Blood salvage and autotransfusion during orthotopic liver transplantation for hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is a significant cause of oncologic mortality worldwide. Liver transplantation represents a curative option for patients with significant liver dysfunction and absence of metastases. However, this therapeutic option is associated with significant blood loss and frequently requires various transfusions and intraoperative blood salvage for autotransfusion (IBS-AT) with or without a leukocyte reduction filter. This study aimed to analyze available evidence on long-term oncologic outcomes of patients undergoing liver transplantation for HCC with and without IBS-AT. METHODS: Per PRISMA guidelines, a systematic review of keywords "Blood Salvage," "Auto-transfusion," "Hepatocellular carcinoma," and "Liver-transplant" was conducted in PubMed, EMBASE, and SCOPUS. Studies comparing operative and postoperative outcomes were screened and analyzed for review. RESULTS: Twelve studies totaling 1704 participants were included for analysis. Length of stay, recurrence rates, and overall survival were not different between IBS-AT group and non IBS-AT group. CONCLUSION: IBS-AT use is not associated with increased risk of recurrence in liver transplant for HCC even without leukocyte filtration. Both operative and postoperative outcomes are similar between groups. Comparison of analyzed studies suggest that IBS-AT is safe for use during liver transplant for HCC.

RNase H-sensitive multifunctional ASO-based constructs as promising tools for the treatment of multifactorial complex pathologies.

Combined therapies play a key role in the fight against complex pathologies, such as cancer and related drug-resistance issues. This is particularly relevant in targeted therapies where inhibition of the drug target can be overcome by cross-activating complementary pathways. Unfortunately, the drug combinations approved to date -mostly based on small molecules- face several problems such as toxicity effects, which limit their clinical use. To address these issues, we have designed a new class of RNase H-sensitive construct (3ASO) that can be disassembled intracellularly upon cell entry, leading to the simultaneous release of three different therapeutic oligonucleotides (ONs), tackling each of them the mRNA of a different protein. Here, we used Escherichia coli RNase H1 as a model to study an unprecedented mode of recognition and cleavage, that is mainly dictated by the topology of our RNA·DNA-based hybrid construct. As a model system for our technology we have created 3ASO constructs designed to specifically inhibit the expression of HER2, Akt and Hsp27 in HER2+ breast cancer cells. These trifunctional ON tools displayed very low toxicity and good levels of antiproliferative activity in HER2+ breast cancer cells. The present study will be of great potential in the fight against complex pathologies involving multiple mRNA targets, as the proposed cleavable designs will allow the efficient single-dose administration of different ON drugs simultaneously.

Improving the Accuracy of Metatarsal Osteotomies in Minimally Invasive Foot Surgery Using a Digital Inclinometer: Preliminary Study.

Minimally invasive foot surgery (MIS) has become a common procedure to treat various pathologies, and accuracy in the angle of metatarsal osteotomies is crucial to ensure optimal results. This randomized controlled trial with 37 patients investigates whether the implementation of a digital inclinometer can improve the accuracy of osteotomies compared to traditional freehand techniques. Patients were randomly allocated to group A (n = 15) receiving inclinometer-assisted surgery or group B (n = 22) receiving conventional surgery. Osteotomies were performed and outcomes were evaluated using an inclinometer. The inclinometer group showed a significant decrease in plantar pressure from 684.1 g/cm2 pretreatment to 449.5 g/cm2 post-treatment (p < 0.001, Cohen's d = 5.477). The control group decreased from 584.5 g/cm2 to 521.5 g/cm2 (p = 0.001, Cohen's d = 0.801). The effect size between groups was large (Cohen's d = -2.572, p < 0.001). The findings indicate a significant improvement in accuracy and reduction in outliers when using an inclinometer, suggesting that this technology has the potential to improve surgical practice and patient outcomes in minimally invasive metatarsal osteotomies.

The investigation of dose rate and photon beam energy dependence of optimized PASSAG polymer gel dosimeter using magnetic resonance imaging.

OBJECTIVE: It seems that dose rate (DR) and photon beam energy (PBE) may influence the sensitivity and response of polymer gel dosimeters. In the current project, the sensitivity and response dependence of optimized PASSAG gel dosimeter (OPGD) on DR and PBE were assessed. MATERIALS AND METHODS: We fabricated the OPGD and the gel samples were irradiated with various DRs and PBEs. Then, the sensitivity and response (R2) of OPGD were obtained by MRI at various doses and post-irradiation times. RESULTS: Our analysis showed that the sensitivity and response of OPGD are not affected by the evaluated DRs and PBEs. It was also found that the dose resolution values of OPGD ranged from 9 to 33 cGy and 12 to 34 cGy for the evaluated DRs and PBEs, respectively. Additionally, the data demonstrated that the sensitivity and response dependence of OPGD on DR and PBE do not vary over various times after the irradiation. CONCLUSIONS: The findings of this research project revealed that the sensitivity and response dependence of OPGD are independent of DR and PBE.

Soluble low-density lipoprotein receptor-related protein 1 as a surrogate marker of carotid plaque inflammation assessed by 18F-FDG PET in patients with a recent ischemic stroke.

BACKGROUND: 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) identifies carotid plaque inflammation and predicts stroke recurrence. AIM: Our aim was to evaluate the performance of soluble low-density lipoprotein receptor-related protein 1 (sLRP1) as an indicator of carotid plaque inflammation. METHODS: A prospective study was conducted among adult patients with recent (< 7 days) anterior circulation ischemic stroke and at least one atherosclerotic plaque in the ipsilateral internal carotid artery. Patients underwent an early (< 15 days from inclusion) 18F-FDG PET, and the maximum standardized uptake value (SUVmax) within the plaque was measured. sLRP1 levels were measured in plasma samples by ELISA. The association of sLRP1 with SUVmax was assessed using bivariate and multivariable linear regression analyses. Hazard ratios (HR) were estimated with Cox regression to evaluate the association between circulating sLRP1 and stroke recurrence. RESULTS: The study was conducted with 64 participants, of which 57.8% had ≥ 50% carotid stenosis. The multivariable linear and logistic regression analyses showed that sLRP1 was independently associated with (i) SUVmax within the plaque (ß = 0.159, 95% CI 0.062-0.257, p = 0.002) and (ii) a probability of presenting SUVmax ≥ 2.85 g/mL (OR = 1.31, 95% CI 1.00-1.01, p = 0.046), respectively. Participants with stroke recurrence showed higher sLRP1 levels at baseline [6447 ng/mL (4897-11163) vs. 3713 ng/mL (2793-4730); p = 0.018]. CONCLUSIONS: sLRP1 was independently associated with carotid plaque inflammation as measured by 18F-FDG PET in patients with recent ischemic stroke and carotid atherosclerosis.

Towards understanding insect species introduction and establishment: A community-level barcoding approach using island beetles.

Since Darwin put forward his opposing hypotheses to explain the successful establishment of species in areas outside their native ranges, the preadaptation and competition-relatedness hypotheses, known as Darwin's naturalization conundrum, numerous studies have sought to understand the relative importance of each. Here, we take advantage of well-characterized beetle communities across laurel forests of the Canary Islands for a first evaluation of the relative support for Darwin's two hypotheses within arthropods. We generated a mitogenome backbone tree comprising nearly half of the beetle genera recorded within the Canary Islands for the phylogenetic placement of native and introduced species sampled in laurel forests, using cytochrome c oxidase I (COI) sequences. For comparative purposes, we also assembled and phylogenetically placed a data set of COI sequences for introduced beetle species that were not sampled within laurel forests. Our results suggest a stronger effect of species preadaptation over resource competition, while also revealing an underappreciated shortfall in arthropod biodiversity data-knowledge of species as being native or introduced. We name this the Humboldtean shortfall and suggest that similar studies using arthropods should incorporate DNA barcode sequencing to mitigate this problem.

Landscape-variability of the carbon balance across managed boreal forests.

Boreal forests are important global carbon (C) sinks and, therefore, considered as a key element in climate change mitigation policies. However, their actual C sink strength is uncertain and under debate, particularly for the actively managed forests in the boreal regions of Fennoscandia. In this study, we use an extensive set of biometric- and chamber-based C flux data collected in 50 forest stands (ranging from 5 to 211 years) over 3 years (2016-2018) with the aim to explore the variations of the annual net ecosystem production (NEP; i.e., the ecosystem C balance) across a 68 km2 managed boreal forest landscape in northern Sweden. Our results demonstrate that net primary production rather than heterotrophic respiration regulated the spatio-temporal variations of NEP across the heterogeneous mosaic of the managed boreal forest landscape. We further find divergent successional patterns of NEP in our managed forests relative to naturally regenerating boreal forests, including (i) a fast recovery of the C sink function within the first decade after harvest due to the rapid establishment of a productive understory layer and (ii) a sustained C sink in old stands (131-211 years). We estimate that the rotation period for optimum C sequestration extends to 138 years, which over multiple rotations results in a long-term C sequestration rate of 86.5 t C ha-1 per rotation. Our study highlights the potential of forest management to maximize C sequestration of boreal forest landscapes and associate climate change mitigation effects by developing strategies that optimize tree biomass production rather than heterotrophic soil C emissions.

On the uncertainty in estimates of the carbon balance recovery time after forest clear-cutting.

An essential metric for describing carbon dynamics in managed forest landscapes is the recovery time of the carbon balance after clear-cutting. Here, we demonstrate how the age-dependent mathematical trajectory is affected by both the selected model and data availability, leading to considerable uncertainty in the modelling of the net ecosystem production (NEP) over stand age. We further show that the initial carbon loss estimates associated with the timing of the source-sink transition (SST) are significant, but may have a limited effect on the total carbon sequestration at the end of the standard (RP, 120 years) or optimal (OCS) rotation periods.

Ru(II)-Cyanine Complexes as Promising Photodynamic Photosensitizers for the Treatment of Hypoxic Tumours with Highly Penetrating 770†nm Near-Infrared Light.

Light-activated treatments, such as photodynamic therapy (PDT), provide temporal and spatial control over a specific cytotoxic response by exploiting toxicity differences between irradiated and dark conditions. In this work, a novel strategy for developing near infrared (NIR)-activatable Ru(II) polypyridyl-based photosensitizers (PSs) was successfully developed through the incorporation of symmetric heptamethine cyanine dyes in the metal complex via a phenanthrimidazole ligand. Owing to their strong absorption in the NIR region, the PSs could be efficiently photoactivated with highly penetrating NIR light (770 nm), leading to high photocytotoxicities towards several cancer cell lines under both normoxic and hypoxic conditions. Notably, our lead PS (Ru-Cyn-1), which accumulated in the mitochondria, exhibited a good photocytotoxic activity under challenging low-oxygen concentration (2 % O2 ) upon NIR light irradiation conditions (770 nm), owing to a combination of type I and II PDT mechanisms. The fact that the PS Protoporphyrin IX (PpIX), the metabolite of the clinically approved 5-ALA PS, was found inactive under the same challenging conditions positions Ru-Cyn-1 complex as a promising PDT agent for the treatment of deep-seated hypoxic tumours.

Early onset of azithromycin to prevent CLAD in lung transplantation: Promising results of a retrospective single centre experience.

INTRODUCTION: Azithromycin (AZI) may be an effective immune modulator in lung transplant (LT) recipients, and can decrease chronic lung allograft dysfunction (CLAD) rates, the leading cause of mortality after the 1st year post-LT. The aim of the study is to assess the effect of AZI initiation and its timing on the incidence and severity of CLAD in LT recipients. METHODS: Single-center retrospective study, including LT recipients from 01/01/2011 to 30/06/2020. Four groups were established: those who started AZI at the 3rd week post-LT (group A), those who received AZI later than the 3rd week post-LT and had preserved FEV1 (B), those who did not receive AZI (C) and those who started AZI due to a decline in FEV1 (D). The dosage of AZI prescribed was 250 mg three times per week. CLAD was defined and graduated according to the 2019 ISHLT criteria. RESULTS: We included 358 LT recipients: 139 (38.83%) were in group A, 94 (26.25%) in group B, 91 (25.42%) in group C, and 34 (9.50%) in group D. Group A experienced the lowest CLAD incidence and severity at 1 (p = .01), 3 (p < .001), and 5 years post-LT, followed by Group B. Groups C and D experienced a higher incidence and severity of CLAD (p = .015). Initiation of AZI prior to FEV1 decline (Groups A and B) proved to be protective against CLAD after adjusting for differences between the treatment groups. CONCLUSIONS: Early initiation of AZI in LT recipients could have a role in decreasing the incidence and severity of CLAD. In addition, as long as FEV1 is preserved, initiating AZI at any time could also be useful to prevent the incidence of CLAD and reduce its severity.

The Impact of Anticoagulation on Indwelling Pleural Catheter Removal due to Pleurodesis in Patients with Malignant Pleural Effusion.

BACKGROUND: A well-recognized therapy to improve the symptoms of patients with malignant pleural effusion (MPE), indwelling pleural catheters (IPCs) can also achieve spontaneous pleurodesis. Chemical pleurodesis is associated with a significant pro-coagulation and fibrinolytic environment. Hence, anticoagulation could theoretically interfere with this process. OBJECTIVE: The aim of this study was to evaluate if anticoagulation can interfere with successful spontaneous pleurodesis in patients treated with IPC. METHODS: This was a cohort study of all patients with MPE treated with IPC. The primary objective was to determine if anticoagulant use after IPC placement decreased the rate of spontaneous pleurodesis. The secondary objective was to identify other factors associated with spontaneous pleurodesis. We used a Fine-Gray subdistribution hazard model and a direct acyclic graph to identify variables associated with time to spontaneous pleurodesis. RESULTS: Of the included 410 patients, 210 patients (51.2%) achieved pleurodesis and had their IPC removed. We found no association between anticoagulation and likelihood of pleurodesis. Multivariate analyses revealed that prior chemotherapy, ECOG score of 2-4 were associated with unsuccessful pleurodesis, while chemotherapy or radiotherapy after IPC placement remained associated with increased likelihood of spontaneous pleurodesis. CONCLUSIONS: We failed to demonstrate an association between anticoagulation and pleurodesis. We found that better performance status and chemotherapy or radiotherapy after IPC placement can increase the rate of pleurodesis and catheter removal.

Incipient Wear Detection of Welding Gun Secondary Circuit by Virtual Resistance Sensor Using Mahalanobis Distance.

Wear of the secondary of the welding gun, caused by mechanical fatigue or due to a bad parameterization of the welding points, causes an increase in quality problems such as non-existent welds or a reduced weld nugget size. In addition to quality problems, this defect causes production stoppages that affect the final cost of the manufactured part. Different studies have focused on evaluating the importance of different welding parameters, such as current, in the final quality of the welding nugget. However, few studies have focused on preventing weld command parameters from degrading or changing. This investigation seeks to determine the wear of the secondary circuit to avoid variability in the current supplied to the welding point caused by this defect and the increase in circuit resistance, especially in industrial environments. In this work, a virtual sensor is developed to estimate the resistance of the welding arm based on previous research, which has shown the possibility of detecting secondary wear by analysing the duty cycle of the power circuit. From the data of the virtual sensor, an anomaly detection method based on the Mahalanobis distance is developed. Finally, an integral system for detecting secondary wear of welding guns in real production lines is presented. This system establishes performance thresholds based on the analysis of the Mahalanobis distance distribution, allowing monitoring of the secondary circuit wear condition after each welding cycle. The results obtained show how the system can detect incipient wear in welding guns, regardless of which part of the secondary the wear occurs, improving decision-making and reducing quality problems.

Virtual Sensor of Gravity Centres for Real-Time Condition Monitoring of an Industrial Stamping Press in the Automotive Industry.

This article proposes the development of a novel tool that allows real-time monitoring of the balance of a press during the stamping process. This is performed by means of a virtual sensor that, by using the tonnage information in real time, allows us to calculate the gravity centre of a virtual load that moves the slide up and down. The present development follows the philosophy shown in our previous work for the development of industrialised predictive systems, that is, the use of the information available in the system to develop IIoT tools. This philosophy is defined as I3oT (industrializable industrial Internet of Things). The tonnage data are part of a set of new criteria, called Criterion-360, used to obtain this information. This criterion stores data from a sensor each time the encoder indicates that the position of the main axis has rotated by one degree. Since the main axis turns in a complete cycle of the press, this criterion allows us to obtain information on the phases of the process and easily shows where the measured data are in the cycle. The new system allows us to detect anomalies due to imbalance or discontinuity in the stamping process by using the DBSCAN algorithm, which allows us to avoid unexpected stops and serious breakdowns. Tests were conducted to verify that our system actually detects minimal imbalances in the stamping process. Subsequently, the system was connected to normal production for one year. At the end of this work, we explain the anomalies detected as well as the conclusions of the article and future works.

Personalized Gamification for Learning: A Reactive Chatbot Architecture Proposal.

A key factor for successfully implementing gamified learning platforms is making students interact with the system from multiple digital platforms. Learning platforms that try to accomplish all their objectives by concentrating all the interactions from users with them are less effective than initially believed. Conversational bots are ideal solutions for cross-platform user interaction. In this paper, an open student-player model is presented. The model includes the use of machine learning techniques for online adaptation. Then, an architecture for the solution is described, including the open model. Finally, the chatbot design is addressed. The chatbot architecture ensures that its reactive nature fits into our defined architecture. The approach's implementation and validation aim to create a tool to encourage kids to practice multiplication tables playfully.

Triangular Silver Nanoplates as a Bioanalytical Tool: Potential COVID-19 Detection.

Nanotechnology offers new possibilities in molecular diagnostics, with nanoparticles gaining attention as biosensor upgrades. This study evaluates gold-coated silver nanoplates coated with PEG for enhanced protection, aiming to detect Spike protein with higher sensitivity, and emphasizes the importance of considering complex environments and appropriate controls for specific binding and accurate analysis. The sensitivity of antibody-coated PEGAuTSNPs as tools for immunoassays is demonstrated through fibronectin (Fn)- anti-fibronectin binding within an isolated extracellular matrix as a complex and native environment of Fn. Moreover, the optimal functionalization volume of Spike protein was determined (4 µg/mL of PEGAuTSNP). Anti-Spike was added to confirm binding, while the TJP1 protein was used as a negative control. The same experiment was used in the presence of horse serum to simulate a complex environment. According to Localized Surface Plasmon Resonance analysis and Dynamic Light Scattering size measurements, anti-Spike exhibited a stronger affinity for the nanoplates, causing TJP1 to be replaced by the antibody on the nanoplates' surface. Future research will involve exploring alternative complex environments, filtering larger molecules, and the optimization of immunoassay performance.

Exploring Structural-Photophysical Property Relationships in Mitochondria-Targeted Deep-Red/NIR-Emitting Coumarins.

Organic fluorophores operating in the optical window of biological tissues, namely in the deep-red and near-infrared (NIR) region of the electromagnetic spectrum, offer several advantages for fluorescence bioimaging applications owing to the appealing features of long-wavelength light, such as deep tissue penetration, lack of toxicity, low scattering, and reduced interference with cellular autofluorescence. Among these, COUPY dyes based on non-conventional coumarin scaffolds display suitable photophysical properties and efficient cellular uptake, with a tendency to accumulate primarily in mitochondria, which renders them suitable probes for bioimaging purposes. In this study, we have explored how the photophysical properties and subcellular localization of COUPY fluorophores can be modulated through the modification of the coumarin backbone. While the introduction of a strong electron-withdrawing group, such as the trifluoromethyl group, at position 4 resulted in an exceptional photostability and a remarkable redshift in the absorption and emission maxima when combined with a julolidine ring replacing the N,N-dialkylaminobenzene moiety, the incorporation of a cyano group at position 3 dramatically reduced the brightness of the resulting fluorophore. Interestingly, confocal microscopy studies in living HeLa cells revealed that the 1,1,7,7-tetramethyl julolidine-containing derivatives accumulated in the mitochondria with much higher specificity. Overall, our results provide valuable insights for the design and optimization of new COUPY dyes operating in the deep-red/NIR region.

High Expression Levels of miR-21-5p in Younger Hospitalized COVID-19 Patients Are Associated with Mortality and Critical Disease.

In COVID-19, critical disease and invasive mechanical ventilation (IMV) increase the risk of death, mainly in patients over 60 years of age. OBJECTIVES: To find the relationship between miR-21-5p and miR-146a-5p in terms of the severity, IMV, and mortality in hospitalized COVID-19 patients younger than 55 years of age. METHODS: The patients were stratified according to disease severity using the IDSA/WHO criteria for severe and critical COVID-19 and subclassified into critical non-survivors and critical survivors. RESULTS: Ninety-seven severe/critical COVID-19 patients were included; 81.3% of the deceased were male and 18.8% were female. Higher expression miR-21-5p levels were associated as follows: severe vs. critical disease (p = 0.007, FC = 0.498), PaO2/FiO2 index, mild vs. severe (p = 0.027, FC = 0.558), and survivors vs. non-survivors (p = 0.03, FC = 0.463). Moreover, we identified correlations with clinical variables: CRP (rho = -0.54, p < 0.001), D-dimer (rho = -0.47, p < 0.05), related to damage in the kidney (rho = 0.60, p < 0.001), liver (rho = 0.41, p < 0.05), and lung (rho = 0.54, p < 0.001). Finally, miR-21-5p thresholds were calculated according to severity (8.191), IMV (8.191), and mortality (8.237); these values increased the risk of developing a critical disease (OR = 4.19), the need for IMV (OR = 5.63), and death (OR = 6.00). CONCLUSION: Increased expression levels of miR-21-5p are related to worse outcome of COVID-19 in younger hospitalized patients.

Future scenarios in the former oil capital: coastal flooding and social vulnerability in Macaé, RJ.

The accelerated urban growth in Macaé had important consequences on socio-spatial organization, especially about housing spaces that became increasingly difficult to be accessed by the low-income population. The most devalued lands, such as mangroves and floodplains, were occupied by the low-income population. The proposal highlighted in this project focuses directly on the problem of rising sea levels and flooding in the urban space of Macaé, which is of social interest. A simulation of future scenarios with sea level rise above the current one, allowing the identification of areas flooded by marine transgression on a time scale of 100 years (for the year 2100). For this, the rate was chosen for the simulation: the greenhouse gas scenario RCP8.5, as given in IPCC's Fifth Assessment Report (AR5) of 2014. A radiative forcing that corresponds to more than 700 ppm CO2-eq, but less than 1500 ppm, the projected increase is 1 m to more than 3 m (medium confidence) and more than 3 m (medium confidence). This assessment is based on the average confidence in the contribution from thermal expansion and low confidence in the modeled contribution modeled contribution of the ice sheets. Therefore, the climate change-induced global mean sea level rise is caused by thermal expansion of ocean water and ocean mass gain, the latter being mainly due to a decrease in land ice mass. The estimated sea-level rise used for the projection of this study is 2.15, as proposed by Grinsted et al. in 2009.

Effects of aerobic and combined training on pain-free walking distance and health-related quality of life in patients with peripheral artery disease: a randomized clinical trial.

Background: Decreased walking ability in patients with peripheral arterial disease is often a clinical problem and limits the quality of life and daily activities of these subjects. physical exercise is important in this scenario, as it improves both the daily walking distance and the ability to withstand intermittent claudication related to the limitations of the peripheral disease. Objectives: Our aim was to compare the effects of two types of exercise training (aerobic training and aerobic training combined with resistance exercises) on pain-free walking distance (PFWD) and health-related quality of life (HRQoL) in a sample composed of patients with peripheral artery disease (PAD). Methods: Twenty patients with claudication symptoms were randomized to either aerobic control (AC) N= 9, or combined training (CT) N= 8, (24 sixty-minute sessions, twice a week). The total walking distance until onset of pain due to claudication was assessed using the 6-minute walk test and HRQoL was measured using the WHOQOL-bref questionnaire (general and specific domains) at baseline and after training. We used generalized estimating equations (GEE) to assess the differences between groups for the PFWD and HRQoL domains, testing the main group and time effects and their respective interaction effects. P values < 0.05 were considered statistically significant. Results: Seventeen patients (mean age 63±9 years; 53% male) completed the study. Both groups experienced improvement in claudication, as reflected by a significant increase in PFWD: AC, 149 m to 299 m (P<0.001); CT, 156 m to 253 m (P<0.001). HRQoL domains also improved similarly in both groups (physical capacity, psychological aspects, and self-reported quality of life; P=0.001, P=0.003, and P=0.011 respectively). Conclusions: Both aerobic and combined training similarly improved PFWD and HRQoL in PAD patients. There are no advantages in adding strength training to conventional aerobic training. This study does not support the conclusion that combined training is a good strategy for these patients when compared with classic training.

Contexto: A diminuição da capacidade de marcha em pacientes com doença arterial periférica é frequentemente um problema clínico e limita a qualidade de vida e as atividades diárias desses indivíduos. O exercício físico é importante nesse cenário, pois melhora tanto a distância caminhada diária quanto a capacidade de suportar a claudicação intermitente relacionada às limitações da doença periférica. Objetivos: Comparar os efeitos do treinamento aeróbico (TA) e do treinamento aeróbico combinado com exercícios de resistência (TC) na distância percorrida livre de dor (DPLD) e na qualidade de vida relacionada à saúde (QVRS) em pacientes com doença arterial periférica (DAP). Métodos: Vinte pacientes com sintomas de claudicação foram randomizados para TA ou TC. Os treinamentos foram realizados em 24 sessões, duas vezes por semana. A DPLD foi avaliada por meio do teste de caminhada de 6 minutos, e a QVRS foi medida pelo instrumento da avaliação de qualidade de vida da Organização Mundial da Saúde (WHOQOL-BREF), no início e após o treinamento. Para avaliar as diferenças entre os grupos para DPLD e os domínios da QVRS, foi utilizado o modelo de equações de estimativa generalizada, testando os efeitos principais do grupo e tempo, bem como os respectivos efeitos de interação. Valores de p < 0,05 foram considerados estatisticamente significativos. Resultados: Dezessete pacientes (idade média: 63±9 anos; 53% do sexo masculino) completaram o estudo. Ambos os grupos apresentaram melhora na claudicação, refletida por um aumento significativo na DPLD: grupo controle aeróbico - de 149 m para 299 m (P < 0,001); grupo de treinamento combinado - de 156 m para 253 m (P < 0,001). Os domínios da QVRS também melhoraram de forma semelhante em ambos os grupos (capacidade física, aspectos psicológicos e qualidade de vida autorreferida; P = 0,001, P = 0,003 e P = 0,011, respectivamente). Conclusões: Ambos os treinamentos melhoraram de forma semelhante a DPLD e a QVRS em pacientes com DAP. Não há vantagens em associar o treinamento de força ao treinamento aeróbico convencional. O estudo não permite concluir que o TC é uma boa estratégia para esses pacientes quando comparado ao treinamento clássico.

Inhaled seralutinib exhibits potent efficacy in models of pulmonary arterial hypertension.

BACKGROUND: Signalling through platelet-derived growth factor receptor (PDGFR), colony-stimulating factor 1 receptor (CSF1R) and mast/stem cell growth factor receptor kit (c-KIT) plays a critical role in pulmonary arterial hypertension (PAH). We examined the preclinical efficacy of inhaled seralutinib, a unique small-molecule PDGFR/CSF1R/c-KIT kinase inhibitor in clinical development for PAH, in comparison to a proof-of-concept kinase inhibitor, imatinib. METHODS: Seralutinib and imatinib potency and selectivity were compared. Inhaled seralutinib pharmacokinetics/pharmacodynamics were studied in healthy rats. Efficacy was evaluated in two rat models of PAH: SU5416/Hypoxia (SU5416/H) and monocrotaline pneumonectomy (MCTPN). Effects on inflammatory/cytokine signalling were examined. PDGFR, CSF1R and c-KIT immunohistochemistry in rat and human PAH lung samples and microRNA (miRNA) analysis in the SU5416/H model were performed. RESULTS: Seralutinib potently inhibited PDGFRα/ß, CSF1R and c-KIT. Inhaled seralutinib demonstrated dose-dependent inhibition of lung PDGFR and c-KIT signalling and increased bone morphogenetic protein receptor type 2 (BMPR2). Seralutinib improved cardiopulmonary haemodynamic parameters and reduced small pulmonary artery muscularisation and right ventricle hypertrophy in both models. In the SU5416/H model, seralutinib improved cardiopulmonary haemodynamic parameters, restored lung BMPR2 protein levels and decreased N-terminal pro-brain natriuretic peptide (NT-proBNP), more than imatinib. Quantitative immunohistochemistry in human lung PAH samples demonstrated increased PDGFR, CSF1R and c-KIT. miRNA analysis revealed candidates that could mediate seralutinib effects on BMPR2. CONCLUSIONS: Inhaled seralutinib was an effective treatment of severe PAH in two animal models, with improved cardiopulmonary haemodynamic parameters, a reduction in NT-proBNP, reverse remodelling of pulmonary vascular pathology and improvement in inflammatory biomarkers. Seralutinib showed greater efficacy compared to imatinib in a preclinical study.