connective tissue diseases and idiopathic ILD, respectively. Furthermore, anti-fibrotics have recently demonstrated safety and efficacy in ILD associated with systemic sclerosis. There remains a critical unmet need to clarify when and in whom to initiate treatment, and which agent(s) to utilise to achieve optimal outcomes for CTD-ILD patients whilst minimising harms through prospective multicentre trials. This review highlights the challenges faced when treating patients with CTD-ILD and summarises available evidence for current, emerging and novel therapies.

Correction to: Tiotropium/Olodaterol: A Review in COPD The article Tiotropium/Olodaterol: A Review in COPD, written by Hannah.

Correction to: Migalastat: A Review in Fabry Disease The article Migalastat: A Review in Fabry Disease, written by Emma H. McCafferty, Lesley J. Scott, was originally published Online First without open access. After publication in volume 79, issue 5, pages 543–554 [funder] requested that the article be Open Choice to make the article an open access publication. Post-publication open access was funded by [funder]. The article is forthwith distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

Targeting ROS1 Rearrangements in Non-small Cell Lung Cancer: Crizotinib and Newer Generation Tyrosine Kinase Inhibitors Abstract ROS1 gene rearrangements exist in 1–2% of non-small cell lung cancers, typically occurring in younger, never or light smokers with adenocarcinoma. ROS1 gene fusions are potent oncogenic drivers, the presence of which results in the susceptibility of tumours to ROS1-targeted therapy. Crizotinib was the first tyrosine kinase inhibitor to demonstrate activity in ROS1-rearranged lung cancer, and remains the recommended first-line therapy for patients with advanced ROS1-rearranged non-small cell lung cancer. Despite excellent initial responses to crizotinib, the majority of patients develop disease progression, which may be intracranial or extracranial. Identification of resistance mechanisms to crizotinib, and newer generation tyrosine kinase inhibitors with increased potency against ROS1 and ROS1-resistance mutations, and improved intracranial activity are under evaluation in clinical trials. In this review, we discuss ROS1 rearrangements in non-small cell lung cancer, and provide an update on targeting ROS1-rearranged non-small cell lung cancer with crizotinib and newer generation tyrosine kinase inhibitors.

Innovations in Oral Therapies for Inflammatory Bowel Disease Abstract Prior to the biologic era, the medical management of patients with inflammatory bowel disease (IBD) was dominated by the use of aminosalicylates, corticosteroids, and immunosuppressants. In the past two decades, the advent of biologic agents that target specific components of the immune response has greatly improved the care of patients with Crohn’s disease and ulcerative colitis (UC). However, not all patients respond or maintain response to biologic therapy and some patients develop adverse events that necessitate treatment discontinuation. Furthermore, sensitization with formation of anti-drug antibodies is an inherent limitation to administration of monoclonal antibodies. This circumstance has generated renewed interest in the development of novel oral small-molecule drugs (SMDs) that are effective and well tolerated. Several classes of SMDs are currently progressing through the pipeline and offer the promise of oral delivery and high potency. In this review, we summarize different mechanisms of oral drug delivery to the gastrointestinal tract, highlight key findings from phase II and III randomized trials of novel oral SMDs, and discuss how oral SMDs are likely to be integrated into future IBD treatment paradigms. The most advanced development programs currently involve evaluation of compounds blocking Janus kinase (JAK) receptors or modulating sphingosine-1-phosphate (S1P) receptors. Tofacitinib, an oral JAK inhibitor, was recently approved for the treatment of moderate-to-severe UC. Several more selective JAK-1 inhibitors, including filgotinib and upadacitinib, have also shown positive results in phase II studies and are currently enrolling in phase III development programs. Similarly, ozanimod, an S1P1 and S1P5 receptor agonist, has shown early favorable results and is enrolling in phase III trials. As these and other novel oral SMDs come to market, several questions will need to be answered. The cost effectiveness, comparative treatment efficacy, predictors of response, and relative safety of oral SMDs compared to existing therapies will need to be evaluated. Given the modest efficacy rates observed with both biologic therapies and novel SMDs to date, the potential for combination therapy based on a non-sensitizing oral option is promising and may be facilitated by development of organ-specific therapies with pharmacodynamic activity restricted to the gut to minimize systemic toxicity.

Pharmacological and Therapeutic Properties of Cannabidiol for Epilepsy Abstract Cannabidiol (CBD) is a major active component of the Cannabis plant, which, unlike tetrahydrocannabinol (THC), is devoid of euphoria-inducing properties. During the last 10 years, there has been increasing interest in the use of CBD-enriched products for the treatment of epilepsy. In 2018, an oil-based highly purified liquid formulation of CBD (Epidiolex) derived from Cannabis sativa was approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). The mechanisms underlying the antiseizure effects of CBD are unclear but may involve, among others, antagonism of G protein-coupled receptor 55 (GPR55), desensitization of transient receptor potential of vanilloid type 1 (TRPV1) channels, and inhibition of adenosine reuptake. CBD has complex and variable pharmacokinetics, with a prominent first-pass effect and a low oral bioavailability that increases fourfold when CBD is taken with a high-fat/high-calorie meal. In four randomized, double-blind, parallel-group, adjunctive-therapy trials, CBD given at doses of 10 and 20 mg/kg/day administered in two divided administrations was found to be superior to placebo in reducing the frequency of drop seizures in patients with LGS and convulsive seizures in patients with DS. Preliminary results from a recently completed controlled trial indicate that efficacy also extends to the treatment of seizures associated with the tuberous sclerosis complex. The most common adverse events that differentiated CBD from placebo in controlled trials included somnolence/sedation, decreased appetite, increases in transaminases, and diarrhea, behavioral changes, skin rashes, fatigue, and sleep disturbances. About one-half of the patients included in the DS and LGS trials were receiving concomitant therapy with clobazam, and in these patients a CBD-induced increase in serum levels of the active metabolite norclobazam may have contributed to improved seizure outcomes and to precipitation of some adverse effects, particularly somnolence.

Cell-Based Quadrivalent Inactivated Influenza Virus Vaccine (Flucelvax ® Tetra/Flucelvax Quadrivalent ® ): A Review in the Prevention of Influenza Abstract Manufacturing influenza virus vaccines using a mammalian cell line rather than embryonated chicken eggs may carry certain advantages. A quadrivalent inactivated influenza virus vaccine produced using the Madin Darby canine kidney cell line has been approved in the EU (Flucelvax® Tetra) and USA (Flucelvax Quadrivalent®; QIVc hereafter) for the prevention of influenza in adults and children. The clinical development of QIVc has built upon that of a cell-based trivalent influenza virus vaccine (TIVc) manufactured using the same processes; the additional influenza B strain contained in QIVc reduces the risk of the strain in the vaccine not matching that in circulation. Pivotal phase III clinical trials in adult and paediatric participants have demonstrated the immunogenicity of QIVc to be noninferior to that of TIVc formulations against shared strains and superior against the influenza B strain absent from each TIVc formulation. Protective efficacy data for TIVc is considered foundational for QIVc and, in a phase III clinical trial, TIVc was effective in protecting adults against antigenically matched influenza strains. Large real-world studies from the 2017/2018 US influenza season further support the prophylactic effectiveness of QIVc, with possible benefits over egg-based vaccines. QIVc was generally well tolerated in clinical trials. In adult and paediatric QIVc recipients, the most common solicited adverse reactions were injection site pain and headache. Reactogenicity was comparable to that of TIVc; no safety signals unique to QIVc emerged. Through circumventing concerns around egg adaptation, QIVc has the potential to be more effective than currently available egg-based quadrivalent vaccines.

Camrelizumab: First Global Approval Abstract Camrelizumab (AiRuiKa™), a programmed cell death 1 (PD-1) inhibitor being developed by Jiangsu Hengrui Medicine Co. Ltd, recently received conditional approval in China for the treatment of relapsed or refractory classical Hodgkin lymphoma. The drug is also being investigated as a treatment for various other malignancies, including B cell lymphoma, oesophageal squamous cell carcinoma, gastric/gastroesophageal junction cancer, hepatocellular carcinoma, nasopharyngeal cancer and non-squamous, non-small cell lung cancer. This article summarizes the milestones in the development of camrelizumab leading to this first approval for classical Hodgkin lymphoma.

Pre-Exposure Prophylaxis for HIV Prevention in Women: Current Status and Future Directions Abstract Pre-exposure prophylaxis (PrEP) is a promising intervention to prevent HIV acquisition, with benefits both to the individual and to population-level health. PrEP is an opportunity to complement ongoing public health efforts to eliminate HIV. For women, PrEP can also serve as a gateway to access sexual and reproductive health (SRH) services. Clinical efficacy of PrEP was initially reported in women using a 1% tenofovir vaginal gel in 2010, followed by an efficacy trial of oral PrEP using TDF/FTC in men who have sex with men (MSM). Since then, further trials have reported efficacy in oral PrEP containing tenofovir in women and heterosexual men, while the subsequent trials for women using tenofovir gel reported no efficacy, stemming from difficulties in achieving adequate adherence. In an effort to offer women additional choices to oral PrEP, alternative modalities are being tested in clinical research, including long-acting injectable formulations and intra-vaginal rings. In 2015, a meta-analysis of clinic trials and open-label extension studies led to the World Health Organization (WHO) strongly recommending the provision of oral PrEP containing tenofovir for any person at substantial risk of HIV infection, irrespective of gender or population group. Currently, PrEP services for women around the world, including those who are either pregnant or breastfeeding, remain limited. Outside sub-Saharan Africa, most PrEP programmes are focused on MSM. South Africa, Kenya, and the USA have the greatest utilization of oral PrEP by women. Yet, since 2012, of the estimated > 300,000 people globally who have initiated PrEP, a minority are women. In this narrative review, we examine the most recent literature on clinical and implementation PrEP research among women. We highlight the high burden of disease related to common sexually transmitted infections (STIs) in women, and the opportunity to integrate PrEP and other HIV prevention services, STI case management, and family planning services, as part of a more robust package of SRH services. Raising awareness on PrEP amongst women and their healthcare providers, minimizing gaps in access, and ensuring adherence and persistence of PrEP during periods of risk are critical issues if PrEP can have a meaningful impact on reducing HIV incidence in women globally.