St. James's Hospital

Hereditary angioedema is a bradykinin-mediated, rare condition characterised by recurrent and potentially life-threatening attacks of subcutaneous and submucosal swelling. Bradykinin B2 receptor antagonism is a proven mechanism for on-demand treatment of attacks, but no evidence exists on its effects when used prophylactically. Deucrictibant is an investigational orally bioavailable bradykinin B2 receptor antagonist. We aimed to evaluate the efficacy, safety, and tolerability of two dose regimens of oral deucrictibant administered as prophylaxis against hereditary angioedema attacks. CHAPTER-1 was a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial conducted in two parts, a double-blind placebo controlled first part and an open-label second part, with only part 1 reported here. Part 1 recruited adults (aged 18-75 years) with hereditary angioedema type 1 or 2 from 37 sites (university hospitals and accredited angioedema centres) across North America, Europe, and Israel. Patients required a documented history of three or more attacks within the last 3 consecutive months before screening or two or more during the screening period (up to 8 weeks) to be eligible. An interactive response technology system randomised eligible patients 1:1:1 to receive oral deucrictibant 20 mg daily, 40 mg daily, or matching placebo for 12 weeks. Randomisation to treatment groups was stratified by the baseline attack rate. Patients, investigators, site personnel, and the sponsor were blinded to treatment assignment. Masking was achieved with identically appearing deucrictibant and placebo capsules. The primary endpoint was the time-normalised number of investigator-confirmed attacks per 4 weeks (monthly attack rate) from weeks 1 to 12 and was assessed using the intention-to-treat set. The endpoint was analysed by comparing each deucrictibant group with the placebo group using a Poisson generalised linear model with a log link function and Pearson's χ2 scaling of SEs to account for potential dispersion. The safety analysis set included all patients who were randomly assigned and who received one or more doses of study drug (deucrictibant or placebo). CHAPTER-1 is registered with ClinicalTrials.gov (NCT05047185) and is now complete. Between March 9, 2022, and June 19, 2023, 44 patients were screened. Of 34 patients who were randomly assigned, 11 patients received deucrictibant 20 mg, 12 patients received deucrictibant 40 mg, and 11 patients received the placebo, with a median follow-up of 85·0 days (IQR 84·0-86·0). 21 (62%) patients were female, 13 (38%) were male, and 34 (100%) patients were White. The least squares mean monthly attack rate (primary analysis) was 0·40 (95% CI 0·18-0·92) for deucrictibant 20 mg, 0·30 (0·11-0·81) for deucrictibant 40 mg, and 1·93 (1·30-2·88) for placebo; percent reduction in attack rate compared with placebo was 79·2% (95% CI 47·2-91·8) for deucrictibant 20 mg (p=0·0010) and 84·5% (95% CI 53·8-94·8) for deucrictibant 40 mg (p=0·0008). Treatment-related treatment-emergent adverse events were experienced by two (18%) patients receiving deucrictibant 20 mg, one (8%) patient receiving deucrictibant 40 mg, and one (9%) patient receiving the placebo; all were mild in severity (grade 1) and did not require dosing modification of the study drug. There were no serious adverse events or deaths in any treatment group. To the best of our knowledge, this trial provides the first clinical evidence and proof-of-concept for bradykinin B2 receptor antagonism as a therapeutic approach for the prevention of hereditary angioedema attacks and supports further investigation of oral deucrictibant for bradykinin-mediated angioedema. Pharvaris.

Lung cancer is the leading cause of cancer-related mortality worldwide, accounting for more deaths than any other malignancy. Despite advances in treatment, it remains highly lethal, with 5-year survival rates showing minimal improvement over the past several decades, highlighting a critical unmet clinical need. Macrophage Migration Inhibitory Factor (MIF) is a multifunctional cytokine that contributes to inflammation and cancer, promoting tumor growth, progression, and metastasis through modulation of the tumor microenvironment, stimulation of angiogenesis, and regulation of immune responses. Polymorphisms in the promoter region of MIF, such as high-expression CATT repeats, influence MIF expression and susceptibility to a range of inflammatory, autoimmune, and malignant disorders, yet their role in lung cancer remains largely unexplored. Therapeutic strategies targeting MIF, including small-molecule inhibitors, antibodies, and peptide-based agents, have shown promise in preclinical models, although their clinical translation is still limited. This review discusses the dual role of MIF in inflammation and oncology, summarizes current therapeutic developments, and emphasizes the potential of MIF-targeted interventions in lung cancer. It discusses the significance of genetic predisposition, particularly high-expression MIF alleles, in guiding personalized treatment strategies for lung cancer and identifying patients who may derive benefit from MIF inhibition.

Staphylococcus aureusis a critical global health threat due to its multidrug resistance (MDR) and virulence. We examined the relationship between MDR and virulence in 250 clinical S. aureus isolates using the Galleria mellonella infection model. Alpha-hemolysin was the most prevalent toxin, with its gene, hla, present in the majority of hemolytic strains. Other virulence genes, including sigB, codY, fnbA, fnbB, clfA, saeS, sarA, arlS, yycG, spoVG, rot, and PVL, were widely distributed across methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) isolates. The ica gene showed a notable increase in expression in hospital-acquired (HA-MRSA) and community-acquired (CA-MRSA) strains. In vivo infections revealed that HA-MRSA strains were more virulent than vancomycin intermediate S. aureus VISA, CA-MRSA, MSSA, and an agr mutant strain, while locally sourced CA-MRSA exhibited the highest virulence among tested strains. Despite differences in antibiotic resistance, MRSA and MSSA shared largely similar virulence gene profiles. These findings highlight the complex interplay between MDR and virulence in S. aureus and emphasize the need for further mechanistic studies.Importance: S. aureus remains a major clinical concern due to its increasing multidrug resistance (MDR) and virulence. Understanding the relationship between resistance mechanisms and virulence is essential for guiding effective treatment and infection control. This study assessed the virulence potential of 250 MDR S. aureus isolates using a clinically relevant invertebrate model (G. mellonella), revealing key virulence gene profiles. Notably, CA-MRSA strains exhibited hypervirulence, with alpha-hemolysin as the most prevalent toxin and significant upregulation of the ica gene in both CA- and HA-MRSA isolates. These findings emphasize the growing threat of CA-MRSA and the importance of integrated surveillance of both resistance and virulence in S. aureus populations.

Dual-specificity phosphatase 1 (DUSP1) is a negative regulator of mitogen-activated protein kinase (MAPK) activity, and a player in the control of glial function. Several disease models have identified that the expression of DUSP1 is altered in tissue samples, which may contribute to disease pathogenesis. Using post-mortem brain tissue from a cohort of progressive multiple sclerosis (MS) cases, this study set out to determine if the expression of DUSP1 is altered in the brain in MS. We employed the use of a combination of PCR, western immunoblotting and immunohistochemical analysis to profile the expression of DUSP1. Data presented herein indicate that DUSP1 is significantly downregulated at gene and protein level in MS white matter tissue, when compared to samples from a non-MS control cohort. We also identify that DUSP1 is expressed on Iba1+ cells in the brain and that ITGAM (CD11b) expression is elevated in white matter in progressive MS. These findings provide evidence that DUSP1 is dysregulated centrally in CNS white matter in progressive MS.

Sepsis and septic shock remain major causes of morbidity and mortality worldwide, and management is largely based on source control, antimicrobial therapy, and supportive care. Despite limited high-quality evidence, adjunctive therapies targeting the dysregulated host response involving immune dysfunction, coagulopathy, and endothelial injury, steroids, vasopressors, and adjunctive therapies are frequently used in clinical practice. This survey aimed to describe real-world patterns of sepsis therapy across Europe. We conducted an open, web-based, multinational survey endorsed by the European Society of Intensive Care Medicine (ESICM) and the Italian Society of Anesthesia, Analgesia, Resuscitation and Intensive Care (SIAARTI). The survey was distributed through professional mailing lists, newsletters, and national society networks. A structured 30-item questionnaire collected information on respondent demographics, ICU characteristics, availability of adjunctive therapies, clinical indications, triggers for initiation, and duration of treatment. Participation was voluntary and anonymous. A total of 442 physicians completed the survey. Data were analyzed descriptively and are presented as proportions and frequencies. More than 80% of respondents reported use of at least one adjunctive therapy for septic shock within the previous year. Corticosteroids were used by over 90% of clinicians, predominantly hydrocortisone for septic shock. Considerable variability was observed regarding indications, timing of initiation, and duration of therapy. Extracorporeal blood purification techniques were used by approximately 75% of respondents, most frequently hemoadsorption in patients with refractory shock; high cost and limited availability were the main barriers to broader implementation. Intravenous immunoglobulins were used by approximately one-third of clinicians, often guided by measured immunoglobulin levels or perceived immune dysfunction. Additional vasoactive and inotropic agents, including levosimendan, methylene blue, and beta-blockers, were employed in selected cases. In contrast, specific immunomodulatory therapies such as interleukin (IL)-1receptor antibodies were rarely used. Across all adjunctive strategies, marked heterogeneity in practice patterns was evident. Adjunctive therapies are widely used in European ICUs, particularly in patients with severe or refractory sepsis, despite limited supporting evidence. The substantial variability in practice highlights ongoing clinical uncertainty and underscores the need for well-designed randomized trials to inform evidence-based and individualized treatment strategies.

<h3>Background and Importance</h3> The European Statements of Hospital Pharmacy recommend <i>‘A European-wide framework for initial post graduate education and training in hospital pharmacy with an assessment of individual competence is essential’</i>.¹ To facilitate the development of evidence-informed recommendations for improving hospital pharmacist education, national data outlining current practice were required. <h3>Aim and Objectives</h3> Evaluate current standards of practice relating to education within hospital pharmacy. Outline perceived barriers to pharmacist engagement in education. <h3>Material and Methods</h3> A national online survey was developed and distributed to hospital pharmacy managers between May and August 2025 inclusive. The survey was distributed via various methods, including central emailing lists and contacts of the research team. Survey questions addressed Staffing structures. Current levels of education provided. Types of educational activities conducted. Perceived gaps in hospital pharmacist education. Barriers to engagement in pharmacist education. Responses results were analysed descriptively. <h3>Results</h3> Fifty-five (65%) pharmacy managers responded. Key findings included: Only 27% of participants reported having a pharmacist responsible for education. Almost two–thirds (63%) reported having a structured induction for pharmacists. Pharmacist induction included dispensary training (91%), clinical training (85%), and corporate induction (79%). Over three–quarters (79%) of inductions lasted &lt;6 weeks. Seventy percent (70%) provided ongoing departmental education, most through journal clubs (77%), case presentations (60%), and near–miss/error meetings (57%). Over two–thirds (69%) of institutions currently support pharmacists on postgraduate courses, mostly in clinical pharmacy (86%) Formal education was provided by pharmacy to nursing (88%), medical (76%) and allied health professionals (33%), as well as undergraduate (47%) and postgraduate (27%) pharmacy students. Perceived gaps in hospital pharmacy education included advanced practice, inpatient and outpatient medication reviews, and clinical skills. Reported barriers to hospital pharmacy education include lack of funding, time constraints, workload and lack of a structured competency framework specific to hospital pharmacy practice. <h3>Conclusion and Relevance</h3> Hospital pharmacy departments display significant commitment to, and engagement with, education activities nationally. Efforts to introduce a standardised hospital-specific competency framework for new-to-hospital pharmacists, and validated accreditation for advanced practice will help further facilitate this. <h3>References and/or Acknowledgements</h3> 1. The European Statements of Hospital Pharmacy. <i>European Journal of Hospital Pharmacy</i> 2014;<b>21</b>:256–258. <h3>Conflict of Interest</h3> Conflict of interest Corporate sponsored research or other substantive relationships: No conflicts of interest

CD19-directed chimeric antigen receptor (CAR) T-cell therapy has exhibited efficacy in treating relapsed/refractory high-grade B-cell malignancies, but off-tumor effects cause prolonged hypogammaglobulinemia and B-cell aplasia. Limited data exist on pathogen-specific IgG titers post-CD19 CAR T-cell therapy. We evaluated the impact of CD19 CAR T-cell therapy on vaccine-preventable infectious disease IgG titers in 20 patients to assess humoral immunity. IgG titers for measles virus (MeV), mumps virus (MuV), rubella virus (RuV), varicella zoster virus (VZV), pneumococcal capsular polysaccharide, Haemophilus influenzae type B (Hib), and tetanus toxoid were measured at baseline and Day 100 post-CD19 CAR T-cell therapy. Seropositivity for all pathogens remained stable from baseline to Day 100. Quantitative IgG titers for MeV, MuV, RuV, VZV, and tetanus also remained stable. Median pneumococcal IgG and Hib IgG titers declined (p<0.05); however, no arbitrary fourfold decreases were observed. Median total IgG concentrations declined (p<0.05). MeV, MuV, RuV, VZV, and tetanus toxoid IgG remained stable following CD19 CAR T-cell therapy, while pneumococcal and Hib IgG titers showed marginal quantitative declines, without any fourfold reductions. Overall, humoral immunity at Day 100 following CD19 CAR T-cell therapy remained largely preserved. These seroprevalence findings suggest that routine revaccination may not be required in our patient cohort and highlight the importance of patient monitoring to inform revaccination decisions.

Elective caesarean section is a common and painful procedure. Uncontrolled pain following caesarean section can profoundly and negatively on a wide range of patient and healthcare-centred outcomes. The aim of this systematic review was to update existing recommendations for postoperative pain management after elective caesarean section performed under neuraxial anaesthesia. A systematic review using the PROcedure SPEcific Postoperative Pain ManagemenT (PROSPECT) methodology was undertaken. Randomised trials evaluating the efficacy of analgesic, anaesthetic and surgical interventions were retrieved. Systematic reviews and meta-analyses of randomised controlled trials were also reviewed. Trials evaluating pain management for emergency surgical deliveries or caesarean section performed under general anaesthesia were not included. Sixty-one randomised controlled trials were included. For patients undergoing elective caesarean section performed under neuraxial anaesthesia, we recommend that clinicians administer intrathecal morphine 50-100 μg or diamorphine 300 μg pre-operatively, and paracetamol, non-steroidal anti-inflammatory drugs and dexamethasone after delivery. If a neuraxial opioid is not administered, clinicians should use one of a range of recommended fascial plane blocks; alternatively, the wound should be infiltrated with local anaesthetic. The postoperative regimen should include regular paracetamol and non-steroidal anti-inflammatory drugs, with opioids used for rescue. The surgical technique should include a Joel-Cohen incision. The peritoneum should not be closed. An analgesic regimen to manage pain safely and effectively after elective caesarean section based on up-to-date evidence is presented. Consideration has been given to balancing analgesic efficacy and potential adverse effects. Future research should determine the optimal dose of dexamethasone and epidural long-acting opioid, establish the most effective regional analgesic technique and develop standardised outcome sets to better compare techniques.