Search

Introduction The top research priority for cavernoma, identified by a James Lind Alliance Priority setting partnership was ‘Does treatment (with neurosurgery or stereotactic radiosurgery) or no treatment improve outcome for people diagnosed with a cavernoma?’ This pilot randomised controlled trial (RCT) aims to determine the feasibility of answering this question in a main phase RCT.Methods and analysis We will perform a pilot phase, parallel group, pragmatic RCT involving approximately 60 children or adults with mental capacity, resident in the UK or Ireland, with an unresected symptomatic brain cavernoma. Participants will be randomised by web-based randomisation 1:1 to treatment with medical management and with surgery (neurosurgery or stereotactic radiosurgery) versus medical management alone, stratified by prerandomisation preference for type of surgery. In addition to 13 feasibility outcomes, the primary clinical outcome is symptomatic intracranial haemorrhage or new persistent/progressive focal neurological deficit measured at 6 monthly intervals. An integrated QuinteT Recruitment Intervention (QRI) evaluates screening logs, audio recordings of recruitment discussions, and interviews with recruiters and patients/parents/carers to identify and address barriers to participation. A Patient Advisory Group has codesigned the study and will oversee its progress.Ethics and dissemination This study was approved by the Yorkshire and The Humber—Leeds East Research Ethics Committee (21/YH/0046). We will submit manuscripts to peer-reviewed journals, describing the findings of the QRI and the Cavernomas: A Randomised Evaluation (CARE) pilot trial. We will present at national specialty meetings. We will disseminate a plain English summary of the findings of the CARE pilot trial to participants and public audiences with input from, and acknowledgement of, the Patient Advisory Group.Trial registration number ISRCTN41647111.

Introduction Unruptured intracranial aneurysms (UIA) are common in the adult population, but only a relatively small proportion will rupture. It is therefore essential to have accurate estimates of rupture risk to target treatment towards those who stand to benefit and avoid exposing patients to the risks of unnecessary treatment. The best available UIA natural history data are the PHASES study. However, this has never been validated and given the known heterogeneity in the populations, methods and biases of the constituent studies, there is a need to do so. There are also many potential predictors not considered in PHASES that require evaluation, and the estimated rupture risk is largely based on short-term follow-up (mostly 1 year). The aims of this study are to: (1) test the accuracy of PHASES in a UK population, (2) evaluate additional predictors of rupture and (3) assess long-term UIA rupture rates.Methods and analysis The Risk of Aneurysm Rupture study is a longitudinal multicentre study that will identify patients with known UIA seen in neurosurgery units. Patients will have baseline demographics and aneurysm characteristics collected by their neurosurgery unit and then a single aggregated national cohort will be linked to databases of hospital admissions and deaths to identify all patients who may have subsequently suffered a subarachnoid haemorrhage. All matched admissions and deaths will be checked against medical records to confirm the diagnosis of aneurysmal subarachnoid haemorrhage. The target sample size is 20 000 patients. The primary outcome will be aneurysm rupture resulting in hospital admission or death. Cox regression models will be built to test each of the study’s aims.Ethics and dissemination Ethical approval has been given by South Central Hampshire A Research Ethics Committee (21SC0064) and Confidentiality Advisory Group support (21CAG0033) provided under Section 251 of the NHS Act 2006. The results will be disseminated in peer-reviewed journals.Trial registration number ISRCTN17658526.

Since the late 2000s, New Zealand has largely followed an asymmetrical hedging strategy in its foreign policy: growing its trade relationship with China while concurrently remaining firmly within the US-led security architecture. However, as the room for hedging in the Indo-Pacific has shrunk, especially after Wellington adopted an Indo-Pacific outlook in 2019, New Zealand has taken steps to lessen its trade reliance on China while further committing itself within the Anglosphere. Since the election of the Sixth National Government of New Zealand in late 2023, Wellington appears to be tentatively switching from a strategy of hedging to something closer to a more conventional balancing strategy, evident in its efforts to participate in AUKUS. While the current situation can still be characterized as an asymmetrical hedge given the ongoing importance of China, if the room for hedging continues to shrink, it is likely that New Zealand will completely abandon its hedge in the future. [ABSTRACT FROM AUTHOR]

The topic of whether New Zealand should participate in AUKUS or not has emerged as a significant debate in popular political discourses in 2024. Thus far, clear pro-AUKUS and anti-AUKUS camps have developed. The pro-AUKUS camp emphasises the growing threat of China in the Indo-Pacific and New Zealand's lacking technological capabilities that have it exposed if a conflict emerges. The anti-AUKUS camp emphasises New Zealand's embedded independent foreign policy and staunch anti-nuclear stance which makes participating in AUKUS an ethically untenable option. However, neither side has considered the deeper, ontological questions on the table and how this affects New Zealand's main foreign policy concern: the Pacific. New Zealand's recent engagement with the Pacific and its experimentation with a Māori foreign policy led it to being a champion of the Blue Pacific narrative, an ontologically distinct approach that challenges the geopolitically-focussed Indo-Pacific concept. Yet, in the wake of New Zealand's flirtation with AUKUS, the Blue Pacific has been largely ignored in debates. Ultimately, the debate about AUKUS misses the big picture as it, so far, limits the focus on the true existential threat to New Zealand and the Pacific which is not China's rise but rather climate change. [ABSTRACT FROM AUTHOR]

Friendship is an important aspect of a state's ability to succeed in great power politics, especially with regards to international order reshaping or building. Through engaging with the extant literature on friendship in International Relations, it is posited that while friendships tend to arise along strategic or normative dimensions, the most important (and enduring) friendships are bilateral relationships which are also culturally and historically aligned—what this article terms a bona fide international friendship. With China's rise continuing apace, the importance for it to have friends, especially powerful ones, is self-evident. This article examines the concept of friendship in the scope of China's foreign policymaking, identifying an increased effort to cultivate friendships. However, this article argues that as it currently stands, China does not appear to have any significant bona fide friends. Russia may yet emerge as a serious contender as a bona fide friend for China, but substantial issues may arise in that friendship in the coming decades. Thus, for China, and other aspiring international powers, building bona fide international friendships with prominent international powers is a critical task ahead because international orders underpinned by bona fide friendships will likely be more resilient than those orders that are not. [ABSTRACT FROM AUTHOR]

Abstract Objective To evaluate the cost‐effectiveness of various topical prophylaxis strategies against posttympanostomy otorrhea using a break‐even analysis. Study Design An economic decision analysis of data collected from purchasing records and the literature. Setting An academic center. Methods Costs of various strategies were calculated by querying our institution's pharmacy as well as GoodRX.com drug prices. Posttympanostomy otorrhea rates were acquired from a review of the literature. Costs for treatment of otorrhea were based upon our institution's self‐pay patient charges. A break‐even analysis was performed to determine the required absolute risk reduction (ARR) in otorrhea rate to make prophylactic treatment cost‐effective. Results The most expensive strategy ciprofloxacin/hydrocortisone otic ($626.83) was not cost‐effective unless the rate of postoperative otorrhea was greater than 92% or if the cost of otorrhea treatment exceeded $4477.36. The cheapest antibiotic/steroid combination, ciprofloxacin/dexamethasone otic ($72.25) was cost‐effective (ARR 10%). Using a conservative initial otorrhea rate (14%) and weighted cost of treatment ($683.39), the most expensive cost‐effective prophylactic intervention possible was $95.67. Conclusion Prophylaxis against posttympanostomy otorrhea can be cost‐effective. Physicians should consider the cost of prophylaxis at their institution as well as the patient's postoperative risk of otorrhea when making treatment decisions.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. The combination of tremelimumab and durvalumab is now a standard treatment option for advanced HCC., Objective: To study immune responses in HCC patients treated with tremelimumab and durvalumab., Design: We treated 28 HCC patients with durvalumab, tremelimumab and locoregional therapies. We performed a high-dimensional multiomics analysis including whole exome sequencing, single-cell RNA seq, CO-Detection by indEXing, flow cytometry and multiplex cytokine/chemokine analysis of patients' blood and tumour samples and integrated this data to elucidate immune correlatives and response mechanisms. Mice with syngeneic HCC were treated with anti-PD-L1 plus anti-CTLA4 for hepatic lymphocytes, tumour-infiltrating lymphocytes and peripheral blood mononuclear cell analysis., Results: The median overall survival was 19.2 months. Tumour tissue analysis revealed enhanced interferon responses, with stronger effects in responders. Gene set variation analysis indicated enhanced antigen presentation in responders. Spatial analysis revealed that non-responder tumours had higher numbers of Tregs located in neighbourhoods enriched with immune cells and expressed higher levels of ICOS and PD-1. Conversely, non-responder PD1+CD8+T in these Treg-enriched neighbourhoods expressed lower ICOS. Cell-communication analysis demonstrated that Treg-CD8+T interaction was enhanced in non-responder tissue. Peripheral blood analysis showed increased classical monocytes in responders and Tregs in non-responders. Treg-CD8+T interaction was confirmed in preclinical models. Finally, single-patient computational analysis from the all-across analysis was performed on 860 features, which led to the identification of multiomics feature sets including Treg features., Conclusion: Our study provides a blueprint for in-depth analysis of immune correlates in immunotherapy studies and demonstrates the importance of Treg distribution in HCC., Trial Registration Numbers: NCT02821754 and the EudraCT identifier: 2019-002767-98., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)