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Abstract To investigate whether and how Social Innovation (SI) can contribute to transformative change, we explored nine Native Seed Collectors Networks (NSCNs) in Brazil. Employing Social Network Analysis, we delved into the organisational structure of four NSCNs. Additionally, we identified five instances of social innovations (SIs) using the guiding questions of the Social Innovation—Forest and Landscape Restoration (SI‐FLR) framework. These networks, which received a total of US$ 12 million in investments from 2018 to 2021, have not only contributed to the production of 180 tonnes of native seeds but also had a significant socioeconomic impact. They have generated a total income of US$ 1.01 million for 997 seed collectors, 46% of whom are from traditional communities and marginalised groups. Furthermore, 55% of these collectors are women, and 23% rely solely on seed collection as their only source of income. While the NSCNs represent a fledgling economy, they have effectively activated local agency capacity. With the support of the NSCNs' social capital, a favourable context and clear motivations, this agency capacity can trigger SIs. By generating positive impacts, these SIs are changing values and empowering local agents (scaling deep), inspiring agents in other geographies (scaling out) and even influencing policies favourable to socially inclusive landscape restoration (scaling up). This three‐dimensional scaling underscores the catalysing power of SI in NSCNs and their potential contribution to transformative change. We also emphasise the role of public bodies in promoting enabling conditions, the vital role of local experimentation and the rarely evidenced local agency capacity to leverage SIs in FLR. Read the free Plain Language Summary for this article on the Journal blog.

Abstract Here we describe the dietary patterns of the culpeo or Andean fox (Lycalopex culpaeus) on a biogeographical scale. We also analyse the influence of exotic lagomorphs on its diet and explore differences between culpeo subspecies. We selected 17 mutually comparable diet studies, which include 19 independent diet assessments. Then, we extracted and standardized the values of the different diet components from these studies and calculated the relative frequency of occurrence of the 10 main trophic groups that we found. Further, we calculated the Shannon‐Wiener H′ trophic diversity index. The results showed that small mammals (41%), lagomorphs (21%), invertebrates (12.4%) and large herbivores (7.3%) were the most consumed groups. A factorial analysis of all trophic groups rendered four orthogonal factors that were used as response variables in relation to a set of environmental predictors. Altitude correlated with most factors (i.e. trophic groups). Exotic lagomorphs were consumed in lowlands, in higher latitudes and in regions showing high values of the human footprint index, enriching in those areas the culpeo's trophic spectrum. There were no differences in diet between the two main culpeo subspecies analysed, L.c. culpaeus and L.c. andinus. Finally, the best explanatory models (general linear model) of trophic diversity selected, using Akaike's information criterion, showed that the most diverse diets were those composed of large herbivores, edentates, carnivorous species, birds and herptiles (i.e. reptiles and frogs). Trophic diversity was low in rainy areas where big rodents dominated the diet. Neither latitude nor altitude seemed to have an effect on the trophic diversity of the culpeos, as they were not retained by the final models.

Abstract The current study analyzed the intersecting biophysical, biochemical, and functional properties of extracellular particles (EPs) with the human immunodeficiency virus type‐1 (HIV‐1) beyond the currently accepted size range for HIV‐1. We isolated five fractions (Frac‐A through Frac‐E) from HIV‐infected cells by sequential differential ultracentrifugation (DUC). All fractions showed a heterogeneous size distribution with median particle sizes greater than 100 nm for Frac‐A through Frac‐D but not for Frac‐E, which contained small EPs with an average size well below 50 nm. Synchronized and released cultures contained large infectious EPs in Frac‐A, with markers of amphisomes and viral components. Additionally, Frac‐E uniquely contained EPs positive for CD63, HSP70, and HIV‐1 proteins. Despite its small average size, Frac‐E contained membrane‐protected viral integrase, detectable only after SDS treatment, indicating that it is enclosed in vesicles. Single particle analysis with dSTORM further supported these findings as CD63, HIV‐1 integrase, and the viral surface envelope (Env) glycoprotein (gp) colocalized on the same Frac‐E particles. Surprisingly, Frac‐E EPs were infectious, and infectivity was significantly reduced by immunodepleting Frac‐E with anti‐CD63, indicating the presence of this protein on the surface of infectious small EPs in Frac‐E. To our knowledge, this is the first time that extracellular vesicle (EV) isolation methods have identified infectious small HIV‐1 particles (smHIV‐1) that are under 50 nm. Collectively, our data indicate that the crossroads between EPs and HIV‐1 potentially extend beyond the currently accepted biophysical properties of HIV‐1, which may have further implications for viral pathogenesis.

Abstract Recommendations regarding the best time to start treatment in patients with relapsed/refractory multiple myeloma (RRMM) after biological relapse/progression (BR) are unclear. This observational, prospective, multicenter registry aimed to evaluate the impact on time to progression (TTP) of treatment initiation at BR versus at symptomatic clinical relapse (ClinR) based on the Spanish routine practice in adult patients with RRMM. Patients had two or less previous treatment lines and at least one previous partial response. Baseline characteristics and treatment outcomes were recorded, and survival was analyzed. Of 225 patients, 110 were treated at BR (TxBR group) and 115 at ClinR (TxClinR group) according to the investigators' criteria. The proportion of patients with higher ECOG, previous noncomplete remission (CR), and second relapse were significantly higher in the TxBR group compared to the TxClinR group. TheTxClinR group showed improved outcomes, including TTP, compared to the TxBR group. Progression‐free survival increased in the TxClinR group (56.2 months) compared to the TxBR group (32.5 months) (p = 0.0137), and median overall survival also increased (p = 0.0897). Median TTP was significantly longer in patients relapsing from a CR (50.4 months) and in their first relapse (38.7 months) compared to those relapsing from a non‐CR response (32.9 months) and in their second relapse (25.2 months). Physicians seemed to start treatment earlier in RRMM patients with poor prognosis features. Previous responses to anti‐MM treatment and the number of prior treatment lines were identified as prognosis factors, whereby relapse from CR and first relapse were associated with a longer time to progression.

Abstract Multi‐terminal high‐voltage direct current technology based on voltage‐source converter stations (VSC‐MTDC) is expected to be one of the most important contributors to the future of electric power systems. In fact, among other features, it has already been shown how this technology can contribute to improve transient stability in power systems by the use of supplementary controllers. Along this line, this paper will investigate in detail how these supplementary controllers affect electromechanical oscillations, by means of small‐signal stability analysis. The paper analyses two control strategies based on the modulation of active‐power injections (P‐WAF) and reactive‐power injections (Q‐WAF) in the VSC stations which were presented in previous work. Both control strategies use global signals of the frequencies of the VSC‐MTDC system and they presented significant improvements on transient stability. The paper will provide guidelines for the design of these type of controllers to improve both large‐ and small‐disturbance angle stability. Small‐signal stability analysis (in Matlab) has been compared with non‐linear time domain simulation (in PSS/E) to confirm the results using CIGRE Nordic32A benchmark test system with a VSC‐MTDC system. The paper analyses the impact of the controller gains and communication latency on electromechanical‐oscillation damping. The main conclusion of the paper is that transient‐stability‐tailored supplementary controllers in VSC‐MTDC systems can be tuned to damp inter‐area oscillations too, maintaining their effectiveness.

Abstract Mycobacteria constitute a large group of microorganisms belonging to the phylum Actinobacteria encompassing some of the most relevant pathogenic bacteria and many saprophytic isolates that share a unique and complex cell envelope. Also unique to this group is the extensive capability to use and synthesize sterols, a class of molecules that include active signalling compounds of pharmaceutical use. However, few mycobacterial species and strains have been established as laboratory models to date, Mycolicibacterium smegmatis mc2155 being the most common one. In this work, we focus on the use of a thermophilic mycobacterium, Mycolicibacterium hassiacum, which grows optimally above 50°C, as an emerging experimental model valid to extend our general knowledge of mycobacterial biology as well as for application purposes. To that end, accurate genomic sequences are key for gene mining, the study of pathogenicity or lack thereof and the potential for gene transfer. The combination of long‐ and short‐massive sequencing technologies is strictly necessary to remove biases caused by errors specific to long‐reads technology. By doing so in M. hassiacum, we obtained from the curated genome clues regarding the genetic manipulation potential of this microorganism from the presence of insertion sequences, CRISPR‐Cas, type VII ESX secretion systems, as well as lack of plasmids. Finally, as a proof of concept of the applicability of M. hassiacum as a laboratory and industrial model, we used this high‐quality genome of M. hassiacum to successfully knockout a gene involved in the use of phytosterols as source of carbon and energy, using an improved gene cassette for thermostable selection and a transformation protocol at high temperature.

Abstract Background The association between protein intake and prostate cancer risk remains unclear. Aims To prospectively investigate the associations of dietary intakes of total protein, protein from different dietary sources, and amino acids with prostate cancer risk and mortality. Methods In 131,425 men from the European Prospective Investigation into Cancer and Nutrition, protein and amino acid intakes were estimated using validated dietary questionnaires. Multivariable‐adjusted Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results During a mean follow‐up of 14.2 years, 6939 men were diagnosed with prostate cancer and 914 died of the disease. Dairy protein was positively associated with overall prostate cancer risk in the three highest fifths compared to the lowest (HRQ3=1.14 (95% CI 1.05–1.23); HRQ4=1.09 (1.01–1.18); HRQ5=1.10 (1.02–1.19)); similar results were observed for yogurt protein (HRQ3=1.14 (1.05–1.24); HRQ4=1.09 (1.01–1.18); HRQ5=1.12 (1.04–1.21)). For egg protein intake and prostate cancer mortality, no association was observed by fifths, but there was suggestive evidence of a positive association in the analysis per standard deviation increment. There was no strong evidence of associations with different tumour subtypes. Discussion Considering the weak associations and many tests, the results must be interpreted with caution. Conclusion This study does not provide strong evidence for an association of intakes of total protein, protein from different dietary sources or amino acids with prostate cancer risk or mortality. However, our results may suggest some weak positive associations, which need to be confirmed in large‐scale, pooled analyses of prospective data.

Beta-thalassemia and particularly its transfusion-dependent form (TDT) is a demanding clinical condition, requiring life-long care and follow-up, ideally in specialized centers and by multidisciplinary teams of experts. Despite the significant progress in TDT diagnosis and treatment over the past decades that has dramatically improved patients’ prognosis, its management remains challenging. On one hand, diagnostic and therapeutic advances are not equally applied to all patients across the world, particularly in several high-prevalence eastern regions. On the other, healthcare systems in low-prevalence western countries that have recently received large numbers of migrant thalassemia patients, were not ready to address patients’ special needs. Thalassaemia International Federation (TIF), a global patient-driven umbrella federation with 232 member-associations in 62 countries, strives for equal access to quality care for all patients suffering from thalassemia or other hemoglobinopathies in every part of the world by promoting education, research, awareness, and advocacy. One of TIF’s main actions is the development and dissemination of clinical practice guidelines for the management of these patients. In 2021, the fourth edition of TIF’s guidelines for the management of TDT was published. The full text provides detailed information on the management of TDT patients and the clinical presentation, pathophysiology, diagnostic approach, and treatment of disease complications or other clinical entities that may occur in these patients, while also covering relevant psychosocial and organizational issues. The present document is a summary of the 2021 TIF guidelines for TDT that focuses mainly on clinical practice issues and recommendations.

Abstract The cause of hepatic portal vein gas (HPVG) is variable. Good knowledge of the possible causes, combined with the clinical assessment of the patient and a good quality imaging, is required to correctly identify the underlying cause of HPVG and to best predict the prognosis.

Abstract Glycerol‐3‐phosphate dehydrogenase 1 deficiency is a rare autosomal recessive disorder caused by mutations in the GPD1 gene (GPD1; OMIM*138420). Very few cases are reported in literature. It usually manifests in early infancy with transient hypertriglyceridemia, hepatomegaly, steatosis, and fibrosis. We report the case of a 16‐year‐old boy followed since the age of 1 year for hepatomegaly, elevated liver enzymes, and persistent hypertriglyceridemia. Abdominal ultrasound showed diffuse liver echogenicity and liver biopsy disclosed cirrhosis with micro and macrovesicular steatosis. Next‐generation sequencing for metabolic and genetic liver diseases was conducted with the identification of the homozygous mutation c.895G>A in GPD1 gene resulting in the aminocidic substitution p.G299R. Considering the persistent and progressive increase of plasma triglycerides, fenofibrate treatment was started at 15 years of age allowing triglyceride level reduction in the following 1‐year follow‐up.

ABSTRACT Extracellular vesicles (EVs) are mediators of intercellular communication under both healthy and pathological conditions, including the induction of pro‐metastatic traits, but it is not yet known how and where functional cargoes of EVs are delivered to their targets in host cell compartments. We have described that after endocytosis, EVs reach Rab7+ late endosomes and a fraction of these enter the nucleoplasmic reticulum and transport EV biomaterials to the host cell nucleoplasm. Their entry therein and docking to outer nuclear membrane occur through a tripartite complex formed by the proteins VAP‐A, ORP3 and Rab7 (VOR complex). Here, we report that the antifungal compound itraconazole (ICZ), but not its main metabolite hydroxy‐ICZ or ketoconazole, disrupts the binding of Rab7 to ORP3–VAP‐A complexes, leading to inhibition of EV‐mediated pro‐metastatic morphological changes including cell migration behaviour of colon cancer cells. With novel, smaller chemical drugs, inhibition of the VOR complex was maintained, although the ICZ moieties responsible for antifungal activity and interference with intracellular cholesterol distribution were removed. Knowing that cancer cells hijack their microenvironment and that EVs derived from them determine the pre‐metastatic niche, small‐sized inhibitors of nuclear transfer of EV cargo into host cells could find cancer therapeutic applications, particularly in combination with direct targeting of cancer cells.

Background Atrial fibrillation (AF) is a major risk factor for mortality. The prevalence, clinical correlates, and prognostic impact of AF in Takotsubo syndrome (TTS) have not yet been investigated in a large patient cohort. This study aimed to investigate the prevalence, clinical correlates, and prognostic impact of AF in patients with TTS. Methods and Results Patients with TTS were enrolled from the International Takotsubo Registry, which is a multinational network with 26 participating centers in Europe and the United States. Patients were dichotomized according to the presence or absence of AF at the time of admission. Of 1584 patients with TTS, 112 (7.1%) had AF. The mean age was higher (P

Background Previous studies investigating the relationship of influenza with acute myocardial infarction (AMI) have not distinguished between AMI types 1 and 2. Influenza and cold temperature can explain the increased incidence of AMI during winter but, because they are closely related in temperate regions, their relative contribution is unknown. Methods and Results The temporal relationship between incidence rates of AMI with demonstrated culprit plaque (type 1 AMI) from the regional primary angioplasty network and influenza, adjusted for ambient temperature, was studied in Madrid region (Spain) during 5 influenza seasons (from June 2013 to June 2018). A time‐series analysis with quasi‐Poisson regression models and distributed lag‐nonlinear models was used. The incidence rate of type 1 AMI according to influenza vaccination status was also explored. A total of 8240 cases of confirmed type 1 AMI were recorded. The overall risk ratio (RR) of type 1 AMI during epidemic periods, adjusted for year, month, and temperature, was 1.23 (95% CI, 1.03–1.47). An increase of weekly influenza rate of 50 cases per 100 000 inhabitants resulted in an RR for type 1 AMI of 1.16 (95% CI, 1.09–1.23) during the same week, disappearing 1 week after. When adjusted for influenza, a decrease of 1ºC in the minimum temperature resulted in an increase of 2.5% type 1 AMI. Influenza vaccination was associated with a decreased risk of type 1 AMI in subjects aged 60 to 64 years (RR, 0.58; 95% CI, 0.47–0.71) and ≥65 years (RR, 0.53; 95% CI, 0.49–0.57). Conclusions Influenza and cold temperature were both independently associated with an increased risk of type 1 AMI, whereas vaccination was associated with a reduced risk among older patients.

In recent years, hyper-complex deep networks (such as complex-valued and quaternion-valued neural networks – QVNNs) have received a renewed interest in the literature. They find applications in multiple fields, ranging from image reconstruction to 3D audio processing. Similar to their real-valued counterparts, quaternion neural networks require custom regularisation strategies to avoid overfitting. In addition, for many real-world applications and embedded implementations, there is the need of designing sufficiently compact networks, with few weights and neurons. However, the problem of regularising and/or sparsifying QVNNs has not been properly addressed in the literature as of now. In this study, the authors show how to address both problems by designing targeted regularisation strategies, which can minimise the number of connections and neurons of the network during training. To this end, they investigate two extensions of [inline-formula] and structured regularisations to the quaternion domain. In the authors’ experimental evaluation, they show that these tailored strategies significantly outperform classical (real-valued) regularisation approaches, resulting in small networks especially suitable for low-power and real-time applications.

This study proposes a time domain methodology for harmonic state estimation (HSE) in power systems. The proposed methodology is formulated to analyse the unbalanced operation of three‐phase power systems including non‐linear loads. It takes into account the optimal number of measuring devices and exploits the property of half‐wave symmetry in voltage and current waveforms to significantly reduce the computational effort of the solution process. The results obtained are in close agreement with the actual response obtained from the time domain power system simulation performed with the SimPowerSystems toolbox of Simulink®. Hence, the proposed methodology can adequately assess the harmonic state in unbalanced power systems. The results show a considerable reduction in the instrumentation resources and time processing needed for HSE in non‐linear power networks.