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IntroductionSevere aorto-iliac steno-occlusive atherosclerotic disease is a major cause of morbidity and amputation in patients with peripheral arterial disease. While both open surgical and endovascular revascularisation are standard treatments in this patient group, there is no high-quality randomised evidence to determine which approach offers superior clinical and cost-effectiveness, leading to uncertainty and poor outcomes after intervention.Methods and analysisThe EVOCC trial is a national, multicentre, parallel-group, superiority randomised controlled trial comparing open surgery to endovascular revascularisation in patients with symptomatic severe aorto-iliac occlusive disease. A total of 628 participants across 30 NHS sites in the UK will be randomised 1:1 to receive either open surgery or endovascular (minimally invasive) intervention. The primary outcome is amputation-free survival, defined as time to first event (major lower limb amputation or death). Secondary outcomes include mortality, cardiovascular events, hospital readmissions, re-interventions and quality-of-life measures. An internal pilot phase (10 sites, 6-month duration) will assess recruitment feasibility. A QuinteT Recruitment Intervention is integrated into the trial to optimise recruitment.Ethics and disseminationThe trial has received ethical approval from a UK Research Ethics Committee (REC reference: 23/SW/0065; trial registration reference: ISRCTN14591444). Informed consent will be obtained from all participants.The EVOCC trial is the first RCT assessing the clinical and cost-effectiveness of open vs endovascular revascularisation for severe aorto-iliac disease worldwide. The results will provide robust evidence to inform clinical practice and healthcare policies globally. Results will be disseminated via patient groups, online lay summaries, a trial website, social media, presentations in conferences, a formal scientific publication in a medical journal and direct communications with policymakers across borders.Trial registration numberISRCTN14591444.

Disruption in reciprocal connectivity between the right anterior insula and the left dorsolateral prefrontal cortex is associated with depression and may be a target for neuromodulation. In a five-center, parallel, double-blind, randomized controlled trial we personalized resting-state functional magnetic resonance imaging neuronavigated connectivity-guided intermittent theta burst stimulation (cgiTBS) at a site based on effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. We tested its efficacy in reducing the primary outcome depression symptoms measured by the GRID Hamilton Depression Rating Scale 17-item over 8, 16 and 26 weeks, compared with structural magnetic resonance imaging (MRI) neuronavigated repetitive transcranial magnetic stimulation (rTMS) delivered at the standard stimulation site (F3) in patients with ‘treatment-resistant depression’. Participants were randomly assigned to 20 sessions over 4–6 weeks of either cgiTBS ( n  = 128) or rTMS ( n  = 127) with resting-state functional MRI at baseline and 16 weeks. Persistent decreases in depressive symptoms were seen over 26 weeks, with no differences between arms on the primary outcome GRID Hamilton Depression Rating Scale 17-item score (intention-to-treat adjusted mean, −0.31, 95% confidence interval (CI) −1.87, 1.24, P  = 0.689). Two serious adverse events were possibly related to TMS (mania and psychosis). MRI-neuronavigated cgiTBS and rTMS were equally effective in patients with treatment-resistant depression over 26 weeks (trial registration no. ISRCTN19674644). A randomized controlled trial found that functional connectivity-guided approaches to intermittent theta burst stimulation and repetitive transcranial magnetic stimulation both reduced depressive symptoms in patients with moderate to severe treatment-resistant depression over 26 weeks.

The lesson example includes (a) class discussions to engage students in a socially relevant problem (the impact of the COVID-19 pandemic) within the context of safety in public settings and (b) a design activity to help students learn and apply core concepts related to Engineering Practice (i.e., Computational Thinking, Prototyping, and Systems Analytics) as well as knowledge related to communication technologies. [...]the lesson will help students to develop knowledge of how COVID-19 is impacting the world and ways in which engineering practices can be employed to enhance safety during this pandemic-helping people return to some sense of normalcy with public events. [...]topics to explore after teaching this lesson could be Center for Disease Control recommendations for maintaining safe behavior during a pandemic, a deeper look into computer science and the application of computational thinking, the analysis of systems at a larger scale (i.e., investigating the components of a manufacturing facility, a specific machine or vehicle, and many other potential systems to explore), and potentially the commercialization of solutions to these problems through entrepreneurial-related activities.

G. G. Simpson, one of the chief architects of evolutionary biology's modern synthesis, proposed that diversification occurs on a macroevolutionary adaptive landscape, but landscape models are seldom used to study adaptive divergence in large radiations. We show that for Caribbean Anolis lizards, diversification on similar Simpsonian landscapes leads to striking convergence of entire faunas on four islands. Parallel radiations unfolding at large temporal scales shed light on the process of adaptive diversification, indicating that the adaptive landscape may give rise to predictable evolutionary patterns in nature, that adaptive peaks may be stable over macroevolutionary time, and that available geographic area influences the ability of lineages to discover new adaptive peaks.

Patients with hidradenitis suppurativa have substantial unmet clinical needs and scarce therapeutic options. We aimed to assess the efficacy and safety of bimekizumab, a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F and IL-17A, in patients with moderate-to-severe hidradenitis suppurativa. BE HEARD I and II were two identically designed, 48-week randomised, double-blind, placebo-controlled, multicentre phase 3 trials. Patients aged 18 years or older with moderate-to-severe hidradenitis suppurativa were randomly assigned 2:2:2:1 using interactive response technology (stratified by worst Hurley Stage at baseline and baseline systemic antibiotic use) to receive subcutaneous bimekizumab 320 mg every 2 weeks; bimekizumab 320 mg every 2 weeks to week 16, then every 4 weeks to week 48; bimekizumab 320 mg every 4 weeks to week 48; or placebo to week 16, then bimekizumab 320 mg every 2 weeks. The primary outcome was an hidradenitis suppurativa clinical response of at least 50%, defined as a reduction in total abscess and inflammatory nodule count of at least 50% from baseline with no increase from baseline in abscess or draining tunnel count (HiSCR50) at week 16. Efficacy analyses included all randomly assigned study patients (intention-to-treat population). Safety analyses included all patients who received at least one full or partial dose of study treatment in the safety set, and of bimekizumab in the active-medication set. These trials are registered at ClinicalTrials.gov, NCT04242446 and NCT04242498, and both are completed. Patients for BE HEARD I were recruited from Feb 19, 2020, to Oct 27, 2021, and 505 patients were enrolled and randomly assigned. Patients for BE HEARD II were recruited from March 2, 2020, to July 28, 2021, and 509 patients were enrolled and randomly assigned. The primary outcome at week 16 was met in the group who received bimekizumab every 2 weeks using modified non-responder imputation; higher responder rates were observed with bimekizumab versus placebo in both trials: 138 (48%) of 289 patients versus 21 (29%) of 72 patients in BE HEARD I (odds ratio [OR] 2·23 [97·5% CI 1·16–4·31]; p=0·0060) and 151 (52%) of 291 patients versus 24 (32%) of 74 patients in BE HEARD II (2·29 [1·22–4·29]; p=0·0032). In BE HEARD II, HiSCR50 was also met in the group who were administered bimekizumab every 4 weeks (77 [54%] of 144 vs 24 [32%] of 74 with placebo; 2·42 [1·22–4·80]; p=0·0038). Responses were maintained or increased to week 48. Serious treatment-emergent adverse events were reported in 40 (8%) patients in BE HEARD I and in 24 (5%) patients in BE HEARD II treated with bimekizumab over 48 weeks. The most frequently reported treatment-emergent adverse events to week 48 were hidradenitis in both trials, in addition to coronavirus infection and diarrhoea in BE HEARD I, and oral candidiasis and headache in BE HEARD II. One death was reported across the two trials, and was due to congestive heart failure in a patient with substantial cardiovascular history treated with bimekizumab every 2 weeks in BE HEARD I (considered unrelated to bimekizumab treatment by the investigator). No new safety signals were observed. Bimekizumab was well tolerated by patients with hidradenitis suppurativa and produced rapid and deep clinically meaningful responses that were maintained up to 48 weeks. Data from these two trials support the use of bimekizumab for the treatment of patients with moderate-to-severe hidradenitis suppurativa. UCB Pharma.

Introduction Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterised by painful skin lesions which negatively impact patients’ physical and mental wellbeing. The HS Symptom Daily Diary (HSSDD) and HS Symptom Questionnaire (HSSQ) are patient-reported outcome (PRO) tools capturing patient-perceived severity of HS symptoms. Here, we report the psychometric properties of HSSDD and HSSQ along with score interpretation thresholds. Methods Pooled data from patients with moderate to severe HS in two phase 3 studies (BE HEARD I II) were analysed. Test-retest reliability was evaluated using intraclass correlation coefficients (ICCs). Convergent validity was assessed between the HSSDD ( N  = 934) and HSSQ ( N  = 1007) compared with relevant PROs and clinician-reported outcomes (ClinROs) at baseline and Week (Wk)16. Known-groups validity was assessed, comparing HSSDD and HSSQ scores between participant subgroups pre-defined using PRO/ClinRO measures (Patient Global Impression [PGI] of HS severity, Hurley stage, International HS Severity Score System). Responsiveness was evaluated by correlating changes from baseline to Wk16 in HSSDD and HSSQ scores with changes in PGI scales. Clinically meaningful within-patient improvement thresholds were estimated using anchor- and distribution-based analyses. Symptom/impact severity thresholds were estimated using receiver operating characteristic curve analyses. Results At Wk16, HSSDD and HSSQ completion rates were 70.1% and 90.2%, respectively. Test-retest reliability analyses demonstrated good score reproducibility (ICC: HSSDD: 0.80–0.86; HSSQ: 0.73–0.82). Correlations between HSSDD and HSSQ scores and other PROs/ClinROs were generally consistent with predefined hypotheses, indicating good convergent validity. HSSDD and HSSQ scores discriminated between pre-defined subgroups, confirming known-groups validity. Sixteen-wk changes from baseline in HSSDD and HSSQ scores and anchors were moderately to strongly correlated (> 0.30), establishing responsiveness. Interpretation thresholds for both HSSDD and HSSQ were estimated. Conclusion HSSDD and HSSQ item scores demonstrated good psychometric performance in participants with moderate to severe HS. The clinically meaningful severity thresholds defined here could be used to assess treatment efficacy. Clinical Trial registration NCT04242446; NCT04242498. Graphical Abstract Plain Language Summary Hidradenitis suppurativa (HS) is a chronic skin condition that causes lesions and painful lumps under the skin. HS can affect patients’ lives by causing pain, emotional distress and difficulty completing daily activities. Currently, there are few medications to treat HS. To understand the impact and effectiveness of new treatments, it is important to look beyond clinical outcomes and capture patient experience. To measure the patient’s perspective and more specifically symptom experience, self-completed questionnaires such as the HS Symptom Daily Diary (HSSDD) and HS Symptom Questionnaire (HSSQ) were developed. The HSSDD and HSSQ determine patients’ perspective on the severity of their HS symptoms (pain, itch, smell or odour and drainage or oozing). Two phase 3 trials used HSSDD and HSSQ to investigate patients’ perspective on the severity of their symptoms. We conducted a series of statistical analyses to assess the validity, reliability and robustness of both questionnaires. We found that HSSDD and HSSQ could assess patients’ experience of symptoms. We showed that both questionnaires were sensitive enough to reveal changes over time. Furthermore, both questionnaires were able to distinguish between patient groups with different levels of HS symptom severity. We also established thresholds that will help clinicians determine whether an improvement in a patient’s HSSDD/HSSQ scores are meaningful to the patient. The results from this study show HSSDD and HSSQ are reliable patient-completed questionnaires that could be useful in informing treatment choices.

As large language models (LLMs) become central tools in science, improving their reasoning capabilities is critical for meaningful and trustworthy applications. We introduce a Socratic agent for scientific reasoning, implemented through a structured system prompt that guides LLMs via classical principles of inquiry. Unlike typical prompt engineering or retrieval-based methods, our approach leverages definition, analogy, hypothesis elimination, and other Socratic techniques to generate more coherent, critical, and domain-aware responses. We evaluate the agent across diverse scientific domains and benchmark it on the abstraction and reasoning corpus challenge dataset, achieving 97.15% under a fixed prompting protocol and without fine-tuning or external tools. Expert evaluation shows improved reasoning depth, clarity, and adaptability over conventional LLM outputs, suggesting that structured prompting rooted in philosophical reasoning can improve the scientific utility of language models.

Understanding processes that have shaped broad-scale biodiversity patterns is a fundamental goal in evolutionary biology. The development of phylogenetic comparative methods has yielded a tool kit for analyzing contemporary patterns by explicitly modeling processes of change in the past, providing neontologists tools for asking questions previously accessible only for select taxa via the fossil record or laboratory experimentation. The comparative approach, however, differs operationally from alternative approaches to studying convergence in that, for studies of only extant species, convergence must be inferred using evolutionary process models rather than being directly measured. As a result, investigation of evolutionary pattern and process cannot be decoupled in comparative studies of convergence, even though such a decoupling could in theory guard against adaptationist bias. Assumptions about evolutionary process underlying comparative tools can shape the inference of convergent pattern in sometimes profound ways and can color interpretation of such patterns. We discuss these issues and other limitations common to most phylogenetic comparative approaches and suggest ways that they can be avoided in practice. We conclude by promoting a multipronged approach to studying convergence that integrates comparative methods with complementary tests of evolutionary mechanisms and includes ecological and biogeographical perspectives. Carefully employed, the comparative method remains a powerful tool for enriching our understanding of convergence in macroevolution, especially for investigation of why convergence occurs in some settings but not others.

BackgroundCOVID-19 disease results in disparate responses between individuals and has led to the emergence of long coronavirus disease (Long-COVID), characterised by persistent and cyclical symptomology. To understand the complexity of Long-COVID, the importance of symptom surveillance and prospective longitudinal studies is evident.MethodsA 9-month longitudinal prospective cohort study was conducted within Scotland (n=287), using a mobile app to determine the proportion of recovered individuals and those with persistent symptoms and common symptoms, and associations with gender and age.Results3.1% of participants experienced symptoms at month 9, meeting the criteria for Long-COVID, as defined by the National Institute for Health and Care Excellence terminology. The random effects model revealed a significant time (month) effect for infection recovery (p<0.001, estimate=0.07). Fatigue, cough and muscle pain were the most common symptoms at baseline, with fatigue persisting the longest, while symptoms like cough improved rapidly. Older age increased the likelihood of reporting pain (p=0.028, estimate=0.07) and cognitive impairment (p<0.001, estimate=0.93). Female gender increased the likelihood of headaches (p=0.024, estimate=0.53) and post-exertional malaise (PEM) frequency (p=0.05, estimate=137.68), and increased time x gender effect for PEM frequency (p=0.033, estimate=18.96).ConclusionsThe majority of people fully recover from acute COVID-19, although often slowly. Age and gender play a role in symptom burden and recovery rates, emphasising the need for tailored approaches to Long-COVID management. Further analysis is required to determine the characteristics of the individuals still reporting ongoing symptoms months after initial infection to identify risk factors and potential predictors for the development of Long-COVID.