University Hospital Southampton NHS Foundation Trust

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.

With the global increase in obesity rates, a newly emerging disease, non-alcoholic fatty pancreatic disease (NAFPD), has garnered increasing attention. The most important characteristic of NAFPD is fat accumulation in the pancreas in individuals with minimal alcohol consumption. However, the underlying pathogenesis remains poorly understood. This condition has been described using terms, such as fatty infiltration, fatty pancreas, or pancreatic steatosis. Similar to fat accumulation in the liver, known as metabolic dysfunction-associated steatotic liver disease (MASLD), fat can accumulate in other organs, including the pancreas. Therefore, MASLD and NAFPD have increasingly captured the attention of researchers and clinicians. However, precise quantification of pancreatic fat poses a significant challenge. Given the numerous challenges in diagnosing NAFPD and identifying its risk factors, pathogenesis, and clinical implications, extensive efforts have been made to understand its nature. This review highlights the recent advancements in NAFPD. Large-scale cohort studies and multicenter research efforts are anticipated to enhance our understanding of NAFPD, paving the way for improved early diagnosis, treatment, and exploration of its clinical associations.

The clinical benefits of intensity-modulated proton therapy (IMPT) compared with intensity-modulated radiation therapy (IMRT) for patients with oropharyngeal squamous cell carcinoma remain uncertain with respect to treatment-related effects on physical function and quality of life. We aimed to compare late functional, patient-reported, disease control, and survival outcomes between IMPT and IMRT. We did a phase 3 trial (TORPEdO) in 20 UK National Health Service hospitals. We randomly assigned (2:1) patients with locally advanced oropharyngeal squamous cell carcinoma to IMPT or IMRT (70 Gy in 33 fractions, for 6·5 weeks) with two cycles of high-dose cisplatin (100 mg/m2, every 3 weeks). Co-primary endpoints at 12 months were gastrostomy-tube dependence (use of feeding tube for nutrition) or severe weight loss (≥20% from baseline) and University of Washington quality of life (UW-QoL) mean physical composite score for saliva, taste, chewing, swallowing, speech and appearance. The study was registered with the ISRCTN registry, ISRCTN16424014; recruitment is complete and follow-up is ongoing. Between Feb 25, 2020, and June 13, 2023, we randomly assigned 205 patients (99 [48%] with T3 or T4 disease and 44 [22%] with bilateral neck lymph node involvement (N2[c]); 136 [66%] to IMPT and 69 [34%] to IMRT). 163 (80%) patients were male and 42 (20%) were female. Ethnicity data were self-reported by 177 (86%) patients; most were White British (167 [94%]). At 12 months, gastrostomy-tube dependence occurred in two (2%) of 119 patients in the IMPT group and in one (2%) of 59 patients in the IMRT group and severe weight loss occurred in 20 (18% [97·5% CI 11 to 28]) of 110 patients in the IMPT group and in three (6% [1 to 17]) of 53 patients in the IMRT group (combined odds ratio 2·80 [97·5% CI 0·75 to 10·4]; p=0·079). Mean UW-QoL physical composite scores at 12 months were 78·3 in the IMPT group versus 77·1 in the IMRT group (difference 1·3 [97·5% CI -3·7 to 6·2]; p=0·56). There were 14 serious adverse events in 12 patients (nine assessed as unrelated to the study treatment [four in the IMPT group and five in the IMRT group] and five study treatment-related [one IMPT vs four IMRT]); the most common events were acute kidney injury (five [36%]) and thromboembolism (four [29%]). There were no treatment-related deaths. At a median follow-up of 28·3 months (IQR 26·5 to 39·3), 24-month freedom from loco-regional recurrence rates were 94% (99% CI 86-98) in the IMPT group versus 97% (82-100) in the IMRT group (hazard ratio [HR] 2·6 [99% CI 0·3 to 20·3; 95% CI 0·5-12·4]; p=0·24), and overall survival rates were 95% (86 to 98) in the IMPT group versus 95% (81-99) in the IMRT group (HR 1·6 [99% CI 0·3 to 8·8; 95% CI 0·4 to 5·9; p=0·47). IMPT and IMRT had similar late physical quality of life scores, gastrostomy-tube dependence, local control, and overall survival. In health-care settings where IMPT is not used routinely for oropharyngeal squamous cell carcinoma, IMRT remains the standard of care. Cancer Research UK.

Abstract Introduction: Transvaginal mesh implants have been widely used to treat stress urinary incontinence and pelvic organ prolapse but have been associated with significant complications in some women. Specialist multidisciplinary Mesh Centres have been established to provide expert diagnosis and management. Pelvic health physiotherapy (PHPT) is recommended as part of this provision; however, to date no published interventional studies have directly evaluated PHPT in this population, and there is no consensus to guide high-quality PHPT service delivery. This study aimed to establish expert consensus on the components of high-quality PHPT for women with vaginal mesh-associated complications. Methods: A three-round modified e-Delphi study was conducted with specialist physiotherapists who were members of the Pelvic, Obstetric and Gynaecological Physiotherapy Mesh Centres Committee. Participants rated proposed quality indicators using a five-point Likert scale and provided free-text feedback. Response rates, agreement levels, and consensus stability were assessed. Consensus was predefined as > 75% agreement and stability as < 10% variation between the final two rounds. Results: Thirteen expert physiotherapists completed all three Delphi rounds. Forty quality indicators achieved stable consensus across five domains: (i) holistic care, (ii) integrated care, (iii) surgical care pathways, (iv) non-surgical care pathways, and (v) PHPT treatment modalities. Conclusion: This study establishes the first expert consensus defining high-quality PHPT services for women with vaginal mesh-associated complications. The resulting quality indicators provide a structured framework to inform commissioning, service design, and clinical practice. In the absence of direct interventional evidence, further research is required to evaluate their implementation and impact on patient-centred outcomes.