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The anti–interleukin-1 antibody canakinumab was effective at controlling and preventing recurrence of flares in autoimmune inflammatory diseases: familial Mediterranean fever, mevalonate kinase deficiency, and the TNF receptor–associated periodic syndrome.

ObjectiveTo evaluate the efficacy of canakinumab, a high-affinity human monoclonal anti-interleukin-1β antibody, in inducing complete or almost complete responses in patients with active tumour necrosis factor receptor-associated periodic syndrome (TRAPS).MethodsTwenty patients (aged 7–78 years) with active recurrent or chronic TRAPS were treated with canakinumab 150 mg every 4 weeks for 4 months (2 mg/kg for those ≤40 kg) in this open-label, proof-of-concept, phase II study. Canakinumab was then withdrawn for up to 5 months, with reintroduction on relapse, and 4 weekly administration (subsequently increased to every 8 weeks) for 24 months. The primary efficacy variable was the proportion of patients achieving complete or almost complete response at day 15, defined as clinical remission (Physician's Global Assessment score ≤1) and full or partial serological remission.ResultsNineteen patients (19/20, 95%; 95% CI 75.1% to 99.9%) achieved the primary efficacy variable. Responses to canakinumab occurred rapidly; median time to clinical remission 4 days (95% CI 3 to 8 days). All patients relapsed after canakinumab was withdrawn; median time to relapse 91.5 days (95% CI 65 to 117 days). On reintroduction of canakinumab, clinical and serological responses were similar to those seen during the first phase, and were sustained throughout treatment. Canakinumab was well tolerated and clinical responses were accompanied by rapid and sustained improvement in health-related quality of life. Weight normalised pharmacokinetics of canakinumab, although limited, appeared to be consistent with historical canakinumab data.ConclusionsCanakinumab induces rapid disease control in patients with active TRAPS, and clinical benefits are sustained during long-term treatment.Trial registration numberNCT01242813; Results.

Progressive decline in allograft function and cardiovascular mortality after kidney transplantation remain major clinical challenges that can potentially be addressed by the mammalian target of rapamycin (mTOR) inhibitors, everolimus and sirolimus. mTOR inhibitors maintain immunosuppressive efficacy after minimization of calcineurin inhibitor (CNI) therapy and can achieve significant long-term improvements in renal function. Recently, data have accumulated that suggest mTOR inhibitors may offer cardioprotective effects. In animal models, inhibition of mTOR leads to regression of cardiac hypertrophy, and the limited data consistently point to a remodeling benefit following heart transplantation. Experimentally, mTOR inhibitors restrict atherogenesis, confirmed clinically by intravascular ultrasound data demonstrating lower rates of transplant vasculopathy in heart transplant recipients on everolimus. Lastly, mTOR inhibitors appear to ameliorate arterial stiffness, a known risk factor for post-transplant cardiovascular events, but data remain sparse. The ELEVATE study will examine the renal effect of early conversion from CNI therapy to everolimus after kidney transplantation. Key secondary endpoints include the change in left ventricular mass index, the first time this endpoint has been included in a prospective study of an mTOR inhibitor. The occurrence of cardiovascular events will be rigorously documented and pulse wave velocity is being measured in a subpopulation of patients. Results from this innovative trial are awaited with interest. Keywords: cardiovascular, calcineurin inhibitors, ELEVATE, everolimus, kidney transplantation, mammalian target of rapamycin

Global patterns of regional (gamma) plant diversity are relatively well known, but whether these patterns hold for local communities, and the dependence on spatial grain, remain controversial. Using data on 170,272 georeferenced local plant assemblages, we created global maps of alpha diversity (local species richness) for vascular plants at three different spatial grains, for forests and non-forests. We show that alpha diversity is consistently high across grains in some regions (for example, Andean-Amazonian foothills), but regional ‘scaling anomalies’ (deviations from the positive correlation) exist elsewhere, particularly in Eurasian temperate forests with disproportionally higher fine-grained richness and many African tropical forests with disproportionally higher coarse-grained richness. The influence of different climatic, topographic and biogeographical variables on alpha diversity also varies across grains. Our multi-grain maps return a nuanced understanding of vascular plant biodiversity patterns that complements classic maps of biodiversity hotspots and will improve predictions of global change effects on biodiversity. Global patterns of regional plant diversity are relatively well known, but whether they hold for local communities is debated. This study created multi-grain global maps of alpha diversity for vascular plants to provide a nuanced understanding of plant diversity hotspots and improve predictions of global change effects on biodiversity.

Reintroduction or reinforcement (RorR) of wild populations is a common conservation strategy. Many conservation projects involve the release of individuals of poorly studied species. This may lead to inefficient results or negative impacts on the conservation efforts. Here, we provide new insights into the conservation implications and potential consequences of a skew in the sex ratio of released birds and of the number of birds supplemented for the demography of a long-lived dimorphic bird species, the Andean condor (Vulturgryphus). We demonstrate that a RorR conservation program may be less effective in conserving a species if the sex ratios of the releases and the recipient populations are not considered. We also show that releases can reduce population declines but only if carried out over long periods (i.e., several decades). This can mean high costs for release programs and the added challenge of maintaining programs over time. If RorR programs are to be implemented, bearing in mind the importance of properly assessing their effectiveness, we urge conservation researchers and managers to consider the implications of sex ratio biases for wild populations, and particularly for dimorphic species with sexually despotic behaviour.

Mutations in ESR1 play a critical role in resistance to endocrine therapy (ET) in hormone receptor-positive (HR +)/HER2- metastatic breast cancer (MBC). Testing for ESR1 mutations is essential for guiding treatment with novel oral selective estrogen receptor degraders (SERDs) like elacestrant or camizestrant. While most studies have utilized liquid biopsy (LB) for mutation detection, the role of formalin-fixed paraffin-embedded (FFPE) tissue biopsy in this context remains unclear. In this study, we analyzed a cohort of HR + /HER2- MBC patients who experienced resistance to ET and CDK4/6 inhibitors. Next-generation sequencing (NGS) was performed on FFPE biopsy samples obtained from metastatic sites at the time of disease progression. ESR1 mutations were detected in 24 out of 38 patients (63.2%), with p.D538G identified in 10 patients (45.5%) and p.Y537S in 6 patients (27.2%) as the most frequent alterations. One patient exhibited dual ESR1 mutations, and a recurrent ESR1-CCDC170 gene fusion was identified, underscoring the diversity and potential interplay of genetic alterations driving resistance in HR + /HER2- MBC. Notably, lung metastases were significantly more common in ESR1 mutant cases (8/24, 33.3%) compared to wild-type cases (1/14, 7.1%), while liver metastases showed no difference between mutant (12/24, 50.0%) and wild-type groups (7/14, 50.0%). Co-mutations in actionable pathways, particularly PIK3CA , were observed in n = 10 ESR1 mutant tumors (41.6%), highlighting their contribution to resistance mechanisms and posing significant challenges for treatment selection, as these alterations may necessitate combination therapies to effectively target multiple resistance pathways. This study presents new insights into the prevalence and clinical significance of ESR1 mutations in HR + /HER2- MBC, highlighting the potential utility of FFPE biopsy samples as a viable alternative or complementary approach to LB for mutation detection, particularly in resource-limited settings where access to ctDNA analysis may be constrained.

Background: Single-cohort studies suggest that second-generation stents (SGS; “mesh stents”) may improve carotid artery stenting (CAS) outcomes by limiting peri- and postprocedural cerebral embolism. SGS differ in the stent frame construction, mesh material, and design, as well as in mesh-to-frame position (inside/outside). Objectives: To compare clinical outcomes of SGS in relation to first-generation stents (FGSs; single-layer) in CAS. Methods: We performed a systematic review and meta-analysis of clinical studies with FGSs and SGS (PRISMA methodology, 3302 records). Endpoints were 30-day death, stroke, myocardial infarction (DSM), and 12-month ipsilateral stroke (IS) and restenosis (ISR). A random-effect model was applied. Results: Data of 68,422 patients from 112 eligible studies (68.2% men, 44.9% symptomatic) were meta-analyzed. Thirty-day DSM was 1.30% vs. 4.11% (p < 0.01, data for SGS vs. FGS). Among SGS, both Casper/Roadsaver and CGuard reduced 30-day DSM (by 2.78 and 3.03 absolute percent, p = 0.02 and p < 0.001), whereas the Gore stent was neutral. SGSs significantly improved outcomes compared with closed-cell FGS (30-day stroke 0.6% vs. 2.32%, p = 0.014; DSM 1.3% vs. 3.15%, p < 0.01). At 12 months, in relation to FGS, Casper/Roadsaver reduced IS (−3.25%, p < 0.05) but increased ISR (+3.19%, p = 0.04), CGuard showed a reduction in both IS and ISR (−3.13%, −3.63%; p = 0.01, p < 0.01), whereas the Gore stent was neutral. Conclusions: Pooled SGS use was associated with improved short- and long-term clinical results of CAS. Individual SGS types, however, differed significantly in their outcomes, indicating a lack of a “mesh stent” class effect. Findings from this meta-analysis may provide clinically relevant information in anticipation of large-scale randomized trials.

Background Report the incidence and results of peri-operative extracorporeal membrane oxygenation (ECMO) and intra-aortic balloon pump (IABP) of patients undergoing mitral valve surgery (MVS) through right mini-thoracotomy (RT) and conventional full sternotomy (FS) for a period of 6 years from eleven tertiary Cardiac Surgery Institutes of GVM Care & Research Italia. Methods From January 2016 to November 2021, a total of 5901 consecutive patients underwent MVS through RT and FS. The primary outcome of the study was the mortality and incidence of low cardiac output syndrome (LCOS) treated with intra-aortic balloon pump (IABP) with or without inotropic support and the incidence of Postcardiotomy Cardiogenic Shock (PCS) treated with Veno-arterial (VA) Extracorporeal Membrane Oxygenation (ECMO) on patients undergoing mitral valve surgery (MVS) through right mini-thoracotomy (RT) versus conventional full sternotomy (FS). Results The mean age was 66 ± 15 years, 3389 patients underwent in RT approach 2512 in FS, 3081 (52%) patients were male and 2.3% had previous cardiac operations. Cardiopulmonary bypass time was 93 min for RT and 81 min for FS and cross clamp time 75 min for RT and 63 min for FS for mitral valve repair. Incidence of perioperative IABP for the treatment of low cardiac output was reported on 99 patients (1.6%), 51 for RT (1.5%), 35% used inotropic support (adrenaline and milrinone) and 48 in FS (1.9), 28% use inotropic support, 21 patients died after IABP (3 RT and 18 FS). Incidence of perioperative VA-ECMO for the PCS treatment was 13 and 4 with IABP, 9 RT (0.2%) and 4 FS approach (0.15%), 12 patients died after VA-ECMO. Conclusion Minimally invasive mitral valve surgery is a safe and reproducible approach associated with low mortality and morbidity. ECMO and IABP incidence for the treatment of PCS was 0.2% and for Low cardiac output syndrome (LCOS) was 1.6% in elective mitral valve surgery is very low. The patients that use the perioperative IABP in minimally invasive mitral valve surgery (MIMVS) trough RT reported a reduced mortality compared to FS in relation to the operative risk and surgical technique. Low incidence of VA-ECMO was found in RT and FS approach, only one patient survived after VA-ECMO after minimally invasive mitral valve surgery.

Background: International and national policies increasingly call for person-centred approaches in disability services, yet little is known about how support intensity needs influence the allocation of resources for individuals with intellectual and developmental disabilities (IDDs). In Italy, where integrated socio-health systems operate within a human rights framework, this quantitative study investigates how individual and contextual factors shape resource use in individualized support planning. Methods: We analyzed data from 1152 adults with IDDs enrolled in 23 service centres across 13 Italian regions. Case managers developed Individualized Support Plans (ISPs) informed by the Supports Intensity Scale and socio-ecological variables. Resource use was measured as weekly counts of adaptive skills training, community participation supports, habilitation services, prosthetics, and assistive technologies. We applied multivariate count models (Sarmanov–Lee) to capture the interdependence across support types. Results: Findings show that gender and level of intellectual functioning did not significantly affect resource allocation. However, individuals with the highest support intensity needs often received fewer supports, particularly in adaptive skills and community participation. Residential settings were associated with higher levels of support provision compared to family or independent living. Assistive technologies and prosthetics were linked with more comprehensive support packages. Conclusions: While person-centred planning frameworks are being implemented, systemic inequities remain, with those at the highest levels of need at risk of receiving fewer enabling supports. Multivariate modelling provides a robust tool for understanding resource use and highlights the importance of equity-focused planning. These findings support policy and practice reforms that operationalize human rights principles and align with the UNCRPD, ensuring more inclusive and responsive systems of support.

BackgroundCriteria such as electrograms voltage or late potentials have been largely utilized in the past to help identify areas of substrate maps that are within the ventricular tachycardia (VT) isthmus; yet their specificity and positive predictive value are quite low. The Lumipoint fractionation tool of the Rhythmia system illuminates regions with fractionated electrograms irrespective of their timing and annotation. We aimed to ascertain whether the use of this tool can rapidly identify areas within VT isthmuses from substrate maps.MethodsThirty patients with structural cardiomyopathy in whom a complete right ventricular–paced substrate map and a full reconstruction of the diastolic isthmus during VT could be obtained were enrolled. The VT isthmus border was projected on each substrate map to verify whether the areas illuminated by Lumipoint fell within those borders. The behavior of the electrograms detected at the illuminated areas of the substrate maps was studied during a right ventricular drive train and extra stimulus protocol: if the near field potentials showed a delayed conduction after a single extra stimulus, defined as a minimum of 10 ms increase of the time interval between the far field and the near field activation measured during the drive train, the electrogram was said to have a “decremental” behavior.ResultsThe logistic analysis showed that areas with fractionated electrograms illuminated by the Lumipoint software and showing the greatest decremental behavior fell within the VT isthmus borders (OR = 1.66, CI: 1.41–1.75, p<0.001; OR=1.57 CI: 1.32–1.72, p<0.001, respectively) with a sensitivity, specificity, and positive predictive value of 87%, 96%, and 97%, respectively.ConclusionsFractionated electrograms illuminated by the automated Lumipoint software on right ventricular–paced substrate maps showing the greatest decremental behavior fall within the VT isthmus borders with a probability of 0.97, irrespective of their timing, annotation, or voltage, without any need for subjective assessment of their involvement in slow conduction areas.