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PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue
Get PDFPIEZO1 variants have been associated with generalized lymphatic dysplasia (GLD) through mechanisms involving reduced PIEZO1 expression. Here, we report variants where the mechanism involves reduced channel mechanical sensitivity. Two of the variants encode amino acid changes in the channel’s cap structure (Ile2270Thr and Arg2335Gln), one in the ninth transmembrane helical unit (THU) below the cap (Gly1978Asp) and one in the fifth THU distant from the cap (Glu829Val). Patch-clamp studies of the cap and sub-cap variant channels revealed abolished or reduced channel mechanical sensitivity with the possibility to activate the channels and partly rescue mechanical sensitivity by the small molecule Yoda1. The potency of Yoda1 at the variant channels was less than at the wild-type channel but chemical synthesis of Yoda1 analogues revealed a molecule with improved potency. The data suggest cases of GLD in which there is decreased channel mechanical sensitivity and the potential to reduce dysfunction pharmacologically
Real-world effectiveness study of guideline-directed COPD STANDARDized management in patients with chronic obstructive pulmonary disease: a cluster randomised trial design
Get PDFIntroduction
Chronic obstructive pulmonary disease (COPD) affects the ageing population worldwide. Exacerbations worsen health status and increase health resource use. Existing guidelines recommend disease management, but they are not fully implemented in a clinical setting. Evidence regarding best practice and real-world effectiveness is limited.
Methods and analysis
A nationwide multicentre clinical effectiveness trial is being performed between 2023 and 2027, involving 99 secondary hospitals in urban and rural areas in China. It is an open-label, adjudicator and assessor-blinded, parallel group, cluster randomised pragmatic trial. Hospitals are randomly allocated to standardised management (SM) or usual care. A total number of 3456 stable patients with COPD who are symptomatic (individuals in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Group B) or have exacerbation risk (individuals with one moderate exacerbation history in Group A and individuals in Group E) using GOLD 2023 ABE classification will be enrolled. In the SM group, an integrated intervention comprising five components will be delivered using a physician and nurse model. These are: (1) long-term inhaled maintenance therapy, (2) periodic inhaler technique assessment and symptom monitoring, (3) annual pulmonary function testing, (4) COPD education session and (5) health behaviour adoption (smoking cessation, vaccination, pulmonary rehabilitation). In the control group, patients will receive routine care. The primary goal is to assess the real-world effectiveness of guideline-directed disease management on exacerbation prevention, with moderate-to-severe exacerbation as the primary outcome and hospital admission, mortality, health status and COPD self-management as secondary outcomes. It is the first pragmatic trial undertaken of this form in a developing country. It is anticipated that it will provide a feasible and effective COPD management model that can inform guidelines and be rolled out into secondary and primary care, with modification, to ensure standardised COPD care nationwide.
Trial registration number
NCT04664491
mTOR pathway diseases: challenges and opportunities from bench to bedside and the mTOR node
Get PDFMechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that regulates key cellular processes including cell growth, autophagy and metabolism. Hyperactivation of the mTOR pathway causes a group of rare and ultrarare genetic diseases. mTOR pathway diseases have diverse clinical manifestations that are managed by distinct medical disciplines but share a common underlying molecular basis. There is a now a deep understanding of the molecular underpinning that regulates the mTOR pathway but effective treatments for most mTOR pathway diseases are lacking. Translating scientific knowledge into clinical applications to benefit the unmet clinical needs of patients is a major challenge common to many rare diseases. In this article we expound how mTOR pathway diseases provide an opportunity to coordinate basic and translational disease research across the group, together with industry, medical research foundations, charities and patient groups, by pooling expertise and driving progress to benefit patients. We outline the germline and somatic mutations in the mTOR pathway that cause rare diseases and summarise the prevalence, genetic basis, clinical manifestations, pathophysiology and current treatments for each disease in this group. We describe the challenges and opportunities for progress in elucidating the underlying mechanisms, improving diagnosis and prognosis, as well as the development and approval of new therapies for mTOR pathway diseases. We illustrate the crucial role of patient public involvement and engagement in rare disease and mTOR pathway disease research. Finally, we explain how the mTOR Pathway Diseases node, part of the Research Disease Research UK Platform, will address these challenges to improve the understanding, diagnosis and treatment of mTOR pathway diseases
“CRP-first” algorithm to guide imaging in suspected renal colic: a retrospective UK cohort study
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To evaluate whether admission C-reactive protein (CRP) can triage patients with suspected renal colic to low dose non contrast CT KUB or contrast enhanced CT of the abdomen and pelvis (CTAP) at first presentation.
Methods
Retrospective single centre diagnostic accuracy study in a United Kingdom emergency department. Index test was admission CRP with a prespecified cut-off of 5 mg/L (positive if CRP ≥ 5 mg/L). Reference standard was CT classified a priori as: A normal, B simple calculus, C complicated calculus, D alternative acute diagnosis. The target condition for accuracy analyses was C or D. We constructed a 2 × 2 table and calculated sensitivity, specificity, predictive values and likelihood ratios with 95% confidence intervals.
Results
Of 1,096 CT examinations during the study window, 233 were for suspected renal colic; 58 patients met eligibility and had admission CRP available (29 with CRP < 5 mg/L and 29 with CRP ≥ 5 mg/L). The target condition was present in 26/58 (44.8%). Using CRP ≥ 5 mg/L, sensitivity was 0.73 (95% CI 0.54–0.86), specificity 0.69 (0.51–0.82), positive predictive value 0.66 (0.47–0.80), negative predictive value 0.76 (0.58–0.88), likelihood ratio positive 2.34 (1.16–4.70) and likelihood ratio negative 0.39 (0.20–0.77).
Conclusion
CRP provided modest but clinically interpretable probability shifts for complicated stones or alternative acute pathology. A CRP first approach may support initial imaging selection between CTAP and CT KUB. Prospective multicentre validation is required
The European Society of Cardiology 2024 Guidelines on Chronic Coronary Syndromes: A Critical Appraisal
Get PDFBackground: During the 2024 annual meeting in London, The European Society of Cardiology released new guidelines (GLs) on chronic coronary syndromes (CCSs) and simultaneously published them in the European Heart Journal. Method: A few experts on the topic from Europe, South America, India, and Asia, who attended the presentation and the Question and Answer sections, met virtually to comment on the GLs after carefully reading the 123-page document. Result: There is a consensus that the presented GLs are a comprehensive, up-to-date, clear document of the available data on how to diagnose and treat CCSs and a definite step forward compared to all previous GLs. Of particular value are (a) the efforts to link both diagnosis and treatment to the underlying pathophysiology with the recognition that not all the ischaemic episodes are the same; (b) the decision to adopt the graphic of the so-called “Diamond Approach”, although its spirit that no antianginal drug is superior to another is not fully adopted; and (c) the innovative way it condenses and expresses the relevant messages with eye-catching illustrations. Conclusions: The present article summarises and comments on the 123-page GLs, highlighting strengths and weaknesses according to the thoughts of the authors
The Contemporary Role of Interventional Radiologists in Endovascular Aortic Repair: A Survey of CIRSE Members
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To describe the outcomes of a survey conducted among CIRSE members on endovascular aortic repair and to outline the future practice and needs of CIRSE members in this area.
Materials and methods
An anonymous online survey with 21 questions was designed by the authors and sent to CIRSE members worldwide; data were collected for 12 weeks.
Results
The survey collected 326 complete responses, with most respondents practicing in Europe. Two-thirds of respondents indicated that aortic repair is performed by multidisciplinary teams including IRs, with more than half reporting that they are equal partners in performing the procedure, and 27% acting as primary operators. In their practice, the most frequently performed endovascular aortic procedures were EVAR and embolisation of endoleaks, followed by FEVAR and TEVAR. A majority of 64% of respondents predict a growth in their endovascular aortic practice in the next 5 to 10 years that could further be supported by training, an increase in the workforce, societal guidelines, and additional qualifications. Hindrances for growth include turf competition as well as hospital management decisions.
Conclusion
The survey indicates that Interventional Radiologists continue to play a significant role in endovascular aortic procedures and identifies challenges and opportunities to further increase the role of IR in endovascular aortic aneurysm procedures for the benefit of patients. The authors consider it essential for national societies as well as CIRSE to facilitate and encourage the clinical role of IRs in standard and complex EVAR to best guide future developments for optimal patient management in aortic disease
The Credibility of Bioethics After the Gaza Genocide
Get PDFBetween October 2023 and January 2025, the Israeli military's sustained attacks on Gaza resulted in an estimated 186,000 deaths and the systematic destruction of healthcare infrastructure. Despite the professed commitment to human dignity, justice, and the minimization of suffering within bioethics, major institutions and scholars in the field have largely remained silent or selectively engaged with the crisis. This paper argues that the Gaza genocide exposes a deeper crisis within bioethics: its growing detachment from urgent, real‐world ethical challenges. Such detachment erodes public trust and raises fundamental questions about the discipline's relevance and credibility. The article interrogates the possible reasons and motivations for the silence and disengagement in the face of genocide in Gaza, and examines the institutional and disciplinary responsibilities that bioethics bears in response to health‐destroying state violence. Framing the inaction as a moral failure with far‐reaching implications, the article proposes alternative routes of ethical engagement and outlines steps toward a more inclusive and responsive bioethics. It calls for the urgent reorientation of the field toward a justice‐driven, politically conscious practice capable of confronting today's most pressing ethical issues
Consensus on the management of traumatic brain injury in older adults: Results from a Delphi study
Get PDFIntroduction
As the world population is rapidly becoming older, the incidence of traumatic brain injury (TBI) is increasing among older adults with vast implications for brain health of older adults in Europe. Due to differences from younger patients, there are areas of uncertainty in the assessment, diagnosis and management of TBI in older adults.
Research question
To reach a consensus among experts on statements regarding the definition of old age, assessment, diagnosis and management of traumatic brain injury in older adults.
Materials and methods
A modified Delphi method consisting of two online rounds was organised, followed by an in-person meeting. Consensus was defined as >75 % agreement. In the second online round the experts were able to view their first assessment and the average of the group. Some statements were rephrased and presented again in the in-person meeting. Questions with numerical data could not be assessed by consensus and descriptive and non-parametric statistics were used to analyze them.
Results
Experts (n = 72), from different nationalities (Europe, United States, Latin America, Africa and Asia) and specialities (Neurosurgery, Emergency Medicine, Intensive care medicine) responded on 62 statements. Consensus was finally reached on 44 statements regarding the definition of older adulthood, as well as the assessment, surgical and intensive care management, discharge, and rehabilitation of patients.
Discussion and conclusions
This consensus reinforces the importance of this area for physicians and researchers interested in traumatic brain injury. It signals important areas of agreement as well as future topics for research and specific knowledge gaps
Emulation of ARISTOTLE and ROCKET AF trials in real-world atrial fibrillation patients results in similar efficacy and safety as original landmark trials: insights from the GARFIELD-AF registry.
Get PDFAIMS: This study aimed to determine the robustness, reproducibility and representativeness of the landmark Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (AF) (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in AF (ROCKET AF) randomised trials through replication in an observational AF patient registry. METHODS AND RESULTS: Patients from the Global Anticoagulant Registry in the FIELD (GARFIELD)-AF registry treated with apixaban, rivaroxaban or vitamin K antagonist (VKA) were assessed for eligibility for the ARISTOTLE and ROCKET AF trials. HRs of apixaban and rivaroxaban versus comparator for stroke/systemic embolism, major bleeding and all-cause mortality within 2 years follow-up were calculated using propensity score overlap-weighted Cox models. Among GARFIELD-AF patients on apixaban, 2570/3615 (71%) would have been eligible for ARISTOTLE. Among patients using rivaroxaban, 2005/4914 (41%) would have been eligible for ROCKET AF. Eligibility rates were steady over time, with minor differences across medical specialties. Real-world AF patients selected according to trial criteria had lower cardiovascular burden than the original trial participants, especially compared with ROCKET AF. HRs (95% CI) for apixaban versus VKA among ARISTOTLE-eligible users were 0.57 (0.34 to 0.94) for stroke/systemic embolism, 0.76 (0.48 to 1.20) for major bleeding and 0.89 (0.70 to 1.12) for all-cause mortality. Among ROCKET AF-eligible rivaroxaban users, HRs for rivaroxaban versus VKA were 0.90 (0.57 to 1.43), 0.92 (0.59 to 1.43) and 0.86 (0.69 to 1.08), respectively. All safety and efficacy estimates were similar to those in the original trials. CONCLUSION: Real-world representativeness of the selection criteria was greater for ARISTOTLE than ROCKET AF. The pivotal randomised trials of apixaban and rivaroxaban versus warfarin can be successfully emulated in real-world AF patients by applying trial-specific selection criteria and appropriate methodology for non-randomised treatment allocation. TRIAL REGISTRATION NUMBER: NCT01090362
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