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BackgroundLanadelumab demonstrated efficacy in preventing hereditary angioedema (HAE) attacks in the phase 3 HELP Study.ObjectiveTo assess time to onset of effect and long-term efficacy of lanadelumab, based on exploratory findings from the HELP Study.MethodsEligible patients with HAE type I/II received lanadelumab 150 mg every 4 weeks (q4wks), 300 mg q4wks, 300 mg q2wks, or placebo. Ad hoc analyses evaluated day 0-69 findings using a Poisson regression model accounting for overdispersion. Least-squares mean monthly HAE attack rate for lanadelumab was compared with placebo. Intrapatient comparisons for days 0-69 versus steady state (days 70-182) used a paired t test for continuous endpoints or Kappa statistics for categorical endpoints.ResultsOne hundred twenty-five patients were randomized and treated. During days 0-69, mean monthly attack rate was significantly lower with lanadelumab (0.41-0.76) vs placebo (2.04), including attacks requiring acute treatment (0.33-0.61 vs 1.66) and moderate/severe attacks (0.31-0.48 vs 1.33, all P ≤ .001). More patients receiving lanadelumab vs placebo were attack free (37.9%-48.1% vs 7.3%) and responders (85.7%-100% vs 26.8%). During steady state, the efficacy of lanadelumab vs placebo was similar or improved vs days 0-69. Intrapatient differences were significant with lanadelumab 300 mg q4wks for select outcomes. Lanadelumab efficacy was durable-HAE attack rate was consistently lower vs placebo, from the first 2 weeks of treatment through study end. Treatment emergent adverse events were comparable during days 0-69 and 70-182.ConclusionProtection with lanadelumab started from the first dose and continued throughout the entire study period.

Abstract Background Warfarin nomograms to guide dosing have been shown to improve control of the international normalized ratio (INR) in the general outpatient setting. However, the effectiveness of these nomograms in hemodialysis patients is unknown. We evaluated the effectiveness of anticoagulation using an electronic warfarin nomogram administered by nurses in outpatient hemodialysis patients, compared to physician directed therapy. Methods Hemodialysis patients at any of the six outpatient clinics in Calgary, Alberta, treated with warfarin anticoagulation were included. Two five-month time periods were compared: prior to and post implementation of the nomogram. The primary endpoint was adequacy of anticoagulation (proportion of INR measurements within range ± 0.5 units). Results Overall, 67 patients were included in the pre- and 55 in the post-period (with 40 patients in both periods). Using generalized linear mixed models, the adequacy of INR control was similar in both periods for all range INR levels: in detail, range INR 1.5 to 2.5 (pre 93.6% (95% CI: 88.6% - 96.5%); post 95.6% (95% CI: 89.4% - 98.3%); p = 0.95); INR 2.0 to 3.0 (pre 82.2% (95% CI: 77.9% - 85.8%); post 77.4% (95% CI: 72.0% - 82.0%); p = 0.20); and, INR 2.5 to 3.5 (pre 84.3% (95% CI: 59.4% - 95.1%); post 66.8% (95% CI: 39.9% - 86.0%); p = 0.29). The mean number of INR measurements per patient decreased significantly between the pre- (30.5, 95% CI: 27.0 - 34.0) and post- (22.3, 95% CI: 18.4 - 26.1) (p = 0.003) period. There were 3 bleeding events in each of the periods. Conclusions An electronic warfarin anticoagulation nomogram administered by nurses achieved INR control similar to that of physician directed therapy among hemodialysis patients in an outpatient setting, with a significant reduction in frequency of testing. Future controlled trials are required to confirm the efficacy of this nomogram.

Background: Hereditary angioedema is a rare disorder characterized by episodic, potentially life-threatening swelling caused by kallikrein-kinin dysregulation. Long-term prophylaxis can stabilize this system. Donidalorsen, an antisense oligonucleotide, specifically reduces prekallikrein expression., Methods: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary angioedema to receive donidalorsen (80 mg subcutaneously) or placebo once every 4 or 8 weeks. The primary end point was the time-normalized number of investigator-confirmed hereditary angioedema attacks per 4 weeks (attack rate) from week 1 to week 25., Results: A total of 90 patients received donidalorsen every 4 weeks (45 patients), donidalorsen every 8 weeks (23 patients), or placebo (22 patients). The least-squares mean time-normalized attack rate was 0.44 (95% CI, 0.27 to 0.73) in the 4-week group, 1.02 (95% CI, 0.65 to 1.59) in the 8-week group, and 2.26 (95% CI, 1.66 to 3.09) in the placebo group. The mean attack rate from week 1 to week 25 was 81% lower (95% CI, 65 to 89) in the 4-week group than in the placebo group (P<0.001) and 55% lower (95% CI, 22 to 74) in the 8-week group than in the placebo group (P = 0.004); the median reduction in the attack rate from baseline was 90% in the 4-week group, 83% in the 8-week group, and 16% in the placebo group. The mean attack rate during weeks 5 to 25 was 87% lower (95% CI, 72 to 94) in the 4-week group than in the placebo group (P<0.001) and 60% lower (95% CI, 25 to 79) in the 8-week group than in the placebo group. Donidalorsen administered every 4 weeks resulted in an improvement in the least-squares mean total score for the change at week 25 on the Angioedema Quality-of-Life Questionnaire (scores range from 0 to 100, with a score of 100 indicating the worst possible quality of life) that was 18.6 points (95% CI, 9.5 to 27.7) better than that with placebo (P<0.001). The most common adverse events were erythema at the injection site, headache, and nasopharyngitis; 98% of adverse events were mild or moderate in severity., Conclusions: Donidalorsen treatment reduced the hereditary angioedema attack rate, a finding that supports potential prophylactic use for hereditary angioedema. (Funded by Ionis Pharmaceuticals; OASIS-HAE ClinicalTrials.gov number, NCT05139810.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Cardiopulmonary resuscitation (CPR) outcomes among patients with cirrhosis are poor, but factors associated with outcomes and provider awareness remain under-evaluated., Aims: We retrospectively investigated in-hospital CPR mortality among patients with cirrhosis, and, using these results, undertook an educational study among providers to improve knowledge of CPR outcomes and code status in patients with cirrhosis., Methods: We identified patients with cirrhosis admitted from 2012 to 2022 who underwent CPR at our center; the primary outcome was survival-to-discharge. A brief video based on these results was presented online to Internal Medicine residents, along with paired pre/post-surveys assessing attitudes toward holding code status conversations and knowledge of CPR outcomes in patients with cirrhosis., Results: 97 cases of CPR were identified. 27 patients (28%) survived to discharge post-CPR. A history of liver decompensation was significantly associated with lower survival (OR 0.21, p < 0.05). 22 residents participated in the educational intervention; afterward, their estimation of survival after CPR for patients with cirrhosis significantly improved (p < 0.05). Mean confidence in answering patient questions about prognosis, measured from 1 to 5, also significantly improved (2.4-"a little confident" vs. 3.8-"confident", p < 0.05). 59% of surveyed residents identified impact on liver transplant candidacy as at least a "somewhat significant" barrier to code status conversations., Conclusions: We identified significant trainee uncertainty about outcomes in patients with cirrhosis. These deficits improved after an educational intervention and gave providers more confidence in holding informed code status conversations with patients with cirrhosis, a population that faces barriers to adequate code discussions., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: The authors have no conflicts to report.

Background: Hereditary angioedema (HAE) is a potentially fatal disease characterized by unpredictable, recurrent, often disabling swelling attacks. In a randomized phase 2 study, donidalorsen reduced HAE attack frequency and improved patient quality-of-life (ISIS721744-CS2, NCT04030598). We report the 2-year interim analysis of the phase 2 open-label extension (OLE) study (ISIS 721744-CS3, NCT04307381)., Methods: In the OLE, the on-treatment study period consisted of fixed (weeks 1-13, donidalorsen 80 mg subcutaneously every 4 weeks [Q4W]) and flexible (weeks 17-105, donidalorsen 80 mg Q4W, 80 mg every 8 weeks [Q8W], or 100 mg Q4W) dosing periods. The primary outcome was incidence and severity of treatment-emergent adverse events (TEAEs). The secondary outcomes included efficacy, pharmacodynamic, and quality-of-life assessments., Results: Seventeen patients continued in the OLE study. No serious TEAEs or TEAEs leading to treatment discontinuation were reported. Mean monthly HAE attack rate was 96% lower than the study run-in baseline rate (mean, 0.06/month; 95% confidence interval [CI], 0.02-0.10; median, 0.04 on-treatment vs. mean, 2.70/month; 95% CI, 1.94-3.46; median, 2.29 at baseline). Mean monthly attack rate for Q8W dosing (n = 8) was 0.29 (range, 0.0-1.7; 95% CI, -0.21 to 0.79; median, 0.00). Mean plasma prekallikrein and D-dimer concentrations decreased, and Angioedema Quality of Life Questionnaire total score improved from baseline to week 105 with donidalorsen., Conclusion: The 2-year interim results of this phase 2 OLE study of donidalorsen in patients with HAE demonstrated no new safety signals; donidalorsen was well tolerated. There was durable efficacy with a 96% reduction in HAE attacks., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Prostaglandin E2 (PGE 2 ) and 16,16-dimethyl-PGE 2 (dmPGE 2 ) are important regulators of hematopoietic stem and progenitor cell (HSPC) fate and offer potential to enhance stem cell therapies [C. Cutler et al. Blood 122 , 3074-3081(2013); W. Goessling et al. Cell Stem Cell 8 , 445-458 (2011); W. Goessling et al. Cell 136 , 1136-1147 (2009)]. Here, we report that PGE 2 -induced changes in chromatin at enhancer regions through histone-variant H2A.Z permit acute inflammatory gene induction to promote HSPC fate. We found that dmPGE 2 -inducible enhancers retain MNase-accessible, H2A.Z-variant nucleosomes permissive of CREB transcription factor (TF) binding. CREB binding to enhancer nucleosomes following dmPGE 2 stimulation is concomitant with deposition of histone acetyltransferases p300 and Tip60 on chromatin. Subsequent H2A.Z acetylation improves chromatin accessibility at stimuli-responsive enhancers. Our findings support a model where histone-variant nucleosomes retained within inducible enhancers facilitate TF binding. Histone-variant acetylation by TF-associated nucleosome remodelers creates the accessible nucleosome landscape required for immediate enhancer activation and gene induction. Our work provides a mechanism through which inflammatory mediators, such as dmPGE 2 , lead to acute transcriptional changes and modify HSPC behavior to improve stem cell transplantation.

Stem cell transplantation presents a potentially curative strategy for genetic disorders of skeletal muscle, but this approach is limited by the deleterious effects of cell expansion in vitro and consequent poor engraftment efficiency. In an effort to overcome this limitation, we sought to identify molecular signals that enhance the myogenic activity of cultured muscle progenitors. Here, we report the development and application of a cross-species small-molecule screening platform employing zebrafish and mice, which enables rapid, direct evaluation of the effects of chemical compounds on the engraftment of transplanted muscle precursor cells. Using this system, we screened a library of bioactive lipids to discriminate those that could increase myogenic engraftment in vivo in zebrafish and mice. This effort identified two lipids, lysophosphatidic acid and niflumic acid, both linked to the activation of intracellular calcium-ion flux, which showed conserved, dose-dependent, and synergistic effects in promoting muscle engraftment across these vertebrate species., Competing Interests: Declaration of interests A.J.W. is a member of the scientific advisory board for Frequency Therapeutics, a company that aims to develop medicines to target endogenous stem cells to restore regenerative capacity; a consultant for Kate Therapeutics, a company that seeks to develop genetic medicines for muscle diseases; and a co-founder of Elevian, Inc., a company aimed at preserving the health of older individuals by targeting blood-borne geroproteins. L.I.Z. and A.J.W. are inventors on patent applications filed through Harvard University and Children’s Hospital regarding myogenic specification of embryonic cells from fish and mammals, and S.T., L.I.Z., and A.J.W. are inventors on patent applications filed through Harvard University regarding chemical modifiers of muscle engraftment by myogenic precursors. L.I.Z. is a founder and stockholder of Fate Therapeutics, CAMP4 Therapeutics, Amagma Therapeutics, and Scholar Rock. He is a consultant for Celularity., (Published by Elsevier Inc.)

Background: Hereditary angioedema is a rare and potentially life-threatening genetic disease that is associated with kallikrein-kinin system dysregulation. Garadacimab (CSL312), a novel, fully-human monoclonal antibody that inhibits activated factor XII (FXIIa), is being studied for the prevention of hereditary angioedema attacks. The aim of this study was to evaluate the efficacy and safety of once-monthly subcutaneous administrations of garadacimab as prophylaxis for hereditary angioedema., Methods: VANGUARD was a pivotal, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial that recruited patients (aged ≥12 years) with type I or type II hereditary angioedema across seven countries (Canada, Germany, Hungary, Israel, Japan, the Netherlands, and the USA). Eligible patients were randomly assigned (3:2) to receive garadacimab or placebo for 6 months (182 days) by an interactive response technology (IRT) system. Randomisation was stratified by age (≤17 years vs >17 years) and baseline attack rate (1 to <3 attacks per month vs ≥3 attacks per month) for the adult group. The randomisation list and code were kept by the IRT provider during the study, with no access by site staff and funding representatives. All patients and investigational site staff, and representatives from the funder (or their delegates) with direct interaction with the study sites or patients, were masked to treatment assignment in a double-blind fashion. Randomly assigned patients received a 400-mg loading dose of subcutaneous garadacimab as two 200-mg injections or volume-matched placebo on day 1 of the treatment period, followed by five additional self-administered (or caregiver-administered) monthly doses of 200-mg subcutaneous garadacimab or volume-matched placebo. The primary endpoint was the investigator-assessed time-normalised number of hereditary angioedema attacks (number of hereditary angioedema attacks per month) during the 6-month treatment period (day 1 to day 182). Safety was evaluated in patients who received at least one dose of garadacimab or placebo. The study is registered with the EU Clinical Trials Register, 2020-000570-25 and ClinicalTrials.gov, NCT04656418., Findings: Between Jan 27, 2021, and June 7, 2022, we screened 80 patients, 76 of whom were eligible to enter the run-in period of the study. Of 65 eligible patients with type I or type II hereditary angioedema, 39 were randomly assigned to garadacimab and 26 to placebo. One patient was randomly assigned in error and did not enter the treatment period (no dose of study drug received), resulting in 39 patients assigned to garadacimab and 25 patients assigned to placebo being included. 38 (59%) of 64 participants were female and 26 (41%) were male. 55 (86%) of 64 participants were White, six (9%) were Asian (Japanese), one (2%) was Black or African American, one (2%) was Native Hawaiian or Other Pacific Islander, and one (2%) was listed as other. During the 6-month treatment period (day 1 to day 182), the mean number of investigator-confirmed hereditary angioedema attacks per month was significantly lower in the garadacimab group (0·27, 95% CI 0·05 to 0·49) than in the placebo group (2·01, 1·44 to 2·57; p<0·0001), corresponding to a percentage difference in means of -87% (95% CI -96 to -58; p<0·0001). The median number of hereditary angioedema attacks per month was 0 (IQR 0·00-0·31) for garadacimab and 1·35 (1·00-3·20) for placebo. The most common treatment-emergent adverse events were upper-respiratory tract infections, nasopharyngitis, and headaches. FXIIa inhibition was not associated with an increased risk of bleeding or thromboembolic events., Interpretation: Monthly garadacimab administration significantly reduced hereditary angioedema attacks in patients aged 12 years and older compared with placebo and had a favourable safety profile. Our results support the use of garadacimab as a potential prophylactic therapy for the treatment of hereditary angioedema in adolescents and adults., Funding: CSL Behring., Competing Interests: Declaration of interests TJC is a speaker for Pharming, CSL Behring, Takeda, Fresenius Kabi, and Grifols; has received research and consultancy grants from CSL Behring, Takeda, BioCryst, Ionis, Spark, BioMarin, Fresenius Kabi, and Grifols; and is on the medical advisory board for the US Hereditary Angioedema Association, Director of ACARE Angioedema Center at Penn State University, Hershey, and on the Board of Directors for the American Academy of Allergy, Asthma, and Immunology. AR received research grants as a principal investigator, speaker, and advisor for CSL Behring, Takeda-Shire, BioCryst, Pharming, Pharvaris, Ionis, and Shulov Innovative Science. HHL is a speaker for Pharming, CSL Behring, Takeda, and BioCryst and has received research and consultancy grants from CSL Behring, Takeda, BioCryst, Ionis, BioMarin, Pharming, and Phavaris. JSJ is a speaker for Takeda-Shire, CSL Behring, Teva, AstraZeneca, GSK, Sanofi Genzyme, and Regeneron and has received research funding or consultancy fees from CSL Behring, Takeda-Shire, BioCryst, Novartis, Genentech, AstraZeneca, Allakos, Fresenius Kabi, GSK, and Regeneron. JAB is a consultant, principal investigator, and speaker for CSL Behring, Takeda-Shire, Pharming, and BioCryst; is a consultant or principal investigator for KalVista, Biomarin, and Ionis; and is a consultant for Astria, ONO Pharmaceutical, Pharvaris, and Cycle Pharmaceuticals. HFa received research grants from CSL Behring, Takeda, and Pharming; has served as an advisor for CSL Behring, Takeda, Pharming, KalVista, ONO Pharmaceutical, and BioCryst; and has participated in clinical trials or registries for BioCryst, CSL Behring, Pharming, KalVista, Pharvaris, and Takeda. WHY has been a speaker and advisory board member and has received honoraria from CSL Behring, Takeda-Shire, Novartis, Sanofi Genzyme, and Merck; has received research grants from CSL Behring, Takeda-Shire, BioCryst, Pharming, Aimmune, DBV Technologies, Eli Lilly, Pharvaris, AstraZeneca, Novartis, GSK, Genentech-Roche, Amgen, Sanofi Genzyme, Regeneron, Galderma, AnaptysBio, Glenmark, ALK Pharma, Dermira, Ionis, and Celgene; serves as a medical advisor (volunteer) for HAE Canada, a patient organisation; and is a member of Angioedema Centers of Reference and Excellence. ESGS has received lecturing or advertising board fees from Amgen, Sanofi, Novartis, AstraZeneca, Esperion, Ionis-Akcea, and Merck, paid to their institution. IO has received honoraria or served as a consultant or participated in advisory boards for CSL Behring, Takeda-Shire, and Torii Pharmaceutical Company. RTa is a speaker for BioCryst, CSL Behring, Pharming, AstraZeneca, Sanofi-Regeneron, GSK, and Takeda; has served as a consultant for BioCryst, CSL Behring, KalVista, Pharming, and Takeda; and has received grants or research support from BioCryst, CSL Behring, Ionis, KalVista, Pharvaris, and Takeda. MEM is a speaker for CSL Behring, Takeda, Pharming, BioCryst, GSK, Amgen, Sanofi-Regeneron, AstraZeneca, Blueprint, and Genentech; has received research grants from CSL Behring, Takeda, Pharming, BioCryst, KalVista, Pharvaris, GSK, Novartis, Merck, and Allakos; and has been a consultant for CSL Behring, Takeda, Pharming, BioCryst, KalVista, and Cycle Pharmaceuticals. WRL is a speaker for CSL Behring, Pharming, AstraZeneca, Sanofi-Regeneron, GSK, and Takeda-Shire; has served as a consultant for BioCryst, BioMarin, CSL Behring, Fresenius Kabi, Intellia, KalVista, Pharming, Pharvaris, and Takeda-Shire; is a board member of the US Hereditary Angioedema Association Medical Advisory Board; and has received grants or research support from ALK Pharma, BioCryst, CSL Behring, Ionis, Gossamer, KalVista, Kedrion, Therapure, and Takeda-Shire. IMS has received honoraria, research funding, and travel grants from BioCryst, CSL Behring, Pharming, Octapharma, KalVista, and Takeda-Shire and has served as a consultant or participated in advisory boards for these companies. EA-P has received honoraria as a speaker or advisor or grant support or clinical trial investigator support from BioCryst, BioMarin Europe, Centogene, CSL Behring, KalVista, Pharming, Pharvaris, and Takeda-Shire. BR has been a speaker and advisory board member for CSL Behring and Takeda, but has not received personal reimbursement for these activities. BR has participated in multiple clinical trials involving investigational drugs for CSL Behring, Takeda, BioCryst, Dyax, and Pharming, but does not hold patents or investments with these companies or involving this product, and serves as a volunteer Medical Scientific Advisor to HAE Canada, a patient organisation. GLS has been an advisory board member for CSL Behring and has participated in clinical trials for investigational drugs for CSL Behring, Takeda, BioCryst, Dyax, Pharming, Pharvaris, and KalVista. JA is a speaker bureau member for CSL Behring, Pharming, BioCryst, and Takeda and has received consulting fees from; is a clinical trial investigator for BioCryst, CSL Behring, Pharming, Takeda, KalVista, Pharvaris, and BioMarin; and has received consulting fees from Cycle Pharmaceuticals. KK has been a clinical trial investigator for CSL Behring. YS has received speaker fees from Novartis, AstraZeneca, Takeda-Shire, and Torii Pharmaceutical Company and has been a clinical trial investigator for CSL Behring. PS has received honoraria, research funding, travel grants, or has served as a consultant or participated in advisory boards for CSL Behring, Octapharma, Pharming, Shire, and Takeda. RTr has received honoraria, travel grants, or has participated in clinical trials or advisory boards for CSL Behring, Shire, and Takeda. HFe, FG, and IJ are full-time employees and shareholders of CSL Behring. MM has received financial support from CSL Behring for acting as a study centre investigator during the conduct of the study and personal fees from CSL Behring, Takeda-Shire, Pharming, BioCryst, Novartis, Octapharma, and KalVista outside the submitted work., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Hereditary angioedema is characterized by recurrent and unpredictable swellings that are disabling and potentially fatal. Selective inhibition of plasma prekallikrein production by antisense oligonucleotide treatment (donidalorsen) may reduce the frequency of attacks and the burden of disease., Methods: In this phase 2 trial, we randomly assigned, in a 2:1 ratio, patients with hereditary angioedema with C1 inhibitor deficiency to receive four subcutaneous doses of either donidalorsen (80 mg) or placebo, with one dose administered every 4 weeks. The primary end point was the time-normalized number of investigator-confirmed angioedema attacks per month (attack rate) between week 1 (baseline) and week 17. Secondary end points included quality of life, as measured with the Angioedema Quality of Life Questionnaire (scores range from 0 to 100, with higher scores indicating worse quality of life), and safety., Results: A total of 20 patients were enrolled, of whom 14 were randomly assigned to receive donidalorsen and 6 to receive placebo. The mean monthly rate of investigator-confirmed angioedema attacks was 0.23 (95% confidence interval [CI], 0.08 to 0.39) among patients receiving donidalorsen and 2.21 (95% CI, 0.58 to 3.85) among patients receiving placebo (mean difference, -90%; 95% CI, -96 to -76; P<0.001). The mean change from baseline to week 17 in the Angioedema Quality of Life Questionnaire score was -26.8 points in the donidalorsen group and -6.2 points in the placebo group (mean difference, -20.7 points; 95% CI, -32.7 to -8.7). The incidence of mild-to-moderate adverse events was 71% among patients receiving donidalorsen and 83% among those receiving placebo., Conclusions: Among patients with hereditary angioedema, donidalorsen treatment resulted in a significantly lower rate of angioedema attacks than placebo in this small, phase 2 trial. (Funded by Ionis Pharmaceuticals; ISIS 721744-CS2 ClinicalTrials.gov number, NCT04030598.)., (Copyright © 2022 Massachusetts Medical Society.)

Objective: The goal of this article is to discuss the importance of differentiating hereditary angioedema (HAE) from other types of angioedema, describe advances in HAE management, especially long-term prophylaxis (LTP), and offer practical recommendations for dermatologists., Commentary: While HAE is rare, dermatologists are likely to encounter patients with this condition at some point over the course of their clinical practice due to the fact that HAE episodes typically involve subcutaneous swelling and sometimes erythema marginatum. HAE is characterized by recurrent episodes of painful and/or disabling bradykinin-mediated angioedema. Unfortunately, HAE is commonly mistaken for other conditions such as allergic and other mast cell-mediated angioedema, but has very different treatment requirements. Delayed diagnosis of HAE can result in years of avoidable debilitating symptoms, inappropriate treatment, potentially unnecessary invasive intervention, and reduced quality of life, and can be life threatening. Thus, timely identification of HAE is essential to ensure appropriate clinical management. Patients with HAE have either deficiency or dysfunction of the C1 inhibitor (C1INH) protein that inhibits proteases in the contact, complement, and fibrinolytic systems. Pathway-specific HAE treatments include C1INH replacement, kallikrein inhibitors, and bradykinin receptor antagonists. Treatment options for managing acute attacks include C1INH replacement (plasma-derived or recombinant formulations), icatibant (kallikrein inhibitor), and ecallantide (bradykinin B2 receptor antagonist). In the past 5 years, several new options for LTP have been approved, including a subcutaneous plasma-derived C1INH formulation and two kallikrein inhibitors (lanadelumab; berotralstat). Optimal management of HAE entails the creation of a comprehensive management plan that addresses both acute and long-term patient needs and includes input from an HAE expert and the patient/caregivers., (© 2021. The Author(s).)

Background: Hereditary angioedema (HAE) is a rare genetic disorder characterized by unpredictable and potentially life-threatening episodes of swelling in various parts of the body. These attacks can be painful and debilitating, and affect a patient's quality of life. Every patient who experiences an attack should be treated with on-demand medication to mitigate attack severity and duration. Many patients with HAE also receive long-term prophylaxis to reduce the frequency and severity of edema episodes. Although long-term prophylaxis reduces the disease burden for patients with HAE, available intravenous and subcutaneous treatments are accompanied by a significant treatment burden because of the logistical, emotional, and physical challenges posed by their long-term parenteral nature. Androgens are an effective oral prophylactic treatment; however, they are associated with significant adverse events and are not suitable for all patients. Thus, the HAE community has expressed interest in the development of alternative oral prophylactic therapies for preventing HAE attacks. Objective: Here, we review the phase II and III clinical data of berotralstat (BCX7353), which was approved by the U.S. Food and Drug Administration in December 2020. Results: Berotralstat is an oral, second-generation, synthetic, small-molecule plasma kallikrein inhibitor taken once daily for the prevention of HAE attacks in patients ages ≥ 12 years. Results from the APeX studies (APeX-1 NCT02870972, APeX-2 NCT03485911, APeX-S NCT03472040, APex-J NCT03873116) demonstrated the efficacy of berotralstat as long-term prophylaxis for patients with HAE, which showed a reduction in the attack rate and on-demand medication usage. Berotralstat was well tolerated, and gastrointestinal treatment-emergent adverse events were generally mild and self-limited. Conclusion: Oral berotralstat is an effective and safe long-term prophylactic treatment for patients with HAE that will provide patients unable to tolerate parenteral therapies with the option of disease control. Berotralstat may be associated with reduced treatment burden compared with injectable therapies, highlighting the importance of patient preference with regard to the administration route of their HAE prophylactic treatment.

Hereditary angioedema is a rare, autosomal dominant genetic disorder that leads to sporadic episodes of swelling, which can affect any part of the body. With a prevalence of 1 in 10,000 to 1 in 50,000, there are other, more common causes of angioedema. Differentiating between bradykinin-mediated and histamine-mediated causes of swelling remains a major challenge. It is critical to develop an appropriate differential diagnosis, work through the various conditions, and obtain the pertinent laboratory evaluation to rule in or out the proposed diagnosis. As an autosomal dominant genetic disorder, there is a 50% chance with each pregnancy of passing on the genetic mutation in the SERPING1 gene. This review addressed the differential diagnosis to consider, the appropriate laboratory evaluation, and the importance of family screening.

Background: Hereditary angioedema (HAE) due to C1 inhibitor (C1INH) deficiency is characterized by recurrent attacks of edema of the skin and mucosal tissues. Symptoms usually present during childhood (mean age at first attack, 10 years). Earlier symptom onset may predict a more severe disease course. Subcutaneous (SC) C1INH is indicated for routine prophylaxis to prevent HAE attacks in adolescents and adults. We analyzed the long-term efficacy of C1INH (SC) in subjects ≤17 years old treated in an open-label extension (OLE) of the pivotal phase III Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1 Inhibitor Replacement Therapy (COMPACT) trial. Methods: Eligible subjects (age ≥6 years, with ≥4 attacks over 2 consecutive months before entry into the OLE or placebo-controlled COMPACT trial) were treated with C1INH (SC) 40 or 60 IU/kg twice weekly for 52-140 weeks. Subgroup analyses by age (≤17 vs. >17 years) were performed for key efficacy endpoints. Results: Ten subjects were ≤17 years old [mean (range) age, 13.3 (8-16) years, 3 subjects <12 years old; exposure range, 51-133 weeks]. All 10 pediatric subjects experienced ≥50% reduction (mean, 93%) in number of attacks versus the prestudy period, with a 97% reduction in the median number of attacks/month (0.11). All subjects had <1 attack/4-week period and 4 had <1 attack/year (1 subject was attack free). No subject discontinued treatment due to a treatment-related adverse event. Conclusions: Data from pediatric subjects treated with C1INH (SC) for up to 2.55 years and adult subjects revealed similar efficacy. C1INH (SC) is effective and well tolerated as long-term prophylaxis in children, adolescents, and adults with HAE., Competing Interests: Donald S. Levy, is a consultant with Takeda, Biocryst, CSL Behring, Pharming; is a speaker for Takeda and CSL Behring; has received clinical research grants from CSL Behring. Teresa Caballero has received grant research, grant support and/or speaker/consultancy fees from BioCryst, CSL Behring, Merck, Novartis, Octapharma, Pharming, and Shire (a Takeda company); has received funding to attend conferences/educational events from CSL Behring, Novartis and Shire; is/has been a clinical trial/registry investigator for Biocryst, CSL Behring, Novartis, Pharming and Shire; and is a researcher from the IdiPAZ program for promoting research activities. Iftikhar Hussain is a speaker for CSL Behring, Grifols, and Optionse; is/has been on the advisory board for Blueprint Medicine and Pfizer; is Principal Investigator for Adare, Sanofi, Cara Therapeutics, Dermira, Lilly, Pfizer, Abbvie, CSL Behring, Astra-Zeneca, and Genentech, ALK. Avner Reshef has received research funding, travel grants, and/or speaker honorarium-consultation fee from CSL-Behring, Pharming, BioCryst, Takeda-Shire, Teva, Stallergens. John Anderson has potential conflicts of interest with CSL Behring, Takeda, BioCryst. James Baker has no conflicts of interest. Lawrence B. Schwartz is/has been HAE clinical trial principal investigator for CSL Behring and Takeda; is/has been on the advisory board for CSL Behring LLC, Takeda Pharmaceuticals, Pharming Healthcare, and BioCryst Pharmaceuticals. Marco Cicardi has potential conflicts of interest with CSL Behring, Shire, and Pharming. Subhransu Prusty, Henrike Feuersenger, and Ingo Pragst are/have been CSL Behring employees. Michael Manning has received grant support from CSL Behring, Takeda/Shire, BioCryst, and KalVista; is a speaker for CSL Behring, Takeda/Shire, and Pharming; is a consultant with and on the advisory boards for CSL Behring, Takeda/Shire, BioCryst, and Pharming., (© Donald Levy et al., 2020; Published by Mary Ann Liebert, Inc.)

Introduction: For prophylaxis of hereditary angioedema (HAE) attacks, replacement therapy with human C1-inhibitor (C1-INH) treatment is approved and available as intravenous [C1-INH(IV)] (Cinryze ® ) and subcutaneous [C1-INH(SC)] HAEGARDA ® preparations. In the absence of a head-to-head comparative study of the two treatment modalities, an indirect comparison of data from 2 independent but similar clinical trials was undertaken., Methods: Two similar randomized, double-blind, placebo-controlled, crossover studies were identified which evaluated either C1-INH(SC) (COMPACT; NCT01912456; 16 weeks) or C1-INH(IV) (CHANGE; NCT01005888; 14 weeks) vs. placebo (on-demand treatment only) for routine prevention of HAE attacks. Individual patient data from each trial were used to conduct an indirect comparison of treatment effects. Attack reductions (absolute and percent of mean/median number of monthly HAE attacks reduction over placebo) were compared between the two C1-INH formulations at approved/recommended doses: C1-INH(SC) 60 IU/kg twice weekly (n = 45) and 1000 U of C1-INH(IV) twice weekly (n = 22). Point estimates were adjusted using mixed and quantile regression models that controlled for study design., Results: The absolute mean monthly numbers of HAE attack reductions were 3.6 (95% CI 2.9, 4.2) for C1-INH(SC) 60 IU/kg vs. placebo and 2.3 (1.4, 3.3) for C1-INH(IV) vs. placebo; between-product difference, 1.3 (0.1, 2.4; P  = 0.034). The mean percent reduction in monthly attack rate was significantly greater with C1-INH(SC) as compared with C1-INH(IV) (84% vs. 51%; P  < 0.001). The percentages of subjects experiencing ≥ 50%, ≥ 70%, and ≥ 90% reductions in monthly HAE attack rates versus placebo were significantly higher with C1-INH(SC) 60 IU/kg as compared to C1-INH(IV) 1000 U (≥ 50% reduction: 91% vs. 50%, odds ratio [OR] = 10.33, P  = 0.003; ≥ 70% reduction: 84% vs. 46%, OR = 6.19, P  = 0.005; ≥ 90% reduction: 57% vs. 18%, OR = 6.04, P  = 0.007)., Conclusion: Within the limitations of an indirect study comparison, this analysis suggests greater attack reduction with twice-weekly C1-INH(SC) 60 IU/kg as compared to twice-weekly C1-INH(IV) 1000 U for the routine prevention of HAE attacks.

Importance: Current treatments for long-term prophylaxis in hereditary angioedema have limitations., Objective: To assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks., Design, Setting, and Participants: Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow-up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized., Interventions: Twenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments., Main Outcome and Measures: Primary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period., Results: Among 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were -1.49 (95% CI, -1.90 to -1.08; P < .001); -1.44 (95% CI, -1.84 to -1.04; P < .001); and -1.71 (95% CI, -2.09 to -1.33; P < .001). The most commonly occurring adverse events with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1% placebo, 52.4% lanadelumab) and dizziness (0% placebo, 6.0% lanadelumab)., Conclusions and Relevance: Among patients with hereditary angioedema type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo. These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema. Further research is needed to determine long-term safety and efficacy., Trial Registration: EudraCT Identifier: 2015-003943-20; ClinicalTrials.gov Identifier: NCT02586805.

Background: Real-world data on usage and associated outcomes with hereditary angioedema (HAE)-specific medications introduced to the United States (US) market since 2009 are very limited. The purpose of this retrospective study was to evaluate real-world treatment patterns of HAE-specific medications in the US and to assess their impact on healthcare resource utilization (HCRU). This analysis used IMS PharMetrics PlusTM database records (2006-2014) of patients with HAE, ≥1 insurance claim for an HAE-specific medication, and continuous insurance enrollment for ≥3 months following the first HAE prescription claim., Results: Of 631 total patients, 434 (68.8%) reported C1-INH(IV) use; 396 (62.8%) reported using ecallantide and/or icatibant. There were 306 episodes of prophylactic use of C1-INH(IV) (defined by continuous refills averaging ≥1500 IU/week for ≥13 weeks) in 155 patients; use of ≥1 on-demand rescue medication was implicated during 53% (163/306) of those episodes. Sixty-eight (20.2%) of 336 C1-INH(IV) users eligible for the HCRU analysis were hospitalized at least once, and 191 (56.8%) visited the emergency department (ED). Eighteen patients (5.4%) had a central venous access device (CVAD); of these, 5 (27.7%) required hospitalization and 14 (77.7%) had an ED visit. The adjusted relative risk of hospitalization and/or ED visits for patients with a CVAD was 2.6 (95% CI: 0.17, 39.23) compared to C1-INH(IV) users without a CVAD., Conclusions: Despite widespread availability of modern HAE medications in the US, we identified a subset of patients requiring long-term prophylaxis who continue to be burdened by frequent rescue medication usage and/or complications related to the use of CVADs for intravenous HAE medication.

Background: Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) impairs health-related quality of life (HRQoL)., Objective: The objective of this study was to assess HRQoL outcomes in patients self-administering subcutaneous C1-INH (C1-INH[SC]; HAEGARDA) for routine prevention of HAE attacks., Methods: Post hoc analysis of data from the placebo-controlled, crossover phase III COMPACT study (Clinical Studies for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy). Ninety patients with C1-INH-HAE were randomized to 1 of 4 treatment sequences: C1-INH(SC) 40 or 60 IU/kg twice weekly for 16 weeks, preceded or followed by 16 weeks of twice weekly placebo injections. All HAE attacks were treated with open-label on-demand treatment as necessary. HRQoL assessments at week 14 (last visit) included the European Quality of Life-5 Dimensions Questionnaire (EQ-5D-3L), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication (TSQM)., Results: Compared with placebo (on-demand treatment alone), treatment with twice weekly C1-INH(SC) (both doses combined) was associated with better EQ-5D visual analog scale general health, less HADS anxiety, less WPAI presenteeism, work productivity loss, and activity impairment, and greater TSQM effectiveness and overall treatment satisfaction. More patients self-reported a "good/excellent" response during routine prevention with C1-INH(SC) compared with on-demand only (placebo prophylaxis) management. For each HRQoL measure, a greater proportion of patients had a clinically meaningful improvement during C1-INH(SC) treatment compared with placebo., Conclusions: In patients with frequent HAE attacks, a treatment strategy of routine prevention with self-administered twice weekly C1-INH(SC) had a greater impact on improving multiple HAE-related HRQoL impairments, most notably anxiety and work productivity, compared with on-demand treatment alone (placebo prophylaxis)., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Pseudomonas syringae pv. tabaci ATCC 11528 produces tabtoxin, a β-lactam-containing dipeptide phytotoxin. Tabtoxinine-β-lactam (TβL), one of tabtoxin's constituent amino acids, structurally mimics lysine, and many of the proteins encoded by the tabtoxin biosynthetic gene cluster are homologs of lysine biosynthetic enzymes, suggesting that the tabtoxin and lysine biosynthetic routes parallel one another. We cloned and expressed TabB and TabD, predicted homologs of tetrahydrodipicolinate (THDPA)-N-acyltransferase and N-acyl-THDPA aminotransferase, respectively, to determine their activities in vitro. We confirmed that TabB succinylates THDPA and that TabD is a PLP-dependent aminotransferase that utilizes glutamate as an amine donor. Surprisingly, we also found that though TabD could utilize the TabB product N-succinyl-THDPA as a substrate, THDPA itself was also recognized. These observations reveal that TabB functionally duplicates DapD, the THDPA-N-succinyltransferase involved in lysine biosynthesis, and reinforce the close relationship between the metabolic logics underpinning the respective biosynthetic pathways., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Nanofiltered C1 inhibitor (human) is approved in the United States for routine prophylaxis of angioedema attacks in patients with hereditary angioedema, a rare disease caused by a deficiency of functional C1 inhibitor., Objective: To assess the safety of escalating doses of nanofiltered C1 inhibitor (human) in patients who were not adequately controlled on the indicated dose (1000 U every 3 or 4 days)., Methods: Eligible patients had >1 attack/month over the 3 months before the trial. Doses were escalated to 1500 U every 3 or 4 days for 12 weeks, at which point, the patients were evaluated. If treatment was successful (≤1 attack/mo) or at the investigator's discretion, the patients entered a 3-month follow-up period. The patients with an average of >1 attack/month were eligible for further escalation to 2000 U and then 2500 U., Results: Twenty patients started at 1500 U; 13 were escalated to 2000 U, and 12 were escalated to 2500 U. Eighteen patients reported adverse events. Two patients reported 4 serious adverse events (cerebral cystic hygroma, laryngeal angioedema attack, anemia, and bile duct stone) that were considered by investigators to be unrelated to treatment. Notably, there were no systemic thrombotic events or discontinuations due to adverse events. Fourteen patients were treated successfully (70%), continued to the follow-up period at the investigator's discretion, or experienced a reduction in attacks of >1.0/month., Conclusions: Dose escalation of nanofiltered C1 inhibitor (human) up to 2500 U was well tolerated and reduced attack frequency in the majority of patients., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the use of Cinryze (nanofiltered C1-esterase inhibitor [C1 INH-nf]) for the acute management and prevention of hereditary angioedema attacks in the subgroup of children and adolescents who participated in 2 placebo-controlled and 2 open-label extension studies., Study Design: In the acute-attack treatment studies, the efficacy of 1000 U of C1 INH-nf (with an additional 1000 U given 1 hour later if needed) was assessed based on the time to the start of symptomatic relief and the proportion of patients experiencing relief within 4 hours of therapy. In the prophylaxis studies, C1 INH-nf 1000 U was given twice weekly, and efficacy was based on the frequency of attacks., Results: Across 4 studies, 46 children received a total of 2237 C1 INH-nf infusions. The median time to the start of unequivocal relief in the acute-attack treatment study (n = 12) was 30 minutes with C1 INH-nf, compared with 2 hours for placebo. In the open-label extension (n = 22), clinical relief began within 4 hours of therapy in 89% of attacks. In the prophylaxis study (n = 4), the number of attacks was reduced by approximately 2-fold with C1 INH-nf compared with placebo. In the prophylaxis open-label extension (n = 23), the median monthly attack rate decreased from 3.0 before treatment to 0.39 with C1 INH-nf use., Conclusion: In children, C1 INH-nf was well tolerated, provided relief from symptoms of hereditary angioedema attacks, and reduced the rate of attacks., (Copyright © 2013 Mosby, Inc. All rights reserved.)

It has been stated that faculty development programmes which are closely linked to particular teaching contexts are most likely to be effective. Over the past 10 years we have developed a model of 'co-teaching' for faculty development which is based upon this premise and which can be applied to any clinical rotation. In this paper we describe our model, in which paired physicians focus on developing their teaching skills while sharing the clinical supervision of residents and medical students. Through iterative phases of teaching, debriefing and planning, co-teachers gain experience in analysing teaching encounters and develop skills in self-evaluation. Teaching occurs in the usual clinical settings such as attending (consultant) teaching rounds, clinic precepting, and case conferences. We discuss our model in the context of educational theory and related literature. We support our positive assessment of the co-teaching model through the precepts of collaborative inquiry and case study methodology. Vignettes, taken from the experiences of the authors, are used to demonstrate how the model is used to develop effective solutions to problems and to help in the maturation of one's skill as an educator. Successful implementation of the model is predicated on the development of a truly collaborative process between co-teachers. We share lessons we have learned from our experience of implementing the model in different clinical venues, such as the contrast between teaching on a hospital ward or in the clinic. This collaborative process has been well received by junior and senior faculty participants in our institution for more than a decade.

Aspirin-induced hypersensitivity affects a substantial number of people, including 20% or more of asthmatic patients. A dramatic flare of symptoms occurs after indigestion of aspirin or a nonsteroidal anti-inflammatory drug, and symptoms can persist even after the agent is discontinued. Fortunately, aspirin desensitization, as described by the authors, now appears to be a treatment option.

We found an increase in peripheral-blood lymphocytes bearing the T-cell-specific activation antigen Ta1 in 20 of 35 patients with progressive multiple sclerosis, 4 of 18 patients with stable or improving multiple sclerosis, 1 of 17 patients with other neurologic diseases, and 1 of 14 normal controls (P less than 0.0002, Fisher's exact test). No increases in two other markers of T-cell activation, T113 and the interleukin-2 receptor, were found. In the cerebrospinal fluid, patients with progressive multiple sclerosis (pleocytosis, 3.9 +/- 1.6 cells per cubic millimeter) had 42 +/- 3.0 per cent Ta1+ cells. In contrast, patients with other inflammatory central nervous system diseases (36 +/- 13 cells per cubic millimeter) had 9.6 +/- 1.8 per cent Ta1+ cells (P less than 0.01). In patients with other neurologic diseases without inflammation (0.7 +/- 0.16 cells per cubic millimeter), the percentage of Ta1+ cells was equivalent to that in patients with multiple sclerosis (39 +/- 5.4 per cent), although the absolute number was lower. There was a positive correlation between the presence of Ta1+ cells in the spinal fluid and blood of patients with other neurologic diseases, but not patients with multiple sclerosis. Less than 1 per cent of lymphocytes from the spinal fluid of patients with multiple sclerosis expressed interleukin-2 receptors, as compared with 9.8 per cent of cells from subjects with other inflammatory neurologic diseases (P less than 0.01). These results suggest that the T cells in the spinal fluid of patients with multiple sclerosis may be activated by a different mechanism or in a different temporal sequence from that in patients with other nervous system diseases. Furthermore, the increase in Ta1+ cells in the peripheral blood of patients with multiple sclerosis demonstrates systemic immune activation in the disease; monitoring such cells may provide an objective measure of abnormal immunologic activity.