Intravenous prostaglandin E1 (alprostadil) bolus in ductus arteriosus-dependent CHD: valid or absolutely contraindicated?

The use of prostaglandin E1 is well documented in ductus arteriosus-dependent CHD or in neonatal pulmonary pathologies that cause severe pulmonary hypertension. The intravenous infusion is well established in loading infusion and maintenance with an onset of action of 30 minutes until 2 hours or even more. Our aim is to report three patients with pulmonary atresia that presented hypercyanotic spell due to a ductal spasm during cardiac catheterisation in whom the administration of a bolus of alprostadil reversed the spasm and increased pulmonary flow, immediately stabilising the condition of the patients allowing subsequent successful stent placement with no serious complications or sequelae after the administration of the bolus. More studies are needed to make a recommendation regarding the use of alprostadil in bolus in cases where the ductal spasm might jeopardise the life of the patient.

Percutaneous transient occlusion of the transtricuspid flow: a new method to evaluate the right ventricle-dependent coronary circulation in pulmonary atresia with intact ventricular septum.

Pulmonary atresia with an intact ventricular septum is characterised by heterogeneity in right ventricle morphology and coronary anatomy. In some cases, the presence of ventriculocoronary connections may promote coronary artery stenosis or interruption, and aortic diastolic pressure may not be sufficient to drive coronary blood flow. This requires a correct evaluation (currently done by angiography) which depends on whether the patient can be offered decompression of the right ventricle. To date, there is no objective method to do so, so we designed a percutaneous, transitory technique with the purpose of occluding the transtricuspid anterograde flow. The manoeuverer was performed in a 25-day-old female with pulmonary atresia with intact ventricular septum, right ventricle at suprasystemic level, and selective coronarography was not conclusive, the anterior descendant with stenosis in its middle third and from this point, thinner with to-fro flow. Occlusion was performed with a balloon catheter. We re-evaluated the coronary flow and the normalised anterior descendant flow. We hope that with this new method, we can give a more accurate diagnosis and determine the cases in which the coronary circulation is truly not right ventricle dependent to offer a greater number of patients biventricular or 1.5 ventricular repairs and thereby improve their quality of life and survival, the ones that turn out to be right ventricular dependant; offer them an early reference for cardiac transplant or in case it is not available to consider univentricular palliation knowing that this probably would not reduce the risk of ischaemia and/or death over time.

RANKL interferes with osteoclastogenesis in PEG-fused U937 cells through LGR4.

INTRODUCTION: RANKL plays an important role in the differentiation and maturation process of preosteoclast cells. The osteoclast is a multinucleated cell that can have various sizes and a variable number of nuclei. However, there are no models that allow us to understand how successive cell fusions have a limit, or how cell fusion is regulated. METHODOLOGY: The present investigation was aimed to determine whether fusing U937 cells with PEG to generate osteoclast-like cells expresses LGR4 and whether applying RANKL to these cells modifies osteoclastic activity compared to non-PEG-fused and RANKL-treated cells. RESULTS: By fusing U937 cells with PEG, it was found that the LGR4 receptor expression was promoted as early as 24 hours of culture. Applying RANKL before or after fusion inhibits osteoclastic activity. Interfering RANKL interaction with LGR4 in PEG-treated cells recovers and increases cell fusion and osteoclastic activity. PEG-fused U937 cells show osteoclast markers similar to those observed in the classical RANKL-stimulated cell model. CONCLUSION: Our model allows us to understand that RANKL has fusogenic activity during the first days of culture and in fused cells modulates fusion, contributing to differentiate the role of RANKL before and after fusion through LGR4.

NT-PROBNP as a screening tool for low-risk patent ductus arteriousus: a follow-up validation study.

The purpose of the study is to test whether NT-proBNP serves as a screening tool for low-risk patent ductus arteriosus and safely avoids routine early echocardiography. This is a prospective observational study in preterm infants ≤32 weeks of gestational age. Infants with ≥5100 pg/ml (positive screening) at 48-72 hours of life received comprehensive echocardiography and were treated according to shunt severity. Infants with NT-proBNP below 5100 pg/ml (negative screening) were managed expectantly. The main outcome was need for ductus treatment within the first 7 days of life. One hundred twenty-five infants were included; 82 had a negative NT-proBNP screening and 43 had a positive NT-proBNP screening. No infant (0%) with a negative screening was treated for ductus while 26 (60.4%) with a positive screening were treated (p < 0.001). NT-proBNP avoided a 65.6% of routine echocardiograms. NT-proBNP had an excellent performance to predict PDA treatment (AUC = 0.967).Conclusion: NT-proBNP at 48-72 hours of life has an excellent performance to detect low risk and avoids unnecessary echocardiograms. This may contribute to optimize PDA management in terms of resource utilization.

Virtual reality-enhanced walking in people post-stroke: effect of optic flow speed and level of immersion on the gait biomechanics.

BACKGROUND: Optic flow-the apparent visual motion experienced while moving-is absent during treadmill walking. With virtual reality (VR), optic flow can be controlled to mediate alterations in human walking. The aim of this study was to investigate (1) the effects of fully immersive VR and optic flow speed manipulation on gait biomechanics, simulator sickness, and enjoyment in people post-stroke and healthy people, and (2) the effects of the level of immersion on optic flow speed and sense of presence. METHODS: Sixteen people post-stroke and 16 healthy controls performed two VR-enhanced treadmill walking sessions: the semi-immersive GRAIL session and fully immersive head-mounted display (HMD) session. Both consisted of five walking trials. After two habituation trials (without and with VR), participants walked three more trials under the following conditions: matched, slow, and fast optic flow. Primary outcome measures were spatiotemporal parameters and lower limb kinematics. Secondary outcomes (simulator sickness, enjoyment, and sense of presence) were assessed with the Simulator Sickness Questionnaire, Visual Analogue Scales, and Igroup Presence Questionnaire. RESULTS: When walking with the immersive HMD, the stroke group walked with a significantly slower cadence (-3.69strides/min, p = 0.006), longer stride time (+ 0.10 s, p = 0.017) and stance time for the unaffected leg (+ 1.47%, p = 0.001) and reduced swing time for the unaffected leg (- 1.47%, p = 0.001). Both groups responded to the optic flow speed manipulation such that people accelerated with a slow optic flow and decelerated with a fast optic flow. Compared to the semi-immersive GRAIL session, manipulating the optic flow speed with the fully immersive HMD had a greater effect on gait biomechanics whilst also eliciting a higher sense of presence. CONCLUSION: Adding fully immersive VR while walking on a self-paced treadmill led to a more cautious gait pattern in people post-stroke. However, walking with the HMD was well tolerated and enjoyable. People post-stroke altered their gait parameters when optic flow speed was manipulated and showed greater alterations with the fully-immersive HMD. Further work is needed to determine the most effective type of optic flow speed manipulation as well as which other principles need to be implemented to positively influence the gait pattern of people post-stroke. TRIAL REGISTRATION NUMBER: The study was pre-registered at ClinicalTrials.gov (NCT04521829).

Mouse intestinal villi as a model system for studies of norovirus infection.

Noroviruses (NoV) are enteric caliciviruses that have been detected in multiple species of mammals, including humans. Establishing an efficient in vitro cell culture system for human norovirus (HuNoV) remains a challenge; however, its replication has been reported in 3D cultured Caco-2 cells and a clone of Caco-2 cells (C2BBe1), human enteroids and human B cells. Isolated mouse intestinal villi, with large diversity of intestinal epithelial cells, are a primary cellular model that has been shown to be permissive for the infection and replication of enteric viruses such as rotaviruses. We hypothesized that they could allow the infection and replication of the human noroviruses. In this report, we indicate that the isolated villi model of the mouse intestine is effective for the infection study and replication of the human noroviruses from faeces and environmental matrices (water, vegetables and air). For successful infection, the virus needs to be activated with trypsin. The virus has an average replicative cycle of 10 h, although viral particles with infectious capacity are found already at 2 hours post infection (2 h.p.i.). The model is efficient in obtaining abundant biological material and is ideal for studying the biological activity of the human noroviruses in the same cell model or for generating antibodies. Keywords: human norovirus; intestinal epithelial cells; intestinal villus isolation; norovirus isolated from water; norovirus isolated from plants; norovirus isolated from air.

Synthesis, in vitro, in silico and in vivo hypoglycemic and lipid-lowering effects of 4-benzyloxy-5-benzylidene-1,3-thiazolidine-2,4-diones mediated by dual PPAR α/γ modulation.

In current work, we prepared a series of nine 4-benzyloxy-5-benzylidene-1,3-thiazolidine-2,4-diones using a two-step pathway. Compounds 1-9 were tested in vitro using a set of three proteins recognized as important targets in diabetes and related diseases: PPARα, PPARγ, and GLUT-4. Compounds 1-3, 5, and 7 showed significant increases in the mRNA expression of PPARγ and GLUT-4, whereas compounds 1-3 did it over PPARα. Compounds 1-3 were identified as a dual PPAR α/γ modulators and were selected for evaluating the in vivo antidiabetic action at 100 mg/kg dose, being orally actives and decreasing blood glucose concentration in a hyperglycemic mice model, as well as reducing the triacylglycerides levels in normolipidemic rats. Docking and molecular dynamics studies were conducted to clarify the dual effect and binding mode of compounds 1-3 on both PPARs. Compounds 2 and 3 exhibited robust in vitro and in vivo efficacy and could be considered dual PPAR modulators with antidiabetic and antidyslipidemic effects.

Interaction between proteins of the PPARγ and NFκB immune response pathways and rotavirus non-structural proteins.

Cells infected with MA104 rotavirus and/or transfected with plasmids expressing NSP proteins, were analyzed for expression of cellular proteins related to NFκB and PPARγ pathways and evaluated through the ELISA, luminescence, flow cytometry and Western blot techniques. The association between cellular and viral (NSPs) proteins was examined by ELISA, epifluorescence and confocal microscopy techniques. It was observed that NSP1 protein interacts with RXR, NSP1, and NSP3 with PPARγ, NSP2 with p-IKKα/ß and NSP5 with NFκB proteins. We have found that phosphorylated PPARγ is localized in cytoplasm and transcriptional activity of PPRE is diminished. These results lead to the conclusion, that RRV activates the proinflammatory pathway, increasing the expression of NFκB and possibly by PPARγ phosphorylation, its translocation to the nucleus is impeded, thus inactivating the proinflammatory pathway. Keywords: rotavirus; PPARγ; NFκB; NSPs; RRV.

An extended approach for the generalized powered uniform distribution.

A new uniform distribution model, generalized powered uniform distribution (GPUD), which is based on incorporating the parameter k into the probability density function (pdf) associated with the power of random variable values and includes a powered mean operator, is introduced in this paper. From this new model, the shape properties of the pdf as well as the higher-order moments, the moment generating function, the model that simulates the GPUD and other important statistics can be derived. This approach allows the generalization of the distribution presented by Jayakumar and Sankaran (2016) through the new GPUD ( J - S ) distribution. Two sets of real data related to COVID-19 and bladder cancer were tested to demonstrate the proposed model's potential. The maximum likelihood method was used to calculate the parameter estimators by applying the maxLik package in R. The results showed that this new model is more flexible and useful than other comparable models.

Ranking of problems and solutions in the teaching and learning of object-oriented programming.

This study describes the most relevant problems and solutions found in the literature on teaching and learning of object-oriented programming (OOP). The identification of the problem was based on tertiary studies from the IEEE Xplore, Scopus, ACM Digital Library and Science Direct repositories. The problems and solutions identified were ranked through the multi-criteria decision methods DEMATEL and TOPSIS in order to determine the best solutions to the problems found and to apply these results in the academic context. The main contribution of this study was the categorization of OOP problems and solutions, as well as the proposal of strategies to improve the problem. Among the most relevant problems it was found: 1) difficulty in understanding, teaching and implementing object-orientation, 2) difficulties related to understanding classes and 3) difficulty in understanding object-oriented relationships. After doing the multicriteria analysis, it was found that the most important solutions to face the problems found in the teaching of OOP were: 1) use of active learning techniques and intrinsic rewards and 2) emphasize on basic programming concepts and introduce the object-oriented paradigm at an early point in the curriculum. As a conclusion, it was evidenced that there is coherence between the literary guarantee that gives support to the problems and solutions in the teaching of OOP presented in this study and the approaches that experts in the area of development highlight as relevant when they identify weaknesses in the process.

Radical Perfluoroalkylation of Arenes via Carbanion Intermediates.

The use of sodium dithionite with perfluoroalkyl iodides under basic conditions facilitates the direct perfluoroalkylation of arenes with pendant benzylic electron-withdrawing groups. This occurs via attack of the arene on the electrophilic perfluoroalkyl radical, through the donation of electron density from a benzylic anion. The substrate scope was expanded beyond benzylic nitriles with cyclic substrates bearing electron-withdrawing groups at the benzylic position-enforcing donation of electron density to the aromatic ring and enabling attack on the perfluoroalkyl radical.

A live porcine model for surgical training in tracheostomy, neck dissection, and total laryngectomy.

OBJECTIVES: Head and neck surgery is associated with a steep learning curve, creating a need for effective training methods. Live animal models can be useful in acquiring the required skills and techniques to perform tracheostomy, neck dissection, and laryngectomy. The aim of this study is to assess the feasibility and usefulness of a porcine model to teach tracheostomy, neck dissection, and laryngectomy, describing the similarities between a swine head and neck surgical model and the human cervical area. METHODS: Twelve surgical training sessions were held with the use of a live porcine model maintained under general anaesthesia; a total of 39 procedures were performed. In each session, one otolaryngology resident per year performed a procedure to acquire the targeted competencies for their respective year of training. Each procedure was time recorded and evaluated based on a modified Objective Structured Assessment of Technical Skills. Linear regression was used to analyse the data and express the results as percentages. RESULTS: Training exercises were performed in shorter times over the study period. A 9% reduction in the time spent was observed. There was a global improvement in the evaluation made by OSATS score of 6% in the first period (2018-2019) and 58% in the second period (2019-2020). CONCLUSION: The porcine model was both manageable and helpful in providing training despite slight anatomical differences between human beings and pigs. However, more studies are necessary to guarantee that the competencies acquired with this type of training are transferable to real-life interventions. LEVEL OF EVIDENCE: Level 5.

Isolation and phenotypic characterization of tumor cells of patients with a diagnosis of ovarian cancer.

Ovarian cancer is the fifth leading cause of cancer-related deaths. It causes approximately 125,000 deaths per year worldwide; its diagnosis is made in advanced stages resulting in a high mortality rate. The objective of the study was optimizing the isolation of cells obtained from the solid tumor and ascitic fluid of patients with ovarian cancer and the phenotype with markers related to the epithelial-mesenchymal transition. For this, the solid tumor tissue was disaggregated and cultivated with different methodologies. As a result, cell growth was obtained and epi-immunofluorescence was performed using antibodies against E-cadherin, EpCAM, N-cadherin, vimentin, CD133, and CD44. The primary culture from the solid tumor was obtained using Dispase II and DMEM/F12. Finally, heterogeneity was detected in terms of the expression of mesenchymal and epithelial type markers in the two types of isolated cells. Additionally, CD133 and CD44 expression was detected, proteins associated with the tumor stem cells phenotype.

Walking with a powered ankle-foot orthosis: the effects of actuation timing and stiffness level on healthy users.

BACKGROUND: In the last decades, several powered ankle-foot orthoses have been developed to assist the ankle joint of their users during walking. Recent studies have shown that the effects of the assistance provided by powered ankle-foot orthoses depend on the assistive profile. In compliant actuators, the stiffness level influences the actuator's performance. However, the effects of this parameter on the users has not been yet evaluated. The goal of this study is to assess the effects of the assistance provided by a variable stiffness ankle actuator on healthy young users. More specifically, the effect of different onset times of the push-off torque and different actuator's stiffness levels has been investigated. METHODS: Eight healthy subjects walked with a unilateral powered ankle-foot orthosis in several assisted walking trials. The powered orthosis was actuated in the sagittal plane by a variable stiffness actuator. During the assisted walking trials, three different onset times of the push-off assistance and three different actuator's stiffness levels were used. The metabolic cost of walking, lower limb muscles activation, joint kinematics, and gait parameters measured during different assisted walking trials were compared to the ones measured during normal walking and walking with the powered orthosis not providing assistance. RESULTS: This study found trends for more compliant settings of the ankle actuator resulting in bigger reductions of the metabolic cost of walking and soleus muscle activation in the stance phase during assisted walking as compared to the unassisted walking trial. In addition to this, the study found that, among the tested onset times, the earlier ones showed a trend for bigger reductions of the activation of the soleus muscle during stance, while the later ones led to a bigger reduction in the metabolic cost of walking in the assisted walking trials as compared to the unassisted condition. CONCLUSIONS: This study presents a first attempt to show that, together with the assistive torque profile, also the stiffness level of a compliant ankle actuator can influence the assistive performance of a powered ankle-foot orthosis.

Most Relevant Neuropathic Pain Treatment and Chronic Low Back Pain Management Guidelines: A Change Pain Latin America Advisory Panel Consensus.

Objective: Chronic pain conditions profoundly affect the daily living of a significant number of people and are a major economic and social burden, particularly in developing countries. The Change Pain Latin America (CPLA) advisory panel aimed to identify the most appropriate guidelines for the treatment of neuropathic pain (NP) and chronic low back pain (CLBP) for use across Latin America. Methods: Published systematic reviews or practice guidelines were identified by a systematic search of PubMed, the Guidelines Clearinghouse, and Google. Articles were screened by an independent reviewer, and potential candidate guidelines were selected for more in-depth review. A shortlist of suitable guidelines was selected and critically evaluated by the CPLA advisory panel. Results: Searches identified 674 and 604 guideline articles for NP and CLBP, respectively. Of these, 14 guidelines were shortlisted for consensus consideration, with the following final selections made: "Recommendations for the pharmacological management of neuropathic pain from the Neuropathic Pain Special Interest Group in 2015-pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis.""Diagnosis and treatment of low back pain: A joint clinical practice guideline from the American College of Physicians and the American Pain Society" (2007). Conclusions: The selected guidelines were endorsed by all members of the CPLA advisory board as the best fit for use across Latin America. In addition, regional considerations were discussed and recorded. We have included this expert local insight and advice to enhance the implementation of each guideline across all Latin American countries.

Powered ankle-foot orthoses: the effects of the assistance on healthy and impaired users while walking.

In the last two decades, numerous powered ankle-foot orthoses have been developed. Despite similar designs and control strategies being shared by some of these devices, their performance in terms of achieving a comparable goal varies. It has been shown that the effect of powered ankle-foot orthoses on healthy users is altered by some factors of the testing protocol. This paper provides an overview of the effect of powered walking on healthy and weakened users. It identifies a set of key factors influencing the performance of powered ankle-foot orthoses, and it presents the effects of these factors on healthy subjects, highlighting the similarities and differences of the results obtained in different works. Furthermore, the outcomes of studies performed on elderly and impaired subjects walking with powered ankle-foot orthoses are compared, to outline the effects of powered walking on these users. This article shows that several factors mutually influence the performance of powered ankle-foot orthoses on their users and, for this reason, the determination of their effects on the user is not straightforward. One of the key factors is the adaptation of users to provided assistance. This factor is very important for the assessment of the effects of powered ankle-foot orthoses on users, however, it is not always reported by studies. Moreover, future works should report, together with the results, the list of influencing factors used in the protocol, to facilitate the comparison of the obtained results. This article also underlines the need for a standardized method to benchmark the actuators of powered ankle-foot orthoses, which would ease the comparison of results between the performed studies. In this paper, the lack of studies on elderly and impaired subjects is highlighted. The insufficiency of these studies makes it difficult to assess the effects of powered ankle-foot orthoses on these users.To summarize, this article provides a detailed overview of the work performed on powered ankle-foot orthoses, presenting and analyzing the results obtained, but also emphasizing topics on which more research is still required.

Peri-articular injection of an analgesic mixture in primary total hip arthroplasty: an effective strategy for pain control during the first post-operative day.

BACKGROUND: Previous studies of soft tissue infiltration in hip arthroplasty present variable results. The purpose of this study is to identify whether injection of an analgesic mixture improves pain management during the immediate post-operative period. MATERIALS AND METHODS: This cohort study compared 129 patients that received peri-articular soft tissue injection with 20 ml of 0.25% bupivacaine and 2 ml of ketorolac (30 mg/1 ml) in 28 ml of saline solution, with 71 patients who did not received injections. Pain intensity in the Verbal Analog Scale (VAS), opioid titration, and consumption (mg morphine equivalents) in the post-anaesthetic care unit (PACU) and during the first post-operative day were assessed for both groups. All patients received the same analgesia protocol. RESULTS: Median VAS score in the PACU was 4 (IQR 2-7) in the injection group and 7 (IQR 4-8) in the non-injection group (p = 0.001). Median opioid titration was 0 mg for the injection group and 2.6 mg for the non-injection group (p = 0.011). In the first post-operative day, the difference in VAS scores between groups was statistically significant (p = 0.009), but there was no difference in opioid consumption. CONCLUSION: Soft tissue injection with local anesthetics and non-steroidal anti-inflammatory drugs allows adequate pain control in the immediate post-operative period and reduces the requirement for opioid consumption. We recommend the implementation of this safe and effective strategy in post-operative pain management after primary hip arthroplasty. LEVEL OF EVIDENCE: Level II, cohort study.

Enantioselective Chemical Syntheses of the Furanosteroids (-)-Viridin and (-)-Viridiol.

Herein we describe concise enantioselective chemical syntheses of (-)-viridin and (-)-viridiol. Our convergent approach couples two achiral fragments of similar complexity and employs an enantioselective intramolecular Heck reaction to set the absolute stereochemical configuration of an all-carbon quaternary stereocenter. To complete the syntheses of these base- and nucleophile-sensitive natural products, we conduct carefully orchestrated site- and diastereoselective oxidations and other transformations. Our work is the first to generate these targets as single enantiomers.

A Mild, Functional Group Tolerant Addition of Organozinc Nucleophiles to N-Activated Quinolines and Isoquinolines.

An addition of organozinc nucleophiles to N-acyl activated quinolines and isoquinolines is described. Simple transmetalation with the corresponding Grignard reagents using ZnCl2 forms organozinc compounds which are functional group tolerant and stable to reactive acyl chloride reagents for extended periods. A wide variety of substrates which include reactive electron-withdrawing groups are well tolerated to form 2-substituted dihydroquinolines and dihydroisoquinolines. This methodology has been applied toward an improved synthetic route of uncialamycin and its analogs.