Royal Free London 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.

Despite accessible and effective HIV treatment, the health and wellbeing of people with HIV can be negatively affected by social and economic disadvantage and stigma. We assessed needs and unmet needs for health and welfare services among people with HIV in the UK. Positive Voices 2022 is a questionnaire study of 4622 adults, conducted between April 11, 2022, and March 31, 2023, at 101 clinics in the UK. Participants self-completed a confidential questionnaire, including questions on sociodemographics, HIV-related factors, lifestyle factors, mental and physical health, and health and social care service needs; we included participants who provided sociodemographic data, year of HIV diagnosis, and at least one response about health care and other needs (4326 [93·6%] of 4622). 27 health and welfare services were grouped into five categories: HIV-related services; mental health services; welfare services; lifestyle services; and drug services. We assessed the association of sociodemographic factors with those who reported a service need, and those with an unmet need among those with a service need, using logistic regression, adjusted for age group, sociodemographic group, and year of HIV diagnosis. For the 4326 participants, the median age was 53 years (IQR 44-60) and 996 (22·3%) were diagnosed with HIV between 2014 and 2023. The study population was predominantly gay, bisexual, and other men who have sex with men ([GBMSM] 2564 [59·3%]) and men of any sexual orientation (3237 [74·8%]). 260 (6·0%) were Black African heterosexual men and 360 (8·3%) were heterosexual men of other ethnicity. Of the 1031 women, 574 (13·3%) were Black African women, 457 (10·6%) were women of other ethnicities; and 2·6% (111) people were from other or undisclosed gender identities or sexualities. The most common reported needs were HIV-related (2779 [64·2%]), followed by mental health services (1877 [43·4%]), lifestyle (1492 [34·4%]), and welfare services (1492 [34·4%]). Need for drug services was lower (305 [7·1%]). For each area, service need was greater for younger people, those facing financial hardship, and those not in employment (compared with those who were employed or retired). GBMSM had lower need for HIV-related, welfare, and lifestyle services than most other sociodemographic groups but higher need for drug services. Heterosexual men had the lowest need for mental health services. Among those with a service need, unmet need was lower for HIV-related services (1153 [41·5%] of 2779) than other service categories (from 66·2% to 70·3%), and was associated with younger age, financial hardship, and demographic group. A substantial proportion of people with HIV who have mental health, welfare, and lifestyle needs in the UK are not receiving these services. Regular assessment of such needs, with referral and service signposting to appropriate services, should be implemented to benefit the wellbeing of this population. UK National Institute for Health Research.

Abstract Background Long-term antiplatelet therapy reduces recurrent stroke after symptomatic carotid endarterectomy (sCEA). While both aspirin and clopidogrel are recommended, regional guidelines differ—and real-world practice may not always align. This study surveyed vascular surgeons to assess global prescribing patterns and compare them to local guideline recommendations. Methods Consultant vascular surgeons in four regions (UK, Europe, Australasia, Brazil) received an online questionnaire regarding their preferred long-term antiplatelet regimen following sCEA. We collected 357 responses (UK:192; Europe:107; Brazil:23; Australasia:35) and compared drug choices to regional guidelines. Mann–Whitney U tests (P < 0.05) and binary logistic regression were used to identify predictors of guideline adherence. Results Prescribing patterns varied significantly by region (P < 0.001). Clopidogrel was most common in the UK (80%), aligning with NICE guidance. Aspirin predominated in Australasia (89%) and Brazil (44%), consistent with local protocols. Guideline adherence was 80% in both the UK and Australasia (P > 0.05), but only 40% in Brazil. In Europe, aspirin and clopidogrel were similarly prescribed (43% 40%), despite ESVS guidance favouring clopidogrel, yielding 55% adherence. Dual-antiplatelet therapy was used by 9.5% overall, most frequently in Brazil (P < 0.01), despite guideline discouragement. Surgeon annual CEA volume and teaching-hospital status did not influence prescribing. Binary logistic regression confirmed region as the sole independent predictor of guideline adherence (P < 0.01). Conclusions Antiplatelet regimens post-sCEA vary globally. While most regions follow local guidelines, adherence is poorest in Europe and Brazil. Off-guideline dual therapy persists in 10% of cases. Improved dissemination and implementation strategies are needed to standardise prescribing and optimise stroke prevention.

Abstract Introduction Minimally invasive techniques have transformed early rectal cancer treatment; yet the optimal approach is unclear. ESD, EMR, and TAMIS are increasingly being used, however, most studies only compare two of these techniques. This meta-analysis directly compares all three in efficacy, safety, and oncological performance. Methods PubMed, Scopus, and Medline were searched to identify relevant studies as of September 2024. Criteria included studies in adults with early rectal cancer treated by ESD, EMR, or TAMIS, reporting at least one outcome and specifying treatment type and cancer stage. Comprehensive Meta-Analysis v4 was used for analysis with heterogeneity assessed via I². Results A total of 127 studies encompassing 8915 patients were included (EMR = 3979, ESD = 4470, and TAMIS = 466). Mean procedural times were: overall 8.3 min (7.7–8.8), I² = 99%; EMR 7.5 (6.9–8.1), I² = 98%; ESD 32.6 (29.3–36), I² = 99%; TAMIS 101.6 (83.9–119.9), I² = 95%. En bloc resection: overall 87.1% (85.6–88.5), I² = 81%; EMR 86.5% (84.4–88.4), I² = 82%; ESD 87.2% (84.4–89.5), I² = 80%; TAMIS 94.1% (88.9–97), I² = 0%. R0 resection: overall 79.7% (78.6–80.8), I² = 80%—EMR 79.9% (78.3–81.5), I² = 85%; ESD 78.7% (77.1–80.3), I² = 76%; TAMIS 87.1% (82.8–90.4), I² = 42%. Conclusions Although EMR appears efficient, it demonstrated less favourable outcomes regarding en bloc resection. ESD showed favourable oncological outcomes while maintaining moderate procedural time. TAMIS is most time-intensive but yields the highest resection quality.

To explore missed opportunities for PrEP use among people with recently acquired HIV in the United Kingdom. Data were derived from CASCADE, an international, longitudinal, mixed-methods study of adults (≥16 years) with recently acquired HIV (≤12 months). Individuals were recruited from nine UK clinics (08/2022-09/2024) to self-complete a questionnaire; a subset participated in semi-structured interviews (SSIs). 46 questionnaires were completed (39 cisgender men and 7 women, including 2 transgender women) and 11 SSIs (1 cisgender woman). Among men, 22 perceived HIV risk before diagnosis; 21 had ≥5 sexual partners and 17 reported group sex in the 3 months before diagnosis. Thirty (29 men and 1 woman) reported sexualized drug use. Twenty men had ever used PrEP; seven of them had not used it in the 6 months prior to diagnosis. No women had ever used PrEP. Most gay, bisexual and other men who have sex with men (GBMSM) were aware of PrEP; however, risk perception, social meanings of PrEP and concerns about side effects hindered utilization. Among five men using event-based dosing (EBD), three described difficulty predicting sexual activity that led to missed or mistimed pre-/post-sex doses - while others were reluctant to take daily PrEP. For women, the biggest barrier was lack of awareness. PrEP barriers vary by population. For GBMSM, addressing barriers to uptake/adherence (e.g., EBD challenges) are key, highlighting the potential benefit of long-acting injectables. However, awareness of PrEP remains a key challenge for women to achieve equity in prevention.

To determine the future priorities for ectopic pregnancy research. Potential research questions were collated from an initial international survey, a systematic review of clinical practice guidelines, and Cochrane systematic reviews. A rationalized list of confirmed research uncertainties was prioritized in an interim international survey. Prioritized research uncertainties were discussed during a consensus development meeting. Using a formal consensus development method, the modified nominal group technique, diverse stakeholders identified the top 10 research priorities for future ectopic pregnancy research. Healthcare professionals, people with lived experience of ectopic pregnancy, and others were brought together in an open and transparent process using formal consensus methods advocated by the James Lind Alliance. Not applicable. Top 10 research priorities for ectopic pregnancy. The initial survey was completed by 855 participants from 35 countries, and 1,220 potential research questions were submitted. Three clinical practice guidelines and 43 Cochrane systematic reviews identified a further 24 potential research questions. A rationalized list of 49 confirmed research uncertainties was entered into an interim prioritization survey completed by 413 respondents from 20 countries. The top 10 research priorities were identified during a consensus development meeting involving 37 participants from 10 countries. These research priorities are diverse and seek answers to questions regarding prevention, treatment, and the longer-term impact of ectopic pregnancy. We anticipate that the identified research priorities, developed to specifically highlight the most pressing clinical needs as perceived by healthcare professionals, people with lived experience of ectopic pregnancy, and others, will help research funding organizations and researchers to develop their future research agenda.

To assess the long-term anatomical and visual outcomes of primary scleral buckle (SB) surgery for rhegmatogenous retinal detachment (RRD) and identify predictors of surgical and functional success. All primary SB procedures performed at Manchester Royal Eye Hospital between January 2008 and December 2023 were reviewed retrospectively. Preoperative, intraoperative and postoperative data were extracted from electronic records. Primary end-points were single-surgery anatomical success (SSAS) and final best-corrected visual acuity (BCVA); univariate and multivariate regression analyses examined predictive variables and complications. 608 eyes were included. SSAS was achieved in 515 eyes (85%) and final anatomical success in 602 eyes (99%). Mean BCVA improved from 0.62±0.85 to 0.32±0.49 logarithm of the minimum angle of resolution (logMAR) (p<0.01). On multivariate analysis, age >40 years (OR 0.55, 95% CI 0.37 to 0.83; p=0.004), macula-off status (OR 0.65, 95% CI 0.44 to 0.97; p=0.034) and ocular trauma (OR 0.40, 95% CI 0.19 to 0.82; p=0.012) independently reduced SSAS. For visual outcomes, macula-off detachment (β=+0.36; p<0.001) and ocular trauma (β=+0.42; p<0.001) were independent predictors of worse postoperative BCVA. The most common complications were subretinal haemorrhage (4.6%), inadvertent deep sutures (3.9%) and postoperative ocular hypertension (7.4%). Primary SB provided high anatomical success, significant visual improvement and a favourable safety profile in this large single-centre study. Age above 40 years, macula-off status and ocular trauma predicted poorer SSAS; trauma and macula-off status were also associated with worse postoperative BCVA on multivariate logistic regression.

Since first being introduced over 50 years ago, ophthalmic viscoelastic devices (OVDs) have revolutionised the fields of cataract, cornea and glaucoma surgery, with extensive published anterior segment safety data available. More recently, these devices have also gained popularity in posterior segment surgery, with particular focus on their potential use as long-lasting, non-toxic, biocompatible and biodegradable vitreous substitutes. The most commercially available products are based on hydrophilic polymers such as hyaluronic acid (HA), hydroxypropylmethylcellulose (HPMC) and chondroitin sulfate (CS). This remains a novel area of research, with very few studies examining their long-term safety profile. We conducted a systematic review on Medline and Embase via OVID, using key words "viscoelastics" and "intraocular". Both databases were searched from inception date, with no language limitations. There is a paucity of high-quality evidence addressing the long-term safety of OVDs in the eye. A total of 38 studies were included for final review. These studies were unsuitable for any direct head-to-head comparisons; therefore, a descriptive analysis is presented. By far, HA-based OVDs have been the most well described, with several long-term intraocular applications. They display highly favourable biophysical properties with minimal adverse reactions in short and long-term in vivo, in vitro and animal studies. There is limited safety data on HPMC and CS-based products, despite their popularity. This represents a gap in the literature and invites the need for high-quality evidence to support their continued use, particularly in the realms of vitreoretinal surgery and chronic hypotony.