Curved layer path planning on a 5-axis 3D printer

Article publication date: 7 October 2021Purpose – This paper aims to provide an approach to print shell-type objects using a 5-axis printer. The proposed approach takes advantage of the two additional printer degrees of freedom to provide a curved layer path planning strategy. Design/methodology/approach – This paper addresses curved layer path planning on a 5-axis printer. This printer considers movements along the three usual axes together with two additional axes at the printing table (rotation and tilt), allowing to build more complex and reliable objects. Curved layer path planning is considered where polygons obtained from the slicing stage are approximated by linear and cubic splines. The proposed printing strategy consists in building an inner core supporting structure followed by outer curved layers. Findings – The curved layer path planning strategy is validated for shell-type objects by considering a 5-axis printer simulator. An example with an aeronautic object is presented to illustrate the proposed approach. Originality/value – The paper presents an approach to curved layer path planning on a 5-axis printer, for shell-type objects.This work was developed under the FIBR3D project Hybrid processes based on additive manufacturing of composites with long or short fibers reinforced thermoplastic matrix (POCI-01-0145-FEDER-016414), supported by the Lisbon Regional Operational Programme 2020, under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)

Disordered hyperuniformity in superconducting vortex lattices

Particles occupying sites of a random lattice present density fluctuations at all length scales. It has been proposed that increasing interparticle interactions reduces long range density fluctuations, deviating from random behaviour. This leads to power laws in the structure factor and the number variance that can be used to characterize deviations from randomness which eventually lead to disordered hyperuniformity. It is not yet fully clear how to link density fluctuations with interactions in a disordered hyperuniform system. Interactions between superconducting vortices are very sensitive to vortex pinning, to the crystal structure of the superconductor and to the value of the magnetic field. This creates lattices with different degrees of disorder. Here we study disordered vortex lattices in several superconducting compounds (Co-doped NbSe$_2$, LiFeAs and CaKFe$_4$As$_4$) and in two amorphous W-based thin films, one with strong nanostructured pinning (W-film-1) and another one with weak or nearly absent pinning (W-film-2). We calculate for each case the structure factor and number variance and compare to calculations on an interacting set of partially pinned particles. We find that random density fluctuations appear when pinning overcomes interactions and show that the suppression of density fluctuations is indeed correlated to the presence of interactions. Furthermore, we find that we can describe all studied vortex lattices within a single framework consisting of a continous deviation from hyperuniformity towards random distributions when increasing the strength of pinning with respect to the intervortex interaction

Urban football narratives and the colonial process in Lourenço Marques

Support for Portuguese football teams, in Mozambique as well as in other former Portuguese colonies, could be interpreted either as a sign of the importance of a cultural colonial heritage in Africa or as a symbol of a perverse and neo-colonial acculturation. This article, focused on Maputo, the capital of Mozambique – formerly called Lourenc¸o Marques – argues that in order to understand contemporary social bonds, it is crucial to research the connection between the colonial process of urbanisation and the rise of urban popular cultures. Despite the existence of social discrimination in colonial Lourenc¸o Marques, deeply present in the spatial organisation of a city divided between a ‘concrete’ centre and the immense periphery, the consumption of football, as part of an emergent popular culture, crossed segregation lines. I argue that football narratives, locally appropriated, became the basis of daily social rituals and encounters, an element of urban sociability and the content of increasingly larger social networks. Therefore, the fact that a Portuguese narrative emerged as the dominant form of popular culture is deeply connected to the growth of an urban community

Critical Review of Gaps in the Diagnosis and Management of Drug-Induced Liver Injury Associated with Severe Cutaneous Adverse Reactions

Drug-induced liver injury (DILI) encompasses the unexpected damage that drugs can cause to the liver. DILI may develop in the context of an immunoallergic syndrome with cutaneous manifes- tations, which are sometimes severe (SCARs). Nevirapine, allopurinol, anti-epileptics, sulfonamides, and antibiotics are the most frequent culprit drugs for DILI associated with SCARs. Interestingly, alleles HLA-B*58:01 and HLA-A*31:01 are associated with both adverse reactions. However, there is no consensus about the criteria used for the characterization of liver injury in this context, and the different thresholds for DILI definition make it difficult to gain insight into this complex disorder. Moreover, current limitations when evaluating causality in patients with DILI associated with SCARs are related to the plethora of causality assessment methods and the lack of consensual complementary tools. Finally, the management of this condition encompasses the treatment of liver and skin injury. Although the use of immunomodulant agents is accepted for SCARs, their role in treating liver injury remains controversial. Further randomized clinical trials are needed to test their efficacy and safety to address this complex entity. Therefore, this review aims to identify the current gaps in the definition, diagnosis, prognosis, and management of DILI associated with SCARs, proposing different strategies to fill in these gaps.Instituto de Salud Carlos III: PI18/01804 Instituto de Salud Carlos III: PI19-00883; Instituto de Salud Carlos III: PT 20/00127; Instituto de Salud Carlos III: UMA18-FEDERJA-194; Instituto de Salud Carlos III: PY18-3364; Consejería de Salud de Andalucía: PI-0310-2018, PEMP-0127-2020; Instituto de Salud Carlos III: Rio Hortega CM17/00243; Instituto de Salud Carlos III: Sara Borrell CD20/00083; Instituto de Salud Carlos III: Sara Borrell CD21/00198

Prevention and management of idiosyncratic drug-induced liver injury: Systematic review and meta-analysis of randomised clinical trials

Conducting randomised clinical trials (RCTs) in idiosyncratic drug-induced liver injury (DILI) is challenging. This systematic review aims to summarise the design and findings of RCTs in the prevention and management of idiosyncratic DILI. A systematic literature search up to January 31st, 2020 was performed. Recognised scales were used to assess methodological bias and quality of the studies. Quantitative and qualitative analyses were performed. Heterogeneity was assessed with I2 statistic. Overall, 22 RCTs were included: 12 on prevention (n = 2,471 patients) and 10 in management (n = 797) of DILI/non-acetaminophen DILI-related acute liver failure (ALF). Silymarin (eight studies), bicyclol (four), magnesium isoglycyrrhizinate (three), N-acetylcysteine (three), tiopronin (one), L-carnitine (one), and traditional Chinese medicines (two) were tested in the intervention arm, while control arm mostly received standard supportive care or placebo. Main efficacy criteria in the prevention RCTs was DILI incidence or peak of liver enzymes value. In management RCTs, the efficacy parameter was usually 50 % decrease or normalisation of liver enzymes, or survival rate in DILI-related ALF patients. Overall, 15 trials described the randomisation method, eight were double-blind (n = 672) and nine had sample size esti- mation (n = 880). Four RCTs involving 377 patients used an intention-to-treat analysis. Based on the scarce number of trials available, tested agents showed limited efficacy in DILI prevention and management and a favourable safety profile. In conclusion, heterogeneity among studies in DILI case qualification and methodologic quality was evident, and the RCTs performed demonstrated limited efficacy of specific interventions. Interna- tional research networks are needed to establish a framework on RCTs design and therapeutic endpoints.This work was supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional - FEDER (contract numbers: PI18/00901; PI18/01804; PT17/0017/0020; PT 20/00127) and Agencia Espan ̃ola del Medicamento. Plataforma de Investigacio ́n Clínica and CIBERehd are funded by ISCIII. MRD holds a Joan Rodes (JR16/00015)/Accio ́n B clinicos investigadores (B-0002-2019), JSC a Rio Hortega (CM17/00243) and IAA a Sara Borrell (CD20/00083) research contract from ISCIII and Consejería de Salud de Andalucía. This publication is based upon work from COST Action “CA17112 - Pro- spective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology). www.cost.e

ERK5 signalling pathway is a novel target of sorafenib: Implication in EGF biology

© 2021 The Authors.Sorafenib is a multikinase inhibitor widely used in cancer therapy with an antitumour effect related to biological processes as proliferation, migration or invasion, among others. Initially designed as a Raf inhibitor, Sorafenib was later shown to also block key molecules in tumour progression such as VEGFR and PDGFR. In addition, sorafenib has been connected with key signalling pathways in cancer such as EGFR/EGF. However, no definitive clue about the molecular mechanism linking sorafenib and EGF signalling pathway has been established so far. Our data in HeLa, U2OS, A549 and HEK293T cells, based on in silico, chemical and genetic approaches demonstrate that the MEK5/ERK5 signalling pathway is a novel target of sorafenib. In addition, our data show how sorafenib is able to block MEK5-dependent phosphorylation of ERK5 in the Ser218/Tyr220, affecting the transcriptional activation associated with ERK5. Moreover, we demonstrate that some of the effects of this kinase inhibitor onto EGF biological responses, such as progression through cell cycle or migration, are mediated through the effect exerted onto ERK5 signalling pathway. Therefore, our observations describe a novel target of sorafenib, the ERK5 signalling pathway, and establish new mechanistic insights for the antitumour effect of this multikinase inhibitor.This work was supported by grants from Fundación Leticia Castillejo Castillo, Ministerio de Ciencia, Innovación y Universidades (MCIU), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) (RTI2018-094093-B-I00) to RSP and MJRH. OR holds a contract for accessing the Spanish System of Science, Technology, and Innovation (SECTI) funded by the University of Castilla-La Mancha (UCLM) and received partial support from the European Social Fund (FSE) through its Operative Program for Castilla-La Mancha (2007–2013). RSP and MJRH's Research Institute, and the work carried out in their laboratory, received partial support from the European Community through the FEDER. RPS and EAL hold a research predoctoral contract cofounded by the European Social Fund and UCLM. The Spanish Ministry of Economy and Competitiveness (MINECO, Project RTI2018-096724-B-C21) and the Generalitat Valenciana (PROMETEO/2016/006) support work in the Encinar´s laboratory. Authors are grateful to Dr.G- Ferrer Mayorga for her assistance in the transwell assays, and to the ‘Centro de Computación Científica’ (CCC-UAM) for letting us to take advantage of the computer cluster Cibeles (https://www.ccc.uam.es/) and for providing computing facilities

N-Acetylcysteine for the Management of Non-Acetaminophen Drug-Induced Liver Injury in Adults : A Systematic Review

Funding Information: The present study has been supported by grants of the Instituto de Salud Carlos III co-founded by Fondo Europeo de Desarrollo Regional–FEDER (contract numbers: PI19/00883, P18‐RT‐3364‐2020), from the Consejería de Economía, Conocimiento, Empresas y Universidad (Junta de Andalucía, Spain) (UMA18‐FEDERJA‐194, PI18‐RT‐3364) and by the Agencia Española del Medicamento. JS-C holds a “Juan Rodés” research contract from the National System of Health, ISCIII (JR21/00066). IA-A holds a Sara Borrell contract (CD20/00083). HN holds a postdoctoral contract from the Junta de Andalucia (POSTDOC_21_00780). CIBERehd and Plataforma ISCIII Ensayos Clínicos (PT20/000127) are funded by ISCIII. This article is based upon work from COST Action “CA17112 - Prospective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology) ( www.cost.eu ). All authors of this manuscript are members of COST Action CA17112. The funding sources had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the report or in the decision to submit the manuscript for publication. Funding Information: The present study has been supported by grants of the Instituto de Salud Carlos III co-founded by Fondo Europeo de Desarrollo Regional–FEDER (contract numbers: PI19/00883, P18‐RT‐3364‐2020), from the Consejería de Economía, Conocimiento, Empresas y Universidad (Junta de Andalucía, Spain) (UMA18‐FEDERJA‐194, PI18‐RT‐3364) and by the Agencia Española del Medicamento. JS-C holds a “Juan Rodés” research contract from the National System of Health, ISCIII (JR21/00066). IA-A holds a Sara Borrell contract (CD20/00083). HN holds a postdoctoral contract from the Junta de Andalucia (POSTDOC_21_00780). CIBERehd and Plataforma ISCIII Ensayos Clínicos (PT20/000127) are funded by ISCIII. This article is based upon work from COST Action “CA17112 - Prospective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology) (www.cost.eu). All authors of this manuscript are members of COST Action CA17112. The funding sources had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the report or in the decision to submit the manuscript for publication. Publisher Copyright: Copyright © 2022 Sanabria-Cabrera, Tabbai, Niu, Alvarez-Alvarez, Licata, Björnsson, Andrade and Lucena.Introduction: Idiosyncratic drug-induced liver injury (DILI) is a rare adverse reaction to drugs and other xenobiotics. DILI has different grades of severity and may lead to acute liver failure (ALF), for which there is no effective therapy. N-acetylcysteine (NAC) has been occasionally tested for the treatment of non-acetaminophen drug-induced ALF. However, limited evidence for its efficacy and safety is currently available. Our aim was to elucidate the benefit and safety of NAC in DILI and evaluate its hepatoprotective effect. Methods: We conducted a systematic review to evaluate the management and prevention focused on NAC in idiosyncratic DILI. The main outcomes included mortality due to DILI, time to normalization of liver biochemistry, transplant-free survival, and adverse events. We included clinical trials and observational studies, either prospective or retrospective. Results: A total of 11 studies were included after literature screening. All studies had different methodologies, and some of them had important risk of bias that may lead to interpreting their findings with caution. The majority of the studies proved NAC efficacy in a cohort of patients with ALF due to different etiologies, where DILI represented a subgroup. NAC seemed to improve transplant-free survival; however, its benefit was inconclusive in terms of overall survival. With regard to safety, NAC showed an adequate safety profile. In prevention studies, NAC showed a possible hepatoprotective effect; however, this finding is limited by the lack of studies and presence of bias. Conclusion: NAC treatment seems to have some benefit in non-acetaminophen drug-induced liver failure patients with acceptable safety; however, due to the lack of evidence and limitations detected across studies, its benefit must be corroborated in clinical trials with adequate methodology.Peer reviewe

Elevated bilirubin, alkaline phosphatase at onset, and drug metabolism are associated with prolonged recovery from DILI

Background & AimsAlthough most drug-induced liver injury (DILI) cases resolve after the culprit medication is discontinued, time to recovery varies among patients, with 6-12% developing a chronic disease. Here, we investigated clinical factors and drug properties as potential risk determinants that influence the time course for DILI recovery and developed a model to predict its trajectory.MethodsWe applied an accelerated failure time model to 294 cases collected by the International Drug-Induced Liver Network Consortium (iDILIC). Factors included in the multivariate recovery score model were selected through univariate analysis. The model was externally validated by 257 cases from the Spanish DILI registry and 191 cases from the LiverTox database.ResultsHigher serum bilirubin and alkaline phosphatase (ALP) at DILI onset, a longer time to onset, and non-significant drug metabolism were associated with a longer recovery and were included in the recovery score model. We defined high- and low-risk groups based on the scores assigned by the model. The estimated probability of recovery by six months was 0.46 (95% confidence interval [CI]:0.26-0.61) for the high-risk group and 0.93 (95% CI:0.58-0.99) for the low-risk group in the iDILIC. Model performance was validated in both validation sets. The high- and low-risk cases identified by the model showed a significantly different time course for recovery, with a majority of low-risk cases recovering sooner.ConclusionThe trajectory of biochemical recovery from DILI is predicted by the extent of culprit drug metabolism, serum bilirubin and ALP at DILI onset. The model can be used to compute an estimated DILI recovery and, when significant delay is predicted, clinicians may consider additional investigations such as histologic evaluation or extended follow up.Lay summaryIn this study, we investigated whether drug properties and clinical factors are associated with the time it takes to recover from drug-induced liver injury (DILI). We found that total bilirubin, alkaline phosphatase level at DILI onset, time to onset, and extent of drug metabolism were consistently associated with recovery time. Using these factors, we built a model to predict the trajectory of recovery from DILI and validated this model in two independent cohorts. Our findings offer important insight into factors influencing the trajectory of recovery from DILI. Additional investigations and longer follow-ups can be planned in those with predicted delayed recovery

Comprehensive analysis and insights gained from long-term experience of the Spanish DILI Registry

Background & aims: Prospective drug-induced liver injury (DILI) registries are important sources of information on idiosyncratic DILI. We aimed to present a comprehensive analysis of 843 patients with DILI enrolled into the Spanish DILI Registry over a 20-year time period. Methods: Cases were identified, diagnosed and followed prospectively. Clinical features, drug information and outcome data were collected. Results: A total of 843 patients, with a mean age of 54 years (48% females), were enrolled up to 2018. Hepatocellular injury was associated with younger age (adjusted odds ratio [aOR] per year 0.983; 95% CI 0.974-0.991) and lower platelet count (aOR per unit 0.996; 95% CI 0.994-0.998). Anti-infectives were the most common causative drug class (40%). Liver-related mortality was more frequent in patients with hepatocellular damage aged ≥65 years (p = 0.0083) and in patients with underlying liver disease (p = 0.0221). Independent predictors of liver-related death/transplantation included nR-based hepatocellular injury, female sex, higher onset aspartate aminotransferase (AST) and bilirubin values. nR-based hepatocellular injury was not associated with 6-month overall mortality, for which comorbidity burden played a more important role. The prognostic capacity of Hy's law varied between causative agents. Empirical therapy (corticosteroids, ursodeoxycholic acid and MARS) was prescribed to 20% of patients. Drug-induced autoimmune hepatitis patients (26 cases) were mainly females (62%) with hepatocellular damage (92%), who more frequently received immunosuppressive therapy (58%).The present study has been supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional – FEDER (contract numbers: PI19/00883, PI16/01748, PI18/00901, PI18/01804, PI-0285-2016, PI-0274-2016, PI-0310- 2018, PT17/0017/0020) and Agencia Española del Medicamento. CIBERehd and Plataforma ISCIII Ensayos Clinicos are funded by Instituto de Salud Carlos III. MRD holds a Joan Rodes (JR16/ 00015)/Acción B clinicos investigadores (B-0002-2019) and JSC a Rio Hortega (CM17/00243) research contract from ISCIII and Consejería de Salud de Andalucía. The funding sources had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the report or in the de- cision to submit the manuscript for publication

Clinical and outcome comparison of genetically positive vs. negative patients in a large cohort of suspected familial hypocalciuric hypercalcemia

Biochemical suspicion of familial hypocalciuric hypercalcemia (FHH) might provide with a negative (FHH-negative) or positive (FHH-positive) genetic result. Understanding the differences between both groups may refine the identification of those with a positive genetic evaluation, aid management decisions and prospective surveillance. We aimed to compare FHH-positive and FHH-negative patients, and to identify predictive variables for FHH-positive cases. Retrospective, national multi-centre study of patients with suspected FHH and genetic testing of the CASR, AP2S1 and GNA11 genes. Clinical, biochemical, radiological and treatment data were collected. We established a prediction model for the identification of FHH-positive cases by logistic regression analysis and area under the ROC curve (AUROC) was estimated. We included 66 index cases, of which 30 (45.5%) had a pathogenic variant. FHH-positive cases were younger (p = 0.029), reported more frequently a positive family history (p < 0.001), presented higher magnesium (p < 0.001) and lower parathormone levels (p < 0.001) and were less often treated for hypercalcemia (p = 0.017) in comparison to FHH-negative cases. Magnesium levels showed the highest AUROC (0.825, 95%CI: 0.709-0.941). The multivariate analysis revealed that family history and magnesium levels were independent predictors of a positive genetic result. The predictive model showed an AUROC of 0.909 (95%CI: 0.826-0.991). The combination of magnesium and a positive family history offered a good diagnostic accuracy to predict a positive genetic result. Therefore, the inclusion of magnesium measurement in the routine evaluation of patients with suspected FHH might provide insight into the identification of a positive genetic result of any of the CaSR-related genes