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Chronic inflammation is an underlying feature of respiratory diseases such as chronic obstructive pulmonary disease (COPD). Novel therapies that target the inflammatory mechanisms driving acute exacerbations of COPD are required. The ST2 receptor, which binds the alarmin interleukin (IL)-33 to initiate an inflammatory response, is a potential target. Astegolimab, a fully human immunoglobulin G2 monoclonal antibody, which binds with high affinity to ST2 to prevent binding of IL-33, is a potential therapy for COPD. However, targeting inflammatory pathways that form part of the immune system may have unintended consequences, such as implications for the response to infection and cardiovascular function. Therefore, an understanding of astegolimab’s safety profile in clinical use is essential. This narrative review summarizes clinical safety data from published clinical trials of astegolimab with a focus on adverse events of interest, including infections and cardiac events. Astegolimab was shown to be well tolerated in > 580 patients with asthma, atopic dermatitis, COPD, and severe COVID-19 pneumonia who took part in Phase II trials. The frequency of adverse events (AEs) and serious AEs was similar between the astegolimab and placebo arms in each trial (AEs: 41–81% vs. 58–77%; serious AEs: 3–29% vs. 0–41%, respectively). The number of deaths was similar between treatment arms and there were no astegolimab-related deaths. Astegolimab did not increase the risk of infection or major adverse cardiac events. Ongoing Phase IIb and Phase III trials of astegolimab in patients with COPD who have a history of frequent acute exacerbation(s) of COPD will provide a future opportunity to confirm the safety profile of astegolimab.

Daclizumab, a humanised monoclonal antibody, reduced multiple sclerosis disease activity in previous non-randomised studies. We aimed to assess whether daclizumab reduces disease activity in patients with active relapsing multiple sclerosis who are receiving interferon beta treatment. We did a phase 2, randomised, double-blind, placebo-controlled study at 51 centres in the USA, Canada, Germany, Italy, and Spain. Patients with active relapsing multiple sclerosis who were taking interferon beta were randomly assigned to receive add-on subcutaneous daclizumab 2 mg/kg every 2 weeks (interferon beta and high-dose daclizumab group), daclizumab 1 mg/kg every 4 weeks (interferon beta and low-dose daclizumab group), or interferon beta and placebo for 24 weeks. The randomisation scheme was generated by Facet Biotech. All patients and assessors were masked to treatment with the exception of Facet Biotech bioanalysts who prepared data for the data safety monitoring board or generated pharmacokinetic or pharmacodynamic data, a drug accountability auditor, and the site pharmacist. The primary endpoint was total number of new or enlarged gadolinium contrast-enhancing lesions measured on brain MRI scans every 4 weeks between weeks 8 and 24. Effects of daclizumab on prespecified subsets of lymphocytes and quantitative T-cell proliferative response were assessed in an exploratory pharmacodynamic substudy. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00109161. From May, 2005, to March, 2006, 288 patients were assessed for eligibility, and 230 were randomly assigned to receive interferon beta and high-dose daclizumab (n=75), interferon beta and low-dose daclizumab (n=78), or interferon beta and placebo (n=77). The adjusted mean number of new or enlarged gadolinium contrast-enhancing lesions was 4·75 in the interferon beta and placebo group compared with 1·32 in the interferon beta and high-dose daclizumab group (difference 72%, 95% CI 34% to 88%; p=0·004) and 3·58 in the interferon beta and low-dose daclizumab group (25%, −76% to 68%; p=0·51). In the pharmacodynamic substudy, daclizumab was not associated with significant changes in absolute numbers of T cells, B cells, or natural killer cells, or T-cell proliferative response compared with interferon beta alone. The number of CD56 bright natural killer cells was seven to eight times higher in both daclizumab groups than in the interferon beta and placebo group (interferon beta and low-dose daclizumab group p=0·002; interferon beta and high-dose daclizumab group p<0·0001). Common adverse events were equally distributed across groups. Add-on daclizumab treatment reduced the number of new or enlarged gadolinium contrast-enhancing lesions compared with interferon beta alone and might reduce multiple sclerosis disease activity to a greater extent than interferon beta alone. Facet Biotech and Biogen Idec.

Astegolimab, a fully human immunoglobulin G2 monoclonal antibody, binds with high affinity to ST2, the interleukin‐33 receptor, thereby blocking ST2/interleukin‐33 binding and subsequent inflammatory cascades involved in inflammatory diseases. Here, we present three randomized, double‐blind, placebo‐controlled, Phase I studies evaluating the safety, tolerability, pharmacokinetics, and immunogenicity of single‐ascending doses of astegolimab in healthy participants and patients with mild atopic asthma (NCT01928368), multiple‐ascending doses in healthy participants (NCT02170337), and single‐ascending doses in healthy Japanese and White adults. Overall, 152 participants were enrolled, randomized, and treated with single‐ or multiple‐ascending doses of astegolimab (n = 112) or placebo (n = 40) subcutaneously (2.1–560 mg) or intravenously (210 or 700 mg). No deaths, serious adverse events, or discontinuations due to adverse events occurred during the studies. No clinically meaningful differences in incidence of TEAEs were observed between treatment arms. Pharmacokinetic exposure increased more than dose proportionally over 2.1–420 mg for single‐ascending doses but were approximately dose proportional for single‐ and multiple‐ascending doses ≥ 70 mg following subcutaneous administration. No pharmacokinetic differences were observed based on ethnicity between Japanese and White participants following body weight adjustments. Incidence of antidrug antibodies to astegolimab in healthy participants in the single‐ and multiple‐ascending dose studies was 14%–23% and 33%–50% for subcutaneous and intravenous administration, respectively. Astegolimab was well tolerated in these Phase I studies with no safety concerns identified. Thus, further assessment of astegolimab in targeted patient populations was justified; the Phase IIb ALIENTO and Phase III ARNASA trials in patients with chronic obstructive pulmonary disease are ongoing.

Background Inhibition of interleukin (IL)-13, a Type 2 inflammatory mediator in asthma, improves lung function and reduces exacerbations; however, more effective therapies are needed. A subset of asthma patients also exhibits elevated IL-17, which is associated with greater disease severity, neutrophilic inflammation, and steroid resistance. BITS7201A is a novel, humanized bispecific antibody that binds and neutralizes both IL-13 and IL-17. Methods Safety, pharmacokinetics, and immunogenicity of BITS7201A were evaluated in a phase 1 study. Part A was a single ascending-dose design with 5 cohorts: 30-, 90-, and 300-mg subcutaneous (SC), and 300- and 750-mg intravenous (IV). Part B was a multiple ascending-dose design with 3 cohorts: 150-, 300-, and 600-mg SC every 4 weeks × 3 doses. Both parts enrolled approximately 8 healthy volunteers into each cohort (6 active: 2 placebo). Part B included an additional cohort of patients with mild asthma (600-mg SC). Results Forty-one subjects (31 active, 10 placebo) and 26 subjects (20 active, 6 placebo) were enrolled into Parts A and B, respectively. The cohort with mild asthma patients was terminated after enrollment of a single patient. No deaths, serious adverse events, or dose-limiting adverse events occurred. In Part A, 12 active (39%) and 5 placebo subjects (50%), and in Part B, 6 active (30%) and 3 placebo subjects (50%) experienced at least 1 treatment-emergent adverse event (TEAE). The most common AEs were fatigue ( n  = 3) and influenza-like illness ( n  = 2). One injection-site reaction was reported. Two subjects with elevated blood eosinophil counts at baseline had transient elevations in blood eosinophils (≥Grade 2, > 1500 cells/μL). In Parts A and B, 16 of 30 (53%) and 16 of 17 (94%) active subjects, respectively, tested positive for anti-drug antibodies (ADAs). No anaphylaxis or hypersensitivity events occurred. BITS7201A exhibited single- and multiple-dose pharmacokinetic characteristics consistent with an IgG monoclonal antibody; exposure generally increased dose-proportionally. Postdose elevations of the serum pharmacodynamic biomarkers, IL-17AA and IL-17FF, occurred, confirming target engagement. Conclusions BITS7201A was well tolerated, but was associated with a high incidence of ADA formation. Trial registration ClinicalTrials.gov , NCT02748642; registered April 6, 2016 (retrospectively registered).

AimTo review the compliance of prescribing and long-term management of aspirin. This retrospective audit aims to review the data in accordance with the anticoagulation guideline for paediatric cardiac patients post-surgical intervention.MethodElectronic records of patients were searched using keywords such as ‘aspirin, cardiology, cardiothoracic, cardiac ward.’ Data was collected between September 2022 to July 2023.Data retrieved was then processed based on data integrity and the inclusion and exclusion criteria set by the ‘Anticoagulation Guideline for Cardiac Patients’1 available on the trust intranet. Each medication note for each patient was then reviewed, to investigate the indication and duration.ResultsAmong the indications included in the guideline, there are three instances that require low-dose aspirin as an antiplatelet: RV-PA conduits using Hancock or Perimount bioprostheses or Contegra, which require a 3-month course after conduit replacement. Kawasaki disease requires high-dose aspirin for its treatment and maintenance. After the inclusion/exclusion criteria was applied, 88 patients were identified.1–4Aspirin was frequently prescribed for staged palliation, specifically the Norwood procedure, with 33 patients undergoing this procedure and being prescribed aspirin for its antiplatelet effects. Overall, 65 out of 88 patients (73.86%) were prescribed aspirin as indicated within the guideline. However, 23 patients (26.14%) were prescribed aspirin off-indication. Among these 23 patients, 8 were related to cardiac catheterisation, and 5 were associated with major artery repair, including the aorta and pulmonary artery.Over 90% of the doses were prescribed in accordance with the guideline. For those doses not prescribed per the guideline, they were still within the licensed range for antiplatelet dosing.Out of 88 patients, 18 required a set duration for their aspirin therapy, but only one patient met the target duration specified in the guideline. Only 5 patients were clearly documented within their records reasons for changes to their aspirin course length.ConclusionThe audit revealed several key points regarding the prescribing and administration of aspirin in patients undergoing staged palliation and other procedures. Firstly, it was observed that majority of prescriptions (73.86%) adhered to the guidelines. However, a significant proportion (26.14%) were prescribed off-indication, highlighting a potential area for improving adherence to prescribing guidelines or for guidance to be updated to match current practice.The high compliance rate (92%) is commendable. Nonetheless, the few deviations, although within the licensed range for antiplatelet dosing, suggest a need for enhanced documentation.One contributing factor to dosing discrepancy could be the transitioning of care after discharge. When patients are discharged to primary or secondary care, dosing appeared to continue as it was during hospitalisation despite patient weight change, potentially leading to sub-optimum dosing. Protocol updates along with continuous education on improving documentation and follow up is needed within the department to meet audit standards.ReferencesGupta WR, Taylor A, Moenkemeyer F, et al. Anticoagulation guideline for cardiac patients. Internal Guideline, Great Ormond Street Hospital, 2023.Schrör K. Aspirin and Platelets: The Antiplatelet Action of Aspirin and Its Role in Thrombosis Treatment and Prophylaxis. Semin Thromb Hemost 1997;23:349–356. DOI: 10.1055/s-2007-996108.Li JS, Yow E, Berezny KY, et al. Clinical outcomes of palliative surgery including a systemic-to-pulmonary artery shunt in infants with cyanotic congenital heart disease. Circulation 2007;116:293-297. DOI: 10.1161/CIRCULATIONAHA.106.652172.Zheng X, Yue P, Liu L, et al. Efficacy between low and high dose aspirin for the initial treatment of kawasaki disease: current evidence based on a meta-analysis. PLOS ONE 2019;14:e0217274. DOI: 10.1371/journal.pone.0217274.

Objective To examine behavioral and body size influences on the underreporting of energy intake by obese and normal-weight women. Design Seven-day estimated food records were kept by subjects before they participated in a 49-day residential study. Self-reported energy intake was compared with energy intake required to maintain a stable body weight during the residential study (reference standard). Energy intake bias and its relationship to various body size and behavioral measures were examined. Subjects Twenty-two, healthy, normal-weight (mean body mass index [BMI]=21.3) and obese (mean BMI=34.2) women aged 22 to 42 years were studied. Statistical analyses Analysis of variance, paired t test, simple linear regression, and Pearson correlation analyses were conducted. Results Mean energy intake from self-reported food records was underreported by normal-weight (−9.7%) and obese (−19.4%) women. BMI correlated inversely with the energy intake difference for normal-weight women ( r=−.67, P=.02), whereas the Beck Depression Inventory correlated positively with the energy intake difference for obese women ( r=.73, P<.01). Conclusion/applications Results suggest that body size and behavioral traits play a role in the ability of women to accurately self-report energy intake. BMI appears to be predictive of underreporting of energy intake by normal-weight women, whereas emotional factors related to depression appear to be more determinant of underreporting for obese women. Understanding causative factors of the underreporting phenomenon will help practicing dietitians to devise appropriate and realistic diet intervention plans that clients can follow to achieve meaningful change. J Am Diet Assoc. 1999;99:300-306.

Mycophenolate mofetil (MMF) is widely used to prevent acute rejection in adults after renal, cardiac, and liver transplantation. This study investigated the safety, tolerability, and pharmacokinetics of MMF suspension in pediatric renal allograft recipients. One hundred renal allograft recipients were enrolled into three age groups (33 patients, 3 months to <6 years; 34 patients, 6 to <12 years; 33 patients, 12 to 18 years). Patients received MMF 600 mg/m2 b.i.d. concomitantly with cyclosporine and corticosteroids with or without antilymphocyte antibody induction. One year after transplantation, patient and graft survival (including death) were 98% and 93%, respectively. Twenty-five patients (25%) experienced a biopsy-proven (Banff grade borderline or higher) or presumptive acute rejection within the first 6 months post-transplantation. Analysis of pharmacokinetic parameters for mycophenolic acid (MPA) and mycophenolic acid glucuronide showed no clinically significant differences among the age groups. The dosing regimen of MMF 600 mg/m2 b.i.d. achieved the targeted early post-transplantation MPA 12-h area under concentration-time curve (AUC0-12) of 27.2 microg h per ml. Adverse events had similar frequencies among the age groups (with the exception of diarrhea, leukopenia, sepsis, and anemia, which were more frequent in the <6 years age group) and led to withdrawal of MMF in about 10% of patients. Administration of MMF 600 mg/m2 b.i.d. is effective in prevention of acute rejection, provides predictable pharmacokinetics, and is associated with an acceptable safety profile in pediatric renal transplant recipients.

Retirement and declining student interest are contributing to a reduction in the United States science and engineering workforce. This reduction is particularly evident in the recruitment and retention of research and development (R&D) personnel in Federal service. An examination of the career paths of scientists and engineers in civil service reveals new possibilities in recruitment and retention. The methodology of this study is participatory research in which each participant is a partner in discourse oriented toward new understanding. Thirty-nine participants (senior-level: n = 18; mid-level: n = 11; entry-level: n = 10) were selected from among Federal R&D scientists and engineers in senior management, mid-management, and entry-level positions within California. Interpretation and analysis of the data were performed using critical theory, critical hermeneutics, and the new biology. Through discourse, self-reflection, critique of work, and examination of assumed meanings, participants and the researcher arrived at a fuller understanding of the meaning of work in the Federal R&D environment. While the R&D work performed by Federal scientists is self-generating, these professionals are housed under a mechanistic, stifling structure. To be able to function despite this structure, these Federal employees need for society in general to recognize their contributions. They need acknowledgement that they, to a greater extent than those outside civil service, are fulfilling the responsibilities of citizenship when they work at below-market salary levels. They need to be granted both the authority and the funding necessary to conduct research which does not necessarily result in a marketable commodity in a short time span. When appropriate, they need a solution to the problem of disparate cost-of-living levels across the United States. A mentor program would greatly ease the transition of research and job responsibilities when Federal employees retire. To ensure a viable Federal scientific workforce for the future, the goals of science-centered higher education need to be reassessed as well.

Purpose This paper reviews whether China’s Guangdong-Hong Kong-Macao Greater Bay Area (GBA) can be developed into a sustainable innovation technology and finance hub through analysing the policy measures and actions taken by the governments to deal with the challenges in the plan implementation. Design/methodology/approach The study employs a qualitative framework based on policy document reviews, including the GBA Development Plan (2021-2035) and cross-border case studies of Hong Kong and Shenzhen. A comparative approach evaluates the GBA’s progress with those of global best practices in sustainable urban development and innovation ecosystems in Japan and the USA. Findings The GBA has made significant achievements in sustainable innovation, driven by strong policy support for R&D investment and cross-border collaboration. However, some challenges such as regulatory harmonisation and economic disparities amongst cities are identified. The case studies of Hong Kong and Shenzhen reveal that Hong Kong is one of the world’s leading finance centres, serving as a gateway between Mainland China and the world. In contrast, Shenzhen has emerged as a pioneer in high-tech industries, advanced manufacturing, and sustainable urban growth. Deeper collaboration between the governments and the communities — the market, private enterprises, and professional communities — is required to ensure long-term policy coherence, collaborative governance, and inclusive growth, in securing the GBA’s position as a 21st-century leader in finance, technology, and sustainability. Originality/value The paper provides a comparative review of the development of the GBA through analysing the two cases of Hong Kong and Shenzhen, as well as a comparison with Tokyo, New York and San Francisco Bay Areas.

In the PREVENT-19 phase 3 trial of the NVX-CoV2373 vaccine (NCT04611802), anti-spike binding IgG concentration (spike IgG), anti-RBD binding IgG concentration (RBD IgG), and pseudovirus 50% neutralizing antibody titer (nAb ID50) measured two weeks post-dose two are assessed as correlates of risk and as correlates of protection against COVID-19. Analyses are conducted in the U.S. cohort of baseline SARS-CoV-2 negative per-protocol participants using a case-cohort design that measures the markers from all 12 vaccine recipient breakthrough COVID-19 cases starting 7 days post antibody measurement and from 639 vaccine recipient non-cases. All markers are inversely associated with COVID-19 risk and directly associated with vaccine efficacy. In vaccine recipients with nAb ID50 titers of 50, 100, and 7230 international units (IU50)/ml, vaccine efficacy estimates are 75.7% (49.8%, 93.2%), 81.7% (66.3%, 93.2%), and 96.8% (88.3%, 99.3%). The results support potential cross-vaccine platform applications of these markers for guiding decisions about vaccine approval and use. Authors have previously reported on the efficacy and safety of the recombinant spike protein nanoparticle vaccine, NVX-CoV2373, in healthy adults. In this work, they assess anti-spike binding IgG, anti-RBD binding IgG and neutralising antibody titer as correlates of risk and protection against COVID-19.