Search

While onsite measurement of air permeability provides a useful approach to assess the service life of concrete structures, the combined use of onsite and laboratory measurement of air permeability is useful to anticipate whether the target service life is to be achieved. This investigation was developed within the aim of founding the application of an air permeability test (Torrent method), based on the experimental observation of specimen geometry and surface influence on air permeability results. An experimental program was developed considering three specimen geometries, two types of surface, and twelve concrete mixes. The results were analysed and no significant influence of the tested specimens geometry and surfaces was detected. Therefore, the use of any of the surfaces or specimens geometry in mix approval or in compliance control processes is possible without correction of the results. This work constitutes a contribution to further understanding of the test method in particular and of concrete air permeability assessment in general. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) has not been well studied in racial and ethnic minorities, as these populations are typically underrepresented in clinical trials. Black or African Americans comprise ∼13 % of the US population, yet are represented by as little as 5 % in clinical trials. Differences in disease course and progression have been reported between races and ethnicities, so there is a need to understand the safety and efficacy of disease-modifying therapies (DMTs) in Black patients, to inform evidence-based approaches to treatment in this population., Methods: EVOLVE-MS-1 (NCT0234307) was an open-label, single-arm, phase 3 study assessing the long-term safety, tolerability, and efficacy of diroximel fumarate (DRF) over 96 weeks in adults with relapsing-remitting multiple sclerosis (RRMS). Patients were either newly initiated to DRF or rolled over from completing EVOLVE-MS-2 (NCT03093324). In this post-hoc analysis of the phase 3 EVOLVE-MS-1 study, we evaluate the safety and exploratory efficacy outcomes for DRF in Black and non-Black patient subgroups., Results: Of 1057 patients enrolled, 72 (6.8 %) were Black. In Black vs non-Black patients, mean age was 42 vs 43 years and 75 % vs 72 % were female, respectively. In both groups, median (range) duration of DRF exposure was 1.8 (0.0-2.0) years and mean Expanded Disability Status Scale (EDSS) was 2.7. The most common prior DMTs for both Black vs non-Black patients were interferons (47 % vs 37 %) and glatiramer acetate (36 % vs 24 %). DRF treatment was discontinued in 33 (46 %) Black and 224 (23 %) non-Black patients; most common reasons for discontinuation were withdrawal by patient (n = 11, 15.3 %), adverse events (AEs; n = 7, 9.7 %), and lost to follow-up (n = 7, 9.7 %) in Black patients; AEs (8.2 %) and withdrawal by patient (7.0 %) in non-Black patients. AEs were reported in 90 % Black and 89 % non-Black patients; most AEs were mild or moderate in both groups. Gastrointestinal (GI) AEs were reported in 36 % Black and 32 % non-Black patients; no Black patients discontinued due to GI AEs, vs 7 (0.7 %) non-Black patients. The most commonly reported AE was flushing (18 % Black and 28 % non-Black patients). No AEs of lymphopenia were reported in Black patients compared with 13 % of non-Black patients. Mean absolute lymphocyte count declined from baseline to week 48 by 15 % in Black patients and 29 % in non-Black patients, then plateaued and remained above the lower limit of normal (LLN; 0.91 × 10 9 /L). Adjusted annualized relapse rate (95 % confidence interval) was reduced by 78.2 % (54.6 - 89.5; p < 0.0001) in Black patients, from 12 months before to 96 weeks after DRF treatment; similar to 81.7 % (78.5 - 84.5 %; p < 0.0001) reduction in non-Black patients. Mean number of patients free from confirmed disability progression was 93.4 % by week 48, then 86.2 % vs 90.4 % by week 96 in Black vs non-Black patients, respectively., Conclusion: This study presents the first analysis of safety and efficacy of DRF in Black patients. Relapse rates remained low in Black patients on DRF, consistent with non-Black patients, and there were no new safety signals identified in the Black patient subgroup in EVOLVE-MS-1. Together, these outcomes support DRF as an effective treatment option in Black patients with RRMS., Competing Interests: Declaration of competing interest SFH has received consulting fees from Alexion, Biogen, BMS, Genentech, Horizon, Janssen, Sanofi, and Serono; contracted research at Anokion, Atara, Biogen, Genentech, Janssen, and Sanofi; and served on speaker bureaus for Biogen, BMS, EMD Serono, Horizon, and Janssen. JWL has received personal compensation for consulting from Biogen, Banner Life Sciences, Genentech, Horizon, and Mapi Pharmaceuticals; conducted clinical trials funded by Anokion, Atara, Biogen, EMD Serono, and Genentech; and received research funding from Genentech and the National MS Society. BO has contracted research at Biogen and served on speaker bureaus for Alexion, Biogen, BMS, Genentech, and Roche. SL, JBL, MS, and ZT are employees and stockholders of Biogen. FB was an employee and stockholder at Biogen at the time of analysis. BS and AA have nothing to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Glioblastoma (GBM) stands for the most common and aggressive type of brain tumour in adults. It is highly invasive, which explains its short rate of survival. Little is known about its risk factors, and current therapy is still ineffective. Hence, efforts are underway to develop novel and effective treatment approaches against this type of cancer. Exosomes are being explored as a promising strategy for conveying and delivering therapeutic cargo to GBM cells. They can fuse with the GBM cell membrane and, consequently, serve as delivery systems in this context. Due to their nanoscale size, exosomes can cross the blood-brain barrier (BBB), which constitutes a significant hurdle to most chemotherapeutic drugs used against GBM. They can subsequently inhibit oncogenes, activate tumour suppressor genes, induce immune responses, and control cell growth. However, despite representing a promising tool for the treatment of GBM, further research and clinical studies regarding exosome biology, engineering, and clinical applications still need to be completed. Here, we sought to review the application of exosomes in the treatment of GBM through an in-depth analysis of the scientific and clinical studies on the entire process, from the isolation and purification of exosomes to their design and transformation into anti-oncogenic drug delivery systems. Surface modification of exosomes to enhance BBB penetration and GBM-cell targeting is also a topic of discussion., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Glioblastoma (GB) is one of the most lethal types of neoplasms with unique anatomic, physiologic, and pathologic features that usually persist after exposure to standard therapeutic modalities. It is biologically aggressive, and the existence of the blood-brain barrier (BBB) limits the efficacy of standard therapies. In this work, we hypothesize the potential of surface-functionalized ultra-small nanostructured lipid carriers (usNLCs) with charge-switchable cell-penetrating peptides (CPPs) to overcome this biological barrier and improve targeted delivery to brain tumor tissues. The big question is: what is the potential of CPPs in directing nanoparticles toward brain tumor tissue? To answer this question, the usNLCs were functionalized with distinct biomolecules [five CPPs, c(RGDfK) and transferrin, Tf] through electrostatic interaction and its ability as a targeting approach to BBB (HBMEC) and glioma cells (U87 cells) evaluated in terms of physicochemical properties, cellular uptake, permeability in a 2D-BBB model, and tumor growth inhibition. Monte Carlo simulations elucidated CPP adsorption patterns. The permeability studies revealed that targeted usNLCs, especially usNLCs Tf and usNLCs CPP4 , exhibited an increased permeability coefficient compared to the non-targeted usNLCs. Functionalized usNLCs evidenced enhanced uptake in BBB cells, with smaller CPPs showing higher internalization (CPP1 and CPP2). Similarly, functionalized usNLCs exhibited more significant cytotoxicity in glioma cells, with specific CPPs promoting favorable internalization. Analysis of the endocytic pathway indicated that usNLCs CPPs were mainly internalized by direct translocation and caveolae-mediated endocytosis. Optimal usNLCs with dual targeting capabilities to both BBB and GB cells provide a promising therapeutic strategy for GB., Competing Interests: Declaration of conflict of interests The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Pregnancy is a common consideration for people with multiple sclerosis (pwMS); MS onset is typically between 20 and 45 years of age, during potential child-bearing years. Pregnancy and postpartum care are a significant factor influencing disease-modifying therapy (DMT) selection for many pwMS. To date, few DMTs are considered safe to continue during pregnancy and real-world treatment patterns before, during, and after pregnancy remain uncharacterized. Evolving guidance is needed regarding how to optimize management of the pregnancy and postpartum periods considering the changing DMT landscape. This analysis in two large claims databases describes DMT utilization for the treatment of MS before, during, and after pregnancy and relapse patterns during pregnancy and postpartum., Methods: In this retrospective, observational study, the US MarketScan Commercial and Medicaid claims database was assessed for female patients aged 18-55 years with ≥1 insurance claim submitted under the diagnosis code of MS from 01 January 2016-30 April 2021 and continuous enrollment eligibility from ≥6 months prior to pregnancy date (preconception) through 6 months of follow-up following delivery (postpartum period). Comorbid conditions were examined preconception and postpartum, including anxiety and depression. Moderate/severe relapse was defined as MS-related hospitalization, or an outpatient visit and one claim within 7 days of the visit with steroids or total plasma exchange., Results: A total of 944 patients (mean [standard deviation] age, 32.4 [5.0] years) were eligible; 688 (73%) were commercially insured and 256 (27%) received Medicaid. Compared with commercially-insured patients, use of DMTs was lower among Medicaid patients at 6 months preconception (25.4% vs 40.4%; p < 0.001), with similar patterns observed both during pregnancy and postpartum. Overall, prevalence of DMT use declined sharply during pregnancy, from 36.3% of patients in the 6 months preconception to 17.9%, 5.3%, and 5.8% in trimesters 1, 2 and 3, respectively. Postpartum DMT utilization increased to 20.9% at 0-3 months and 24.4% at 4-6 months. Of all patients in the preconception period, the most frequently used DMTs were glatiramer acetate (14.3%), dimethyl fumarate (6.0%), interferon (5.2%), and natalizumab (4.9%). Due to small sample size, information was limited for anti-CD20s and alemtuzumab. The proportion of patients with any moderate/severe relapse declined over pregnancy (preconception, n = 82 [8.7%]; pregnancy, n = 25 [2.6%]), but increased postpartum (n = 94 [10.0%]). Of the 889 patients who stopped DMT during pregnancy, the risk of postpartum relapses was lower in the patients who resumed DMT postpartum (10/192) than in patients who did not (76/697) (5.2% vs 10.9%; odds ratio, 0.455 [95% confidence interval 0.216-0.860], p = 0.018). Cases of postpartum depression and anxiety were significantly lower in commercially-insured patients vs Medicaid patients (postpartum depression, 13.7% vs 27.0%, p < 0.01; postpartum anxiety, 16.3% vs 30.5%, p < 0.01)., Conclusion: DMT utilization declined sharply during pregnancy; it gradually increased postpartum but remained below pre-pregnancy use. The proportion of pwMS experiencing a moderate/severe relapse and number of relapses declined over pregnancy but increased postpartum. Reinitiation of DMT during the postpartum period was associated with lower risk of relapses, supporting a role for early reinitiation of DMT postpartum., Study Supported by: Biogen., Competing Interests: Declaration of competing interest R Bove: research support from Biogen, DOD, NIH, NMSS, Novartis, NSF, and Roche-Genentech; consulting and scientific advisory board fees from Alexion, EMD Serono, Horizon, Jansen, and TG Therapeutics. A Applebee: speaker bureaus for Biogen, Genzyme, Genentech, and Serono; advisory boards for Bristol Myers Squibb, Genzyme, and Horizon. K Bawden: speaker bureau for Banner Life Sciences, Biogen, and TG Therapeutics in 2022. C Fine: nothing to disclose. A Shah: advisory boards for Roche-Genentech and TG Therapeutics; received funds for nonpromotional education talks from NCQA, Novartis, and Rocky Mountain MS Center. RL Avila: employee of and holds stock/stock options in Biogen. N Belviso: employee of and holds stock/stock options in Biogen. F Branco: employee of and holds stock/stock options in Biogen. K Fong: employee of and holds stock/stock options in Biogen. JB Lewin: employee of and holds stock/stock options in Biogen. J Liu: employee of and holds stock/stock options in Biogen. SM England: employee of and holds stock/stock options in Biogen. M Vignos: employee of and holds stock/stock options in Biogen., (Copyright © 2024. Published by Elsevier B.V.)

Glioblastoma (GBM) remains the epitome of aggressiveness and lethality in the spectrum of brain tumors, primarily due to the blood-brain barrier (BBB) that hinders effective treatment delivery, tumor heterogeneity, and the presence of treatment-resistant stem cells that contribute to tumor recurrence. Nanoparticles (NPs) have been used to overcome these obstacles by attaching targeting ligands to enhance therapeutic efficacy. Among these ligands, peptides stand out due to their ease of synthesis and high selectivity. This article aims to review single and multiligand strategies critically. In addition, it highlights other strategies that integrate the effects of external stimuli, biomimetic approaches, and chemical approaches as nanocatalytic medicine, revealing their significant potential in treating GBM with peptide-functionalized NPs. Alternative routes of parenteral administration, specifically nose-to-brain delivery and local treatment within the resected tumor cavity, are also discussed. Finally, an overview of the significant obstacles and potential strategies to overcome them are discussed to provide a perspective on this promising field of GBM therapy.

One of the most remarkable features in sauropod dinosaurs relates to their pneumatized skeletons permeated by a bird-like air sac system. Many studies described the late evolution and diversification of this trait in mid to late Mesozoic forms but few focused on the origin of the invasive respiratory diverticula in sauropodomorphs. Fortunately, it is possible to solve this thanks to the boom of new species described in the last decade as well as the broad accessibility of new technologies. Here we analyze the unaysaurid sauropodomorph Macrocollum itaquii from the Late Triassic (early Norian) of southern Brazil using micro-computed tomography. We describe the chronologically oldest and phylogenetically earliest unambiguous evidence of an invasive air sac system in a dinosaur. Surprisingly, this species presented a unique pattern of pneumatization in non-sauropod sauropodomorphs, with pneumatic foramina in posterior cervical and anterior dorsal vertebrae. This suggests that patterns of pneumatization were not cladistically consistent prior to the arrival of Jurassic eusauropods. Additionally, we describe the protocamerae tissue, a new type of pneumatic tissue with properties of both camellae and camerae. This reverts the previous hypothesis which stated that the skeletal pneumatization first evolved into camarae, and derived into delicate trabecular arrangements. This tissue is evidence of thin camellate-like tissue developing into larger chambers. Finally, Macrocollum is an example of the gradual evolution of skeletal tissues responding to the fastly specializing Respiratory System of saurischian dinosaurs., (© 2023 The Authors. The Anatomical Record published by Wiley Periodicals LLC on behalf of American Association for Anatomy.)

Background: Dimethyl fumarate (DMF) has a favorable benefit-risk profile treating people with multiple sclerosis and should be used in pregnant women only if the potential benefits outweigh potential risks to the fetus., Objective: Assess pregnancy outcomes in a completed international registry (TecGistry) of women with MS exposed to DMF., Methods: TecGistry included pregnant women with MS exposed to DMF, with data collected at enrollment, 6-7 months gestation, 4 weeks after estimated due date, and at postpartum weeks 4, 12, and 52. Outcomes included live births, gestational size, pregnancy loss, ectopic/molar pregnancies, birth defects, and infant/maternal death., Results: Of 397 enrolled, median (range) age was 32 years (19-43). Median (range) gestational week at enrollment was 10 (0-39) and at first DMF exposure was 1 (0-13). Median (range) duration of gestational DMF exposure was 5 weeks (0-40). Fifteen (3.8%) spontaneous abortions occurred. Of 360 (89.1%) live births, 323 were full term and 37 were premature. One neonatal death and no maternal deaths occurred. Adjudicator-confirmed EUROCAT birth defects were found in 2.2%., Conclusion: DMF exposure during pregnancy did not adversely affect pregnancy outcomes; birth defects, preterm birth, and spontaneous abortion were in line with rates from the general population., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K.H. participated on scientific advisory boards for Bayer, Biogen, Merck, Novartis, Roche, Sanofi, and Teva; received speaker honoraria and research support from Bayer, Biogen, Genzyme, Merck, Novartis, Sanofi, and Teva; received support for congress participation from Bayer, Biogen, Genzyme, Merck, Roche, and Teva. D.R. received consulting and/or speaker fees from Biogen, Celgene, Hikma, Janssen, MedDay, Merck, Novartis, Roche, Sanofi and Teva; research support (paid to institutional fund) from Actelion, Biogen, Janssen, Merck, Mitsubishi, Novartis, Sanofi, Teva and TG Therapeutics. C.M. received honoraria for consultancy work and/or research funding from Actelion, Biogen, Merck, Novartis, Roche, Sandoz, and Sanofi-Genzyme. M.K.H. participated on advisory boards for Biogen, Merck, Novartis, Roche, Sanofi, and Teva; received research support from Biogen, Genzyme, and Merck. D.R.B. participated on advisory boards for Biogen, Celgene, EMDSerono, Genentech, Novartis, and Sanofi-Genzyme. O.M., S.L., N.E., and X.L. are full-time employees of and hold stock/stock options in Biogen. F.B. was a full-time employee of and held stock/stock options in Biogen at the time the research was conducted.

Glioblastoma (GB) is one of the most lethal types of neoplasms. Its biologically aggressive nature and the presence of the blood-brain barrier (BBB) limit the efficacy of standard therapies. Several strategies are currently being developed to both overcome the BBB and deliver drugs site specifically to tumor cells. This work hypothesizes a two-pronged approach to tackle GB: drug repurposing with celecoxib (CXB) and a nanoformulation using ultra-small nanostructured lipid carriers (usNLCs). CXB antitumor druggable activity was inspected bioinformatically and screened in four glioma cell lines aiming at the comparison with temozolomide (TMZ), as standard of care. Delving into formulation design, it was tailored aiming at (i) improving the drug solubility/loading properties, (ii) assigning a thermal-triggerable drug release based on a lipid matrix with a low melting point, and (iii) enhancing the cytotoxic effect by selecting a template targetable to tumor cells. For this purpose, an integrated analysis of the critical material attributes (CMAs), critical process parameters (CPPs), and critical quality attributes (CQAs) was conducted under the umbrella of a quality by design approach. CMAs that demonstrate a high-risk level for the final quality and performance of the usNLCs include the drug solubility in lipids (solid and liquid), the lipid composition (envisioning a thermoresponsive approach), the ratio between lipids (solid vs. liquid), and the surfactant type and concentration. Particle size was shown to be governed by the interaction lipid-surfactant followed by surfactant type. The drug encapsulation did not influence colloidal characteristics, making it a promising carrier for lipophilic drugs. In general, usNLCs exhibited a controlled drug release during the 72 h at 37 °C with a final release of ca. 25%, while at 45 °C this was doubled. The in vitro cellular performance depended on the surfactant type and lipid composition, with the formulations containing a sole solid lipid (Suppocire ® NB) and Kolliphor ® RH40 as surfactant being the most cytotoxic. usNLCs with an average diameter of ca. 70 nm and a narrow size distribution (PdI lower than 0.2) were yielded, exhibiting high stability, drug protection, sustained and thermo-sensitive release properties, and high cytotoxicity to glioma cells, meeting the suitable CQAs for parenteral administration. This formulation may pave the way to a multi-addressable purpose to improve GB treatment., (© 2023. The Author(s).)

Long-term immune evasion by the African trypanosome is achieved through repetitive cycles of surface protein replacement with antigenically distinct versions of the dense Variant Surface Glycoprotein (VSG) coat. Thousands of VSG genes and pseudo-genes exist in the parasite genome that, together with genetic recombination mechanisms, allow for essentially unlimited immune escape from the adaptive immune system of the host. The diversity space of the "VSGnome" at the protein level was thought to be limited to a few related folds whose structures were determined more than 30 years ago. However, recent progress has shown that the VSGs possess significantly more architectural variation than had been appreciated. Here we combine experimental X-ray crystallography (presenting structures of N-terminal domains of coat proteins VSG11, VSG21, VSG545, VSG558, and VSG615) with deep-learning prediction using Alphafold to produce models of hundreds of VSG proteins. We classify the VSGnome into groups based on protein architecture and oligomerization state, contextualize recent bioinformatics clustering schemes, and extensively map VSG-diversity space. We demonstrate that in addition to the structural variability and post-translational modifications observed thus far, VSGs are also characterized by variations in oligomerization state and possess inherent flexibility and alternative conformations, lending additional variability to what is exposed to the immune system. Finally, these additional experimental structures and the hundreds of Alphafold predictions confirm that the molecular surfaces of the VSGs remain distinct from variant to variant, supporting the hypothesis that protein surface diversity is central to the process of antigenic variation used by this organism during infection., Competing Interests: The authors declare that no competing interests exist., (Copyright: © 2023 Đaković et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Dimethyl fumarate (DMF) showed favorable benefit-risk in patients with relapsing-remitting multiple sclerosis (MS) in phase 3 DEFINE and CONFIRM trials and in the ENDORSE extension study. Disease activity can differ in younger patients with MS compared with the overall population., Methods: Randomized patients received DMF 240 mg twice daily or placebo (PBO; years 0-2 DEFINE/CONFIRM), then DMF (years 3-10; continuous DMF/DMF or PBO/DMF; ENDORSE); maximum follow-up (combined studies) was 13 years. This integrated post hoc analysis evaluated safety and efficacy of DMF in a subgroup of young adults aged 18-29 years., Results: Of 1736 patients enrolled in ENDORSE, 125 were young adults, 86 treated continuously with DMF (DMF/DMF) and 39 received delayed DMF (PBO/DMF) in DEFINE/CONFIRM. Most (n = 116 [93%]) young adults completed DMF treatment in DEFINE/CONFIRM. Median (range) follow-up time in ENDORSE was 6.5 (2.0-10.0) years. Young adults entering ENDORSE who had been treated with DMF in DEFINE/CONFIRM had a model-based Annualized Relapse Rate (ARR; 95% CI) of 0.24 (0.16-0.35) vs. 0.56 (0.35-0.88) in PBO patients. ARR remained low in ENDORSE: 0.07 (0.01-0.47) at years 9-10 (DMF/DMF group). At year 10 of ENDORSE, EDSS scores were low in young adults: DMF/DMF, 1.9 (1.4); PBO/DMF, 2.4 (1.6). At ~ 7 years, the proportion of young adults with no confirmed disability progresion was 81% for DMF/DMF and 72% for PBO/DMF. Patient-reported outcomes (PROs) (SF-36 and EQ-5D) generally remained stable during ENDORSE. The most common adverse events (AEs) in young adults during ENDORSE were MS relapse (n = 53 [42%]). Most AEs were mild (n = 20 [23.3%], n = 7 [17.9%]) to moderate (n = 45 [52.3%], n = 23 [59.0%]) in the DMF/DMF and PBO/DMF groups, respectively. The most common serious AE (SAE) was MS relapse (n = 19 [15%])., Conclusion: The data support a favorable benefit-risk profile of DMF in young adults, as evidenced by well-characterized safety, sustained efficacy, and stable PROs., Clinical Trial Information: Clinical trials.gov, DEFINE (NCT00420212), CONFIRM (NCT00451451), and ENDORSE (NCT00835770)., (© 2023. The Author(s).)

Water scarcity is becoming an issue of more significant concern with a major impact on global sustainability. For it, new measures and approaches are urgently needed. Digital technologies and tools can play an essential role in improving the effectiveness and efficiency of current water management approaches. Therefore, a solution is proposed and validated, given the limited presence of models or technological architectures in the literature to support intelligent water management systems for domestic use. It is based on a layered architecture, fully designed to meet the needs of households and to do so through the adoption of technologies such as the Internet of Things and cloud computing. By developing a prototype and using it as a use case for testing purposes, we have concluded the positive impact of using such a solution. Considering this is a first contribution to overcome the problem, some issues will be addressed in a future work, namely, data and device security and energy and traffic optimisation issues, among several others.

The African trypanosome survives the immune response of its mammalian host by antigenic variation of its major surface antigen (the variant surface glycoprotein or VSG). Here we describe the antibody repertoires elicited by different VSGs. We show that the repertoires are highly restricted and are directed predominantly to distinct epitopes on the surface of the VSGs. They are also highly discriminatory; minor alterations within these exposed epitopes confer antigenically distinct properties to these VSGs and elicit different repertoires. We propose that the patterned and repetitive nature of the VSG coat focuses host immunity to a restricted set of immunodominant epitopes per VSG, eliciting a highly stereotyped response, minimizing cross-reactivity between different VSGs and facilitating prolonged immune evasion through epitope variation., Competing Interests: Declaration of interests F.N.P., C.E.S., and J.P.V. report being shareholders of Panosome GmbH. F.N.P. and C.E.S. report being the managing directors of Panosome GmbH., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

During infection of mammalian hosts, African trypanosomes thwart immunity using antigenic variation of the dense Variant Surface Glycoprotein (VSG) coat, accessing a large repertoire of several thousand genes and pseudogenes, and switching to antigenically distinct copies. The parasite is transferred to mammalian hosts by the tsetse fly. In the salivary glands of the fly, the pathogen adopts the metacyclic form and expresses a limited repertoire of VSG genes specific to that developmental stage. It has remained unknown whether the metacyclic VSGs possess distinct properties associated with this particular and discrete phase of the parasite life cycle. We present here three novel metacyclic form VSG N-terminal domain crystal structures (mVSG397, mVSG531, and mVSG1954) and show that they mirror closely in architecture, oligomerization, and surface diversity the known classes of bloodstream form VSGs. These data suggest that the mVSGs are unlikely to be a specialized subclass of VSG proteins, and thus could be poor candidates as the major components of prophylactic vaccines against trypanosomiasis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Chandra et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: Health care providers (HCPs) treating multiple sclerosis (MS) in clinical practice have numerous disease-modifying therapies (DMTs) to consider when evaluating treatment options. This study assessed the treatment preferences of HCPs in the United States, both direct (explicit) and derived (explicit and implicit), when selecting MS DMTs based on clinical and logistical treatment attributes., Materials and Methods: A 45-minute web-enabled questionnaire was administered to HCPs who manage patients with MS to assess the importance of treatment attributes. HCPs were recruited through an online panel. This study examined treatment attributes relevant to treatment decisions in MS, with a focus on the burden to HCPs and their staff, as well as HCP attitudes toward various aspects of MS care such as diagnosis, treatment prioritization, and ease of initiating or switching DMTs. The study also employed a discrete choice experiment (DCE) to assess direct and derived treatment preferences., Results: The study recruited 145 HCPs. Direct assessments (a score of greater than 7.0 was considered important) suggested that safety (mean importance rating = 7.8/9) and relative risk reduction in relapses (7.6/9) and disability progression (7.5/9) were most important when selecting DMTs. In contrast, derived importance from the DCE (higher points corresponding to greater importance) suggested that logistical attributes such as dose frequency (mean relative attribute importance = 17.5%), dose titration (10.3%), formulation (9.4%), and volume of calls (9.1%) were important considerations, along with efficacy (16.5%), safety (9.8%), and gastrointestinal tolerability (9.4%)., Limitations: This study may have been subject to selection bias due to the application of eligibility criteria, the convenient sampling recruitment methodology, and recruitment of HCPs with internet access., Conclusion: In the direct assessment, clinical attributes were chosen as the most important treatment attributes by HCPs. However, in the DCE, derived treatment decisions rated logistical attributes as also being as important in treatment choice.

The origin of the air sac system present in birds has been an enigma for decades. Skeletal pneumaticity related to an air sac system is present in both derived non-avian dinosaurs and pterosaurs. But the question remained open whether this was a shared trait present in the common avemetatarsalian ancestor. We analyzed three taxa from the Late Triassic of South Brazil, which are some of the oldest representatives of this clade (233.23 ± 0.73 Ma), including two sauropodomorphs and one herrerasaurid. All three taxa present shallow lateral fossae in the centra of their presacral vertebrae. Foramina are present in many of the fossae but at diminutive sizes consistent with neurovascular rather than pneumatic origin. Micro-tomography reveals a chaotic architecture of dense apneumatic bone tissue in all three taxa. The early sauropodomorphs showed more complex vascularity, which possibly served as the framework for the future camerate and camellate pneumatic structures of more derived saurischians. Finally, the evidence of the absence of postcranial skeletal pneumaticity in the oldest dinosaurs contradicts the homology hypothesis for an invasive diverticula system and suggests that this trait evolved independently at least 3 times in pterosaurs, theropods, and sauropodomorphs., (© 2022. The Author(s).)

Even though being perceived as a novel approach, multiple authors claim that the digital transition of all sectors in society started when information and communication technologies (ICT) started to be an integral part of our daily lives. The education sector currently represents one of the contexts where the use of ICT is more promising and allows to reach greater benefits, mostly due to the wide range of tools, applications, and management and methodological approaches that are associated with e-learning. With the above in mind, a bibliometric analysis of the e-learning adoption topic has been performed, aiming on delivering a detailed analysis of the status of the topic. This analysis was carried out by analyzing the scientific literature indexed in the Scopus database that addressed the multiple stages of the e-learning adoption process (i.e., acceptance, adoption, and use). Our study analyzed 896 documents published between 1989 and 2021, of which 98.3% represented papers published in journals and conference proceedings., Competing Interests: Conflict of interestOn behalf of all authors, the corresponding author states that there is no conflict of interest., (© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

The concept of polypharmacology embraces multiple drugs combined in a therapeutic regimen (drug combination or cocktail), fixed dose combinations (FDCs), and a single drug that binds to different targets (multi-target drug). A polypharmacology approach is widely applied in the treatment of acquired immunodeficiency syndrome (AIDS), providing life-saving therapies for millions of people living with HIV. Despite the success in viral load suppression and patient survival of combined antiretroviral therapy (cART), the development of new drugs has become imperative, owing to the emergence of resistant strains and poor adherence to cART. 3'-azido-2',3'-dideoxythymidine, also known as azidothymidine or zidovudine (AZT), is a widely applied starting scaffold in the search for new compounds, due to its good antiretroviral activity. Through the medicinal chemistry tool of molecular hybridization, AZT has been included in the structure of several compounds allowing for the development of multi-target-directed ligands (MTDLs) as antiretrovirals. This review aims to systematically explore and critically discuss AZT-based compounds as potential MTDLs for the treatment of AIDS. The review findings allowed us to conclude that: (i) AZT hybrids are still worth exploring, as they may provide highly active compounds targeting different steps of the HIV-1 replication cycle; (ii) AZT is a good starting point for the preparation of co-drugs with enhanced cell permeability.

Importance: With few approved multiple sclerosis therapies in the pediatric population, there is a need for further approved treatment options. Limited data exist for dimethyl fumarate (DMF) treatment in pediatric-onset multiple sclerosis (POMS)., Objective: To compare the efficacy, safety, and tolerability of DMF vs intramuscular interferon β-1a (IFNβ-1a) in POMS., Design, Setting, and Participants: The CONNECT study was an active-controlled, open-label, rater-blinded 96-week randomized clinical trial in patients with POMS aged 10 to less than 18 years treated between August 2014 and November 2020. Data were analyzed from January through October 2021., Interventions: Patients were randomized to DMF or IFNβ-1a., Main Outcomes and Measures: The primary end point was the proportion of patients free of new or newly enlarging (N or NE) T2 hyperintense lesions at week 96 among trial completers. Secondary end points included number of N or NE T2 lesions, proportion of patients free of relapse, annualized relapse rate (ARR), and safety. The estimated proportion of participants who were relapse free up to week 96 was calculated based on the Kaplan-Meier method. Adjusted ARR was obtained from a negative binomial regression adjusted for baseline relapse rate, baseline Expanded Disability Status Scale (EDSS) score, and age group., Results: Among 150 patients with POMS in the intention-to-treat (ITT) population (median [range] age, 15 [10-17] years; 101 [67.3%] female patients), 78 individuals received DMF and 72 individuals received IFNβ-1a. At week 96, the proportion of patients with no N or NE T2 hyperintense lesions among 103 trial completers was 16.1% (95% CI, 8.0%-27.7%) for DMF vs 4.9% (95% CI, 0.6%-16.5%) for IFNβ-1a, and in a sensitivity analysis among the ITT population, the proportions were 10 patients receiving DMF (12.8%) vs 2 patients receiving IFNβ-1a (2.8%). The estimated proportion of patients who remained relapse free at week 96 was 66.2% for DMF vs 52.3% for IFNβ-1a. Adjusted ARR (95% CI) at week 96 was 0.24 (95% CI, 0.15-0.39) for DMF vs 0.53 (95% CI, 0.33-0.84) for IFNβ-1a; the rate ratio for DMF vs IFNβ-1a was 0.46 (95% CI, 0.26-0.80; P = .006). The number of treatment-emergent adverse events (TEAEs; 74 patients [94.9%] vs 69 patients [95.8%]), serious TEAEs (18 patients [23.1%] vs 21 patients [29.2%]), and treatment discontinuations due to TEAEs (5 patients [6.4%] vs 8 patients [11.1%]) was similar for DMF vs IFNβ-1a., Conclusions and Relevance: This study found that more pediatric patients with POMS treated with DMF were free of new or newly enlarging T2 lesions and that the adjusted ARR was lower among these patients compared with those treated with interferon β-1a. DMF was well tolerated., Trial Registration: ClinicalTrials.gov Identifier: NCT02283853.

RNA modifications are important regulators of gene expression 1 . In Trypanosoma brucei, transcription is polycistronic and thus most regulation happens post-transcriptionally 2 . N 6 -methyladenosine (m 6 A) has been detected in this parasite, but its function remains unknown 3 . Here we found that m 6 A is enriched in 342 transcripts using RNA immunoprecipitation, with an enrichment in transcripts encoding variant surface glycoproteins (VSGs). Approximately 50% of the m 6 A is located in the poly(A) tail of the actively expressed VSG transcripts. m 6 A residues are removed from the VSG poly(A) tail before deadenylation and mRNA degradation. Computational analysis revealed an association between m 6 A in the poly(A) tail and a 16-mer motif in the 3' untranslated region of VSG genes. Using genetic tools, we show that the 16-mer motif acts as a cis-acting motif that is required for inclusion of m 6 A in the poly(A) tail. Removal of this motif from the 3' untranslated region of VSG genes results in poly(A) tails lacking m 6 A, rapid deadenylation and mRNA degradation. To our knowledge, this is the first identification of an RNA modification in the poly(A) tail of any eukaryote, uncovering a post-transcriptional mechanism of gene regulation., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: To evaluate the performance of a non-invasive test (Fibromax™, Ferring Pharmaceutical, Saint-Prex, Switzerland) and inflamatory markers (IL-1β, IL-6, IL-8, TNF-α, MCP-1) in the diagnosis and staging of patients with non-alcoholic fatty liver disease., Methods: Patients older than 18 years with steatosis were prospectively evaluated at a tertiary hospital in southern Brazil. Liver biopsy, Fibromax™ test and inflamatory markers (IL-1β, IL-6, IL-8, TNF-α, MCP-1) were performed. Measures of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were used, considering liver biopsy as the gold standard., Results: Seventy-three Fibromax™ tests were analyzed. SteatoTest presented a sensitivity of 95.5% and PPV of 97.0% for the diagnosis of steatosis. NashTest obtained a sensitivity of 83.3%, specificity of 37.5%, PPV of 90.9% and NPV of 23.1% for the diagnosis of non-alcoholic steatohepatitis (NASH). FibroTest presented a sensitivity of 38.9%, specificity of 92.7%, PPV of 63.6% and NPV of 82.3% to evaluate advanced fibrosis. In the evaluation of patients with grade 2 and 3 steatosis, ROC analyses showed an area under the curve (AUROC) for SteatoTest of 0.68 (P=0.015). NashTest AUROC was 0.59 (P=0.417) for the evaluation of NASH. FibroTest AUROC was 0.79 (P<0.001) for advanced fibrosis. Kappa coefficient values for SteatoTest, NashTest and FibroTest were not statistically significant. Thirty-seven patients performed also analysis of the inflamatory markers, showing that patients with inflammatory activity grade 2-3 on liver biopsy had significantly higher levels of IL6 (P=0.016) and lower TNF-α (P=0.034), but there was no other difference when analysed fibrosis or steatosis., Conclusions: The Fibromax™ test and the inflamatory markers (IL-1β, IL-6, IL-8, TNF-α, MCP-1) did not present a satisfactory performance to be considered a good alternative to replace liver biopsy in the evaluation of non-alcoholic fatty liver disease.

Isoniazid is a first-line drug for the treatment of tuberculosis, a bacterial disease caused by Mycobacterium tuberculosis. Its terminal amino group is highly reactive, leading to significant metabolic deactivation, drug interactions and hepatotoxicity. It is speculated that the activity of isoniazid derivatives is, in part, related to the cleavage of the protecting group. Therefore, this study aimed to evaluate the cleavage characteristics of previously developed isoniazid derivatives through kinetic studies by high-performance liquid chromatography with ultraviolet-diode array detectio to establish a comparison between the rates of the process and the respective activities against M. tuberculosis. Chromatographic separations were performed on an XDB C18 column coupled to an XDB C18 precolumn. The mobile phase consisted of ultrapure water and acetonitrile in gradient mode. The flow rate was 1.0 mL/min, the injection volume was 20 μL, and the detection wavelengths were 230 nm (derivatives and isatins) and 270 nm (isoniazid). Incubation of derivatives was carried out for 5 days in 10 mmol/L phosphate buffer solution (pH 3.0, 7.4, 8.0) or in fetal bovine serum at 37 °C. The incubation reduced the concentration of the derivatives and led to the formation of isoniazid in a first-order kinetic reaction. Isoniazid formation was logarithmically correlated with the minimum inhibitory concentration of the derivatives. The results showed that higher cleavage rates are associated with greater activities against M. tuberculosis, providing important information for the development of future generations of isoniazid derivatives and for screening drug candidates for the treatment of tuberculosis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This study reports the occurrence of pneumosteum (osteohistological structure related to an avian-like air sac system) in a nanoid (5.7-m-long) saltasaurid titanosaur from Upper Cretaceous Brazil. We corroborate the hypothesis of the presence of an air sac system in titanosaurians based upon vertebral features identified through external observation and computed tomography. This is the fifth non-avian dinosaur taxon in which histological traces of air sacs have been found. We provided a detailed description of pneumatic structures from external osteology and CT scan data as a parameter for comparison with other taxa. The camellate pattern found in the vertebral centrum (ce) of this taxon and other titanosaurs shows distinct architectures. This might indicate whether cervical or lung diverticula pneumatized different elements. A cotylar internal plate of bone tissue sustains radial camellae (rad) in a condition similar to Alamosaurus and Saltasaurus. Moreover, circumferential chambers (cc) near the cotyle might be an example of convergence between diplodocoids and titanosaurs. Finally, we also register for the first time pneumatic foramina (fo) and fossae connecting camellate structures inside the neural canal in Titanosauria and the second published case in non-avian dinosaurs. The extreme pneumaticity observed in this nanoid titanosaur contrasts with previous assumptions that this feature correlates with the evolution of gigantic sizes in sauropodomorphs. This study reinforces that even small-bodied sauropod clades could present a hyperpneumatized postcranial skeleton, a character inherited from their large-bodied ancestors., (© 2021. The Author(s).)

Background and Objectives: Oral delayed-release dimethyl fumarate (DMF) is not recommended during pregnancy and should only be used if the potential benefit justifies the potential fetal risk. Although DMF was well tolerated in clinical trials with consistent safety results in postmarketing surveillance, data are limited in pregnant women. The objective was to provide pregnancy outcomes and DMF exposure information from an interim analysis from a prospective, international registry (TecGistry; NCT01911767)., Methods: Women exposed to DMF from the first day of their last menstrual period before conception or during pregnancy were evaluated. Data were obtained at enrollment; 6-7 months' gestation; 4 weeks after estimated due date; and 4, 12, and 52 weeks after birth. Outcomes included live births, gestational size, pregnancy loss, birth defects, and infant or maternal death after delivery. Outcomes were analyzed cumulatively from October 30, 2013 (the start of TecGistry), to April 8, 2020., Results: Of 345 enrolled patients, median (range) age was 32 (20-43) years. The mean (SD) duration of gestational weeks of DMF exposure was 4.9 (3.8). Most infants were full-term at birth (n = 249/274; 91%) and of average gestational size (n = 190/232; 82%). Of 351 outcomes, 277 were live births; 17 (5%) spontaneous abortions (95% confidence interval [CI] 2.6%-7.1%), including 1 (<1%) molar and 1 (<1%) ectopic pregnancy, were reported. There were 8 (2.9% [95% CI 1.3%-5.6%]) adjudicator-confirmed birth defects among the 277 live births., Discussion: Interim results from this large registry indicate that early DMF exposure was not significantly associated with adverse pregnancy outcomes. Outcomes are consistent with previous smaller reports and with the general population., Trial Registration Information: TecGistry; clinical trial registration number: NCT01911767., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Most researchers who study unicellular eukaryotes work with an extremely limited number of laboratory-adapted isolates that were obtained from the field decades ago, but the effects of passage in laboratory rodents, and adaptation to in vitro culture, have been little studied. For example, the vast majority of studies of Trypanosoma brucei biology have concentrated on just two strains, Lister 427 and EATRO1125, which were taken from the field over half a century ago and have since have undergone innumerable passages in rodents and culture. We here describe two new Trypanosoma brucei brucei strains. MAK65 and MAK98, which have undergone only 3 rodent passages since isolation from Ugandan cattle. High-coverage sequencing revealed that adaptation of the parasites to culture was accompanied by changes in gene copy numbers. T. brucei has so far been considered to be uniformly diploid, but we also found trisomy of chromosome 5 not only in one Lister 427 culture, but also in the MAK98 field isolate. Trisomy of chromosome 6, and increased copies of other chromosome segments, were also seen in established cultured lines. The two new T. brucei strains should be useful to researchers interested in trypanosome differentiation and pathogenicity. Initial results suggested that the two strains have differing infection patterns in rodents. MAK65 is uniformly diploid and grew more reproducibly in bloodstream-form culture than MAK98., Competing Interests: The authors have declared that no competing interests exist.

African trypanosomes cause disease in humans and livestock, avoiding host immunity by changing the expression of variant surface glycoproteins (VSGs); the major glycosylphosphatidylinositol (GPI) anchored antigens coating the surface of the bloodstream stage. Proper trafficking of VSGs is therefore critical to pathogen survival. The valence model argues that GPI anchors regulate progression and fate in the secretory pathway and that, specifically, a valence of two (VSGs are dimers) is critical for stable cell surface association. However, recent reports that the MITat1.3 (M1.3) VSG N-terminal domain (NTD) behaves as a monomer in solution and in a crystal structure challenge this model. We now show that the behavior of intact M1.3 VSG in standard in vivo trafficking assays is consistent with an oligomer. Nevertheless, Blue Native Gel electrophoresis and size exclusion chromatography-multiangle light scattering chromatography of purified full length M1.3 VSG indicates a monomer in vitro. However, studies with additional VSGs show that multiple oligomeric states are possible, and that for some VSGs oligomerization is concentration dependent. These data argue that individual VSG monomers possess different propensities to self-oligomerize, but that when constrained at high density to the cell surface, oligomeric species predominate. These results resolve the apparent conflict between the valence hypothesis and the M1.3 NTD VSG crystal structure., (© 2021 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Background & Aims: The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems and it may have heavily impacted patients with liver cancer (LC). Herein, we evaluated whether the schedule of LC screening or procedures has been interrupted or delayed because of the COVID-19 pandemic., Methods: An international survey evaluated the impact of the COVID-19 pandemic on clinical practice and clinical trials from March 2020 to June 2020, as the first phase of a multicentre, international, and observational project. The focus was on patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma, cared for around the world during the first COVID-19 pandemic wave., Results: Ninety-one centres expressed interest to participate and 76 were included in the analysis, from Europe, South America, North America, Asia, and Africa (73.7%, 17.1%, 5.3%, 2.6%, and 1.3% per continent, respectively). Eighty-seven percent of the centres modified their clinical practice: 40.8% the diagnostic procedures, 80.9% the screening programme, 50% cancelled curative and/or palliative treatments for LC, and 41.7% modified the liver transplantation programme. Forty-five out of 69 (65.2%) centres in which clinical trials were running modified their treatments in that setting, but 58.1% were able to recruit new patients. The phone call service was modified in 51.4% of centres which had this service before the COVID-19 pandemic (n = 19/37)., Conclusions: The first wave of the COVID-19 pandemic had a tremendous impact on the routine care of patients with liver cancer. Modifications in screening, diagnostic, and treatment algorithms may have significantly impaired the outcome of patients. Ongoing data collection and future analyses will report the benefits and disadvantages of the strategies implemented, aiding future decision-making., Lay Summary: The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems globally. Herein, we assessed the impact of the first wave pandemic on patients with liver cancer and found that routine care for these patients has been majorly disrupted, which could have a significant impact on outcomes., Competing Interests: SM.-M.: Speaker fees from Bayer and travel funding from 10.13039/100004326Bayer and 10.13039/501100014382Eisai. V.S.: Travel grants from 10.13039/100004326Bayer. A.F.: Lecture fees from Bayer, Gilead and MSD; consultancy fees from Bayer, AstraZeneca, Roche and Guerbert. J-C.N.: Received research grant from 10.13039/100004326Bayer for Inserm UMR1138. L.R.: Reports receiving consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, Celgene, Eisai, Exelixis, Hengrui, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi; lectures fees from AbbVie, Amgen, Eisai, Gilead, Incyte, Ipsen, Lilly, Roche, Sanofi; travel fees from Ipsen; and institutional research funding from Agios, ARMO BioSciences, 10.13039/100004325AstraZeneca, BeiGene, 10.13039/501100003769Eisai, 10.13039/100010544Exelixis, 10.13039/100006591Fibrogen, Incyte, 10.13039/501100014382Ipsen, 10.13039/100004312Lilly, 10.13039/100007054MSD, 10.13039/100004337Roche. B.S.: Reports consultancy fees from Adaptimmune, AstraZeneca, Bayer, BMS, BTG, Eli Lilly, Ipsen, Novartis, Merck, Roche, Sirtex Medical, Terumo; and research grants from 10.13039/100002491BMS and Sirtex Medical. J. Bruix: Consultancy: AbbVie, ArQule, Astra, Basilea, Bayer, BMS, Daiichi Sankyo, GlaxoSmithKline, Gilead, Kowa, Lilly, Medimune, Novartis, Onxeo, Polaris, Quirem, Roche, Sanofi-Aventis, Sirtex, Terumo/Grants: 10.13039/100004326Bayer and 10.13039/501100014382Ipsen. M.S.Z.: Received speaker fees and travel grants from 10.13039/100004326Bayer and 10.13039/100014869BTG, 10.13039/100007054MSD. M.B.: Consultant and Advisory Board for: Bayer Pharma, Ipsen, BMS, Eisai, Roche, AstraZeneca, Sirtex Medical. D.J.P.: Received lecture fees from ViiV Healthcare and Bayer Healthcare and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, and AstraZeneca; received research funding (to institution) from MSD and BMS. T.M.: Consultancy: Eisai, Roche, BTG, Ipsen, Bayer, Adaptimmune. Research funding: Bayer, BTG. H.W.: Served as speaker for Bayer, Eisai, and Ipsen, and as a consultant for Bayer, Eisai, Lilly, BMS, Roche, and Ipsen. B.M.: Consultancy: Bayer-Shering Pharma /Speaker fees: Eisai, MSDG. C. Consultancy fees from Bayer, Ipsen. P.R.G.: Bayer, BMS, MSD, AstraZeneca, Adaptimmune, Sirtex, Lilly Ipsen, Roche, Eisai. M.R.A.S.: Has received Research grants, advisory board or speaker fees for 10.13039/100006483AbbVie, 10.13039/100004326Bayer, Biolab, Intercept, 10.13039/501100014382Ipsen, 10.13039/100008799Gilead, 10.13039/100009947MSD, 10.13039/100004336Novartis, and 10.13039/100004337Roche. J.T.: Has received research grants from 10.13039/100004337Roche and 10.13039/501100014382Ipsen. He has received speaker and consulting honoraria from AstraZeneca, Amgen, Bayer Healthcare, Bristol Myers-Squibb, Eisai, Ipsen, Merck Serono, Merck Sharp & Dome, Lilly Imclone, and Roche. J. Bridgewater: Consultancy Bayer, BMS, Incyte, Taiho, Roche, MSD and Merck Serono. Research funding from Incyte. G.C.: Consultancy fees from Bayer, Ipsen. A.L.: Consultancy CAScination, Advisory Board Neuwave and Histosonics. H.T.: Speaker fees from AbbVie, Gilead, MSD, and Bayer. R.V.: Research grant from 10.13039/100006483Abbvie. A.M.M.P.: Speaker honorarium from Bayer, BMS, Boston Scientific and EISAI. Consulting honorarium from Bayer, AstraZeneca and EISAI. Advisory honorarium from Bayer, AstraZeneca and EISAI. Grants from 10.13039/100004326Bayer and 10.13039/100008497Boston Scientific. M.D.: Has received consulting and training fees from Bayer and Eisai. B.B.: Reports Consultancy for GenMab (paid to Institution); Advisory Boards for Roche (paid to Institution), Eisai Europe Limited (paid to Institution), research grant from 10.13039/100006436Celgene Ltd (paid to Institution), Speakers Bureau for Eisai Europe Limited (paid to Institution), Travel and registration for Congress from Bayer. L.d.F.: Lectures fees from BMS, Roche and Bayer. B.M.M.: Advisory/Speaker: Amgen, AstraZeneca, Bayer, BMS, Eisai, Ipsen, Merck, Roche, Sanoffi Genzyme, Taiho. Expert Testimony: Eisai, Roche. Travel: Eisai, Merck. Research: Sillajen (Individual); AstraZeneca, H3/Eisai, Galera, GSK, Exelixis (Institution). M.S.: Travel/ accommodation/meeting expenses: Bayer. Eisai. Speaker fees: Bayer. C.R.L.: Travel grants from 10.13039/100004326Bayer. M.R-G.: Reports grants from Intercept, grants from 10.13039/100005564Gilead-Sciences, personal fees from Shionogi, personal fees from Alfa-Wasserman, personal fees from Prosciento, personal fees from Kaleido, personal fees from Novonrdisk, personal fees from MSD, personal fees from BMS, personal fees from Allergan, personal fees from Boehriger-Ingelheim, personal fees from Zydus, personal fees from Intercept Pharma, personal fees from Gilead-Sciences, outside the submitted work. F.P.: Disclosures: Received speaker honoraria from Bayer, Roche, LKM-Biotoscana, RAFFO. Research Grants from INC Argentinean 10.13039/100013137National Institute of Corrections, 10.13039/100004337Roche. V.M.: Lectures sponsored by Bayer. G.B.: Advisory board Eli-Lilly and Incyte. M. Vergara: Travel grants from 10.13039/100004326Bayer, 10.13039/100008799Gilead, 10.13039/100009947MSD and 10.13039/100006483Abbvie. Lectures sponsored by Gilead, Abbvie, Intercept, and MSD. M.L.: Lectures and educational presentations: Abbvie. Travel/accommodation, meeting expenses covered by Bayer, Gilead, Abbvie. M.I.: Received speaker honoraria from Bayer, Gilead Sciences, BMS, Janssen, Ipsen, MSD, BTG-Boston Scientific, AbbVie, EISAI, and was consultant for BTG-Boston Scientific, Bayer, and Guerbet. M.R.: Consultancy: Bayer-Schering Pharma, BMS, Roche, Ipsen, AstraZeneca, Lilly, BTG/Paid conferences: Bayer-Schering Pharma, BMS, Gilead, Lilly/Research Grants: 10.13039/100004326Bayer-Schering Pharma, 10.13039/501100014382Ipsen. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Authors.)

Background and Aims: Colorectal cancer (CRC) is a heterogeneous disease with distinctive genetic pathways, such as chromosomal instability, microsatellite instability and methylator pathway. Our aim was to correlate clinical and genetic characteristics of CRC patients in order to understand clinical implications of tumour genotype., Methods: Single-institution retrospective cohort of patients who underwent curative surgery for CRC, from 2012 to 2014. RAS and BRAF mutations were evaluated with the real-time PCR technique Idylla®. Mismatch repair deficiency (dMMR) was characterized by absence of MLH1, MSH6, MSH2 and/or PMS2 expression, evaluated by tissue microarrays. Overall survival (OS) and disease-free survival (DFS) were assessed using survival analysis., Results: Overall, 242 patients were included (males 57.4%, age 69.3 ± 12.9 years; median follow-up 49 months). RAS -mutated tumours were associated with reduced DFS ( p = 0.02) and OS ( p = 0.045) in stage I-III CRC. BRAF -mutated tumours were more predominant in females and in the right colon, similarly to dMMR tumours. BRAF status did not influence OS (4 years)/DFS (3.5 years) in stage I-III disease. However, after relapse, length of survival was 3.5 months in BRAF -mutated tumours in contrast to 18.6 months in BRAF wild-type tumours ( p = NS). No germline mutations in mismatch repair genes were so far identified in the patients with dMMR tumours. Molecular phenotype ( RAS, BRAF and MMR) did not influence OS in metastatic patients. Our small sample size may be a limitation of the study., Conclusion: In our cohort, RAS -mutated tumours were associated with worse DFS and OS in early-stage CRC, whereas the remaining molecular variables had no prognostic influence., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2021 by S. Karger AG, Basel.)

Background: Hepatocellular carcinoma (HCC) is the most frequent primary cancer of the liver and cirrhosis is considered a pre-malignant disease. In this context, the evolutionary sequence from low grade dysplastic nodule and high grade dysplastic nodule (HGDN) to early HCC and advanced HCC has been studied. The differential diagnosis between HGDN and early HCC is still a challenge, especially in needle biopsies., Objective: To evaluate an immunohistochemistry panel to differentiate dysplastic nodules and HCC., Methods: Patients with cirrhosis who underwent surgical resection or liver transplantation were included. The sensitivity, specificity and accuracy for the diagnosis of neoplasia were analyzed by evaluating five markers: heat shock protein 70, glypican 3, glutamine synthetase, clathrin heavy chain and beta-catenin. P≤0.05 was considered statistically significant., Results: One hundred and fifty-six nodules were included; of these, 57 were HCC, 14 HGDN, 18 low grade dysplastic nodules and 67 regenerative macronodules. Sensitivity of HCC diagnosis was 64.9% for glypican 3 and 77.2% for glutamine syntetase, while specificity was 96.0% and 96.0% respectively. When the panel of four markers was considered (excluding beta catenin), the specificity ranged from 87.9% for one positive marker to 100% for at least three markers. The best accuracy for HCC diagnosis was obtained with at least two positive markers, which was associated with a sensitivity of 82.5% and specificity of 99%., Conclusion: Differential diagnosis of dysplastic nodules and HCC by morphological criteria can be challenging. Immunomarkers are useful and should be used for the differential diagnosis between HCC and HGDN.

We analysed changes in mean annual air temperature (MAAT), vegetation and biomass burning on a long and continuous lake-peat sediment record from the Colônia basin, southeastern Brazil, examining the responses of a wet tropical rainforest over the last 180 ka. Stronger southern atmospheric circulation up to the latitude of Colônia was found for the penultimate glacial with lower temperatures than during the last glacial, while strengthening of the South American summer monsoon (SASM) circulation started during the last interglacial and progressively enhanced a longer wet summer season from 95 ka until the present. Past MAAT variations and fire history were possibly modulated by eccentricity, although with signatures which differ in average and in amplitude between the last 180 ka. Vegetation responses were driven by the interplay between the SASM and southern circulation linked to Antarctic ice volume, inferred by the presence of a cool mixed evergreen forest from 180 to 45 ka progressively replaced by a rainforest. We report cooler temperatures during the marine isotope stage 3 (MIS 3: 57-29 ka) than during the Last Glacial Maximum (LGM: 23-19 ka). Our findings show that tropical forest dynamics display different patterns than mid-latitude during the last 180 ka.

Background: Venous thromboembolism (VTE) is a frequent complication in patients with cancer and causes considerable morbidity and mortality. The risk of VTE is higher in patients with pancreatic cancer and is often associated with treatment delays or interruptions. Recently, the ONKOTEV score was proposed as a VTE risk predictor model for patients with cancer, but its validation is still ongoing., Patients and Methods: We conducted a retrospective study to determine the incidence of VTE and to evaluate the ONKOTEV score as a VTE predictive tool in a population of patients with pancreatic cancer., Results: Between February 2012 and May 2017, 165 patients were included in the study. The median age was 73 years, 45.5% of patients were female, and 55.8% had stage IV disease. Fifty-one patients had a VTE (30.9%); 23.5% had pulmonary embolism, 25.5% had deep venous thrombosis, and 51.0% had visceral VTE (VsT). At a median follow-up time of 6.3 months, cumulative incidence of VTE was less than 10% for ONKOTEV scores 0 or 1 and approximately 40% and 70% for scores 2 and ≥3, respectively., Conclusion: The high VTE incidence observed in this study is consistent with prior reports. Patients at high risk for VTE with no increase in hemorrhagic risk should be considered for primary thromboprophylaxis. The ONKOTEV score may stratify VTE risk in patients with pancreatic cancer, with ONKOTEV score ≥2 being associated with a higher VTE occurrence., Implications for Practice: Venous thromboembolism (VTE) is a frequent complication of patients with pancreatic cancer and causes considerable morbidity, treatment delays or interruptions, and mortality. Thromboprophylaxis is not used routinely in ambulatory patients. Tools to stratify the risk of VTE are important to help select patients who may benefit from thromboprophylaxis. Recently, the ONKOTEV score was proposed as a VTE risk predictor model for patients with cancer, but its validation is still ongoing. In this patient series, ONKOTEV score ≥2 was associated with high VTE occurrence and may stratify VTE risk in patients with pancreatic cancer, suggesting that ONKOTEV can be considered to select patients with pancreatic cancer for primary thromboprophylaxis., (© AlphaMed Press 2019.)

Introduction: Febrile neutropenia (FN) is a potentially life-threatening complication of systemic chemotherapy (CT) that often requires hospital admission. Delay in diagnosis and treatment are associated with higher morbidity and mortality., Objective: We aimed to determine the factors that influence FN episodes outcomes in the emergency room (ER)., Methods: This was a retrospective study of all FN episodes (with a collected blood culture [BC]) that occurred between 2012 and 2016 at our institution. FN was defined as a temperature ≥38°C and an absolute neutrophil count (ANC) <1,000/μL, expected to decrease to <500/μL in the following week., Results: Between 2012 and 2016, there were 173 FN episodes in 153/1,947 patients treated with intravenous CT. Most of these episodes (n = 121, 70%) were diagnosed in the ER, 29 in the outpatient clinic, and 23 as inpatients. In the ER, the median time was 36 min from hospital nurse triage to medical observation, and 52 min from medical observation to complete blood count specimen collection. There was a positive BC in 33 FN episodes, 72% with Gram-negative bacteria. A total of 160 FN episodes led to hospital admission and 13 were treated as outpatients. Mortality associated with the FN episode was 15% and an ANC <100/μL was predictive of increased mortality., Conclusion: This study confirms that FN is a serious and common complication of IV CT which must be diagnosed and treated promptly. Profound neutropenia was the only predictive factor of mortality., (© 2020 S. Karger AG, Basel.)

Trypanosoma brucei parasites successfully evade the host immune system by periodically switching the dense coat of variant surface glycoprotein (VSG) at the cell surface. Each parasite expresses VSGs in a monoallelic fashion that is tightly regulated. The consequences of exposing multiple VSGs during an infection, in terms of antibody response and disease severity, remain unknown. In this study, we overexpressed a high-mobility group box protein, TDP1, which was sufficient to open the chromatin of silent VSG expression sites, to disrupt VSG monoallelic expression, and to generate viable and healthy parasites with a mixed VSG coat. Mice infected with these parasites mounted a multi-VSG antibody response, which rapidly reduced parasitemia. Consequently, we observed prolonged survival in which nearly 90% of the mice survived a 30-d period of infection with undetectable parasitemia. Immunodeficient RAG2 knock-out mice were unable to control infection with TDP1-overexpressing parasites, showing that the adaptive immune response is critical to reducing disease severity. This study shows that simultaneous exposure of multiple VSGs is highly detrimental to the parasite, even at the very early stages of infection, suggesting that drugs that disrupt VSG monoallelic expression could be used to treat trypanosomiasis., Competing Interests: The authors declare no competing interest., (Copyright © 2019 the Author(s). Published by PNAS.)

The construction sector has been using supplementary materials in concrete production worldwide, such as coal fly ash. Nowadays, several sub/products or wastes have been studied to be incorporated in construction materials, and one of those wastes is biomass fly ash. However, using high volumes of these materials has some drawbacks, one of them being carbonation. In order to understand phenomena such as this, it is important to study the interaction between the additions and hydration of cement. This paper focuses on the study of hydration and carbonation of cementitious pastes containing biomass fly ash and/or coal fly ash by using thermogravimetric analysis and X-ray diffraction analysis and by accelerated carbonation tests. BFA present different chemical and mineralogical composition than CFA. The results show that incorporating biomass fly ash into construction materials has a similar carbonation behaviour to coal fly ash. Biomass fly ash seems to give some extra alkalinity to the mixtures, and this may present benefits to the construction materials and for the ash management., (Copyright © 2019 Elsevier Ltd. All rights reserved.)