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IntroductionPeripheral arterial disease (PAD) is a marker of cardiovascular morbidity, causing disability, loss of mobility and poor quality of life, manifesting clinically in the form of intermittent claudication (IC). Physical exercise increases the distance walked and improves quality of life. The aim of our study will be increased walking distance prolonging the time of onset of pain in patients with symptomatic PAD (IC).Methods and analysisThis study will be performed in Mataró Hospital’s vascular surgery service and School of Health Sciences, TecnoCampus. This population comes from 15 primary healthcare centres ofNorth Barcelona, Spain (450 000 inhabitants).This study will be a four-group parallel, longitudinal, randomised controlled trial, blind to analysis.The main primary outcome of this study will be the improvement in pain-free walking distance. Others primary objectives are and improvement in functional status, quality of life and Ankle-Brachial Index (ABI). Secondary outcomes will be the analysis of cardiorespiratory fitness, evaluation of muscle fitness, determine the maintenance of primary objectives at 6 and 12 months.We will be included 124 patients (31 per group). The changes of the outcome (Barthel, SF-12, VascQOL-6, ABI) of the three intervention groups vs the control group at 3, 6 and 12 months will be compared, both continuously (linear regression) and categorically (logistic regression). A person who has not performed at least 75% of the training will be considered to have not completed the intervention.Ethics and disseminationThe study will be conducted according to the Declaration of Helsinki . It was approved by the Ethics Committee of the Research Institute Primary Health IDIAP Jordi Gol (20/035 P),Barcelona 6 October 2020. Informed consent will be obtained from all patients before the start of the study. We will disseminate results through academic papers and conference presentations.Trial registration numberNCT04578990.

The electronic structure of phosphorene nanoflakes (PNFs) doped with Al and Si has been explored using hybrid functional BHandHlyp/def2-SVP and complete active space (CASSCF) methods. Doping increases the bond length alternation and changes the overall PNF shape. Doping also decreases singlet-triplet splitting in the PNFs. This effect is most notable for Si doping where singlet and triplet states become virtually degenerated. Doping also reduces band gaps and changes the nature of the ground states for Si-doped systems. The ground state of Si-doped PNFs becomes polyradicalic. In general, dopants with even number of valence electrons promote polyradicalic ground state. Doped systems show increased electron affinities (EAs), while the ionization potentials are much less affected. Larger EAs are related with the delocalization of an extra electron over the empty or partially empty 3 p orbitals of the dopants. Doping increases the reorganization energies in all cases. Al-doped PNFs are the hole transport materials while Si-doped nanoflakes tend to be electron transport systems. Graphical abstract

Ontogenetic changes in venom composition have important ecological implications due the relevance of venom in prey acquisition and defense. Additionally, intraspecific venom variation has direct medical consequences for the treatment of snakebite. However, ontogenetic changes are not well documented in most species. The Mexican Black-tailed Rattlesnake (Crotalus molossus nigrescens) is large-bodied and broadly distributed in Mexico. To document venom variation and test for ontogenetic changes in venom composition, we obtained venom samples from twenty-seven C. m. nigrescens with different total body lengths (TBL) from eight states in Mexico. The primary components in the venom were detected by reverse-phase HPLC, western blot, and mass spectrometry. In addition, we evaluated the biochemical (proteolytic, coagulant and fibrinogenolytic activities) and biological (LD50 and hemorrhagic activity) activities of the venoms. Finally, we tested for recognition and neutralization of Mexican antivenoms against venoms of juvenile and adult snakes. We detected clear ontogenetic venom variation in C. m. nigrescens. Venoms from younger snakes contained more crotamine-like myotoxins and snake venom serine proteinases than venoms from older snakes; however, an increase of snake venom metalloproteinases was detected in venoms of larger snakes. Venoms from juvenile snakes were, in general, more toxic and procoagulant than venoms from adults; however, adult venoms were more proteolytic. Most of the venoms analyzed were hemorrhagic. Importantly, Mexican antivenoms had difficulties recognizing low molecular mass proteins (<12 kDa) of venoms from both juvenile and adult snakes. The antivenoms did not neutralize the crotamine effect caused by the venom of juveniles. Thus, we suggest that Mexican antivenoms would have difficulty neutralizing some human envenomations and, therefore, it may be necessary improve the immunization mixture in Mexican antivenoms to account for low molecular mass proteins, like myotoxins.

Background: Intermittent Claudication symptomatic peripheral arterial disease (ICSPAD) is associated with reduced mobility, functional capacity, and quality of life. Physical exercise is an effective non-pharmacological intervention for the management of ICSPAD. Adherence to exercise programs is challenging, due to the nature of the disease and the complex comorbidities associated with it. This study aimed to determine adherence to three supervised physical exercise programs (a walking intervention, strength intervention, and concurrent intervention) and an unsupervised exercise program (standard advice) in individuals with ICSPAD. Methods: In this clinical trial, 122 patients were divided into four groups based on the type of exercise program they followed: standard advice, walking intervention, strength intervention, and concurrent intervention. Results: The results revealed that while the demographic characteristics were similar, the strength intervention group had a younger mean age, and the walking group had a higher prevalence of hypertension and increased usage of anti-hypertensive drugs. Adherence to physical exercise and pedometer wearing was highest in the standard advice group. Logistic regression analysis showed lower odds of adherence to exercise and pedometer wearing in the intervention groups compared to the standard advice group. Adherence did not significantly vary across ankle-brachial index categories. Furthermore, there was no significant difference in adherence between the severity levels of intermittent claudication, though mild cases tended to exhibit higher adherence. Conclusions: The results show that the standard advice from healthcare professionals positively influences treatment adherence.

Background Antiplatelet and anticoagulant therapy are commonly used before, during and after peripheral arterial endovascular intervention. This survey aimed to establish antiplatelet and anticoagulant choice for peripheral arterial endovascular intervention in contemporary clinical practice. Methods Pilot-tested questionnaire distributed via collaborative research networks. Results One hundred and sixty-two complete responses were collected from responders in 22 countries, predominantly the UK (48%) and the rest of the European Union (44%). Antiplatelet monotherapy was the most common choice pre-procedurally (62%). In the UK, there was no difference between dual and single antiplatelet therapy use post procedure (50% vs. 37% p  = 0.107). However, a significant majority of EU respondents used dual therapy (68% vs. 20% p  < 0.001). There was variation in choice of antiplatelet therapy by the device used and the anatomical location of the intervention artery. The majority (82%) of respondents believed there was insufficient evidence to guide antithrombotic therapy after peripheral endovascular intervention and most (92%) would support a randomised trial. Conclusions There is widespread variation in the use of antiplatelet therapy, especially post peripheral arterial endovascular intervention. Clinicians would support the development of a randomised trial comparing dual antiplatelet therapy with monotherapy.

An amendment to this paper has been published and can be accessed via the original article.

Pistachio is a sustainable nut crop with exceptional climate resilience and nutritional value. To advance pistachios as a future food source and a model system for hard-shelled fruits, we generated a chromosome-scale reference genome of the most widely grown pistachio cultivar (Pistacia vera ‘Kerman’) and a spatiotemporal developmental study of the hull, shell, and kernel. Our study defined four distinct stages of pistachio growth and maturation by integrating tissue-level physiological and molecular data from thousands of nuts across twenty-four time points over three growing seasons. Transcriptional and metabolic changes in the kernel elucidate molecular pathways governing nutritional quality, such as the accumulation of unsaturated fatty acids, which are vital for shelf-life and dietary value. This work yields new knowledge and resources that will inform other woody crops and facilitate further improvement of pistachio as a globally significant, sustainable, and nutritious crop.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19) pandemic, affecting more than 219 countries and causing the death of more than 5 million people worldwide. The genetic background represents a factor that predisposes the way the host responds to SARS-CoV-2 infection. In this sense, genetic variants of ACE and ACE2 could explain the observed interindividual variability to COVID-19 outcomes. In order to improve the understanding of how genetic variants of ACE and ACE2 are involved in the severity of COVID-19, we included a total of 481 individuals who showed clinical manifestations of COVID-19 and were diagnosed by reverse transcription PCR (RT-PCR). Genomic DNA was extracted from peripheral blood and saliva samples. ACE insertion/deletion polymorphism was evaluated by the high-resolution melting method; ACE single-nucleotide polymorphism (SNP) (rs4344) and ACE2 SNPs (rs2285666 and rs2074192) were genotyped using TaqMan probes. We assessed the association of ACE and ACE2 polymorphisms with disease severity using logistic regression analysis adjusted by age, sex, hypertension, type 2 diabetes, and obesity. The severity of the illness in our study population was divided as 31% mild, 26% severe, and 43% critical illness; additionally, 18% of individuals died, of whom 54% were male. Our results showed in the codominant model a contribution of ACE2 gene rs2285666 T/T genotype to critical outcome [odds ratio (OR) = 1.83; 95%CI = 1.01–3.29; p = 0.04] and to require oxygen supplementation (OR = 1.76; 95%CI = 1.01–3.04; p = 0.04), in addition to a strong association of the T allele of this variant to develop critical illness in male individuals (OR = 1.81; 95%CI = 1.10–2.98; p = 0.02). We suggest that the T allele of rs2285666 represents a risk factor for severe and critical outcomes of COVID-19, especially for men, regardless of age, hypertension, obesity, and type 2 diabetes.

The arrival of Pfizer’s blue pill Sildenafil in 1998 brought a great relief both to patient and physician signalling the start of a great era of medical therapy in sexual medicine. Since then the sexual medicine experts have been prescribing sildenafil in erectile dysfunction with acceptable minor adverse events. But the use of sildenafil in premature ejaculation (PE) is still debated. 2018 being the 20th anniversary of sildenafil, we have compiled interesting facts about the role of sildenafil in PE from various original articles, systematic reviews, meta-analyses, economic brochures and sexual medicine committee guidelines. The major issues in most of these studies were the heterogeneity in the definition of PE and estimating the exact ejaculatory latency time. This perspective article highlights the positive role of sildenafil in the management of PE (even without ED) with acceptable adverse events. Now that we have a standardised definition of PE from International Society of Sexual Medicine (ISSM) and a psychogenic component in PE definition, more randomised placebo-controlled studies are required to further establish its role.

Plant-insect interactions are a determining factor for sustainable crop production. Although plants can resist or tolerate herbivorous insects to varying degrees, even with the use of pesticides, insects can reduce plant net productivity by as much as 20%, so sustainable strategies for pest control with less dependence on chemicals are needed. Selecting plants with optimal resistance and photosynthetic traits can help minimize damage and maintain productivity. Here, 27 landrace accessions of lima beans, Phaseolus lunatus L., from the Yucatan Peninsula were evaluated in the field for morphological resistance traits, photosynthetic characteristics, insect damage and seed yield. Variation was found in physical leaf traits (number, area, and dry mass of leaves; trichome density, specific leaf thickness and hardness) and in physiological traits (photosynthetic rate, stomatal conductance, intercellular carbon, water-use efficiency, and transpiration). Five accessions (JMC1325, JMC1288, JMC1339, JMC1208 and JMC1264) had the lowest index for cumulative damage with the highest seed yield, although RDA analysis uncovered two accessions (JMC1339, JMC1288) with strong positive association of seed yield and the cumulative damage index with leaf production, specific leaf area (SLA) and total leaf area. Leaf traits, including SLA and total leaf area are important drivers for optimizing seed yield. This study identified 12 important morphological and physiological leaf traits for selecting landrace accessions of P. lunatus for high yields (regardless of damage level) to achieve sustainable, environmentally safe crop production.