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The double empathy problem proposes a lack of shared understanding between autistic and non-autistic people leads to interaction difficulties between them. Social self-efficacy (confidence in one's social abilities) makes an important contribution to social interactions. Research has shown that autistic people show a social identity (one's sense of self based on membership of social groups) with other autistic people, and this impacts positively on well-being. In addition, research shows that autistic people have a number of social identities. This study aims to understand whether social self-efficacy relates to mental well-being in autistic adults, and whether social identity plays a role in this relationship. A total of 512 autistic adults completed measures of social self-efficacy, social identity, mental well-being and autistic traits. In-group social self-efficacy was found to be higher than out-group social self-efficacy. Second, in-group social self-efficacy was positively associated with well-being. Finally, social identity did not mediate the relationships between social self-efficacy and mental well-being. These findings suggest social self-efficacy may relate to the nature of the group one interacts with. The findings support further research into the relationship between social self-efficacy and well-being, as well as using the double empathy problem as a framework for further investigations in other social groups.

Goldstein’s conceptions of pathological states as specific relationships to the milieu, based on his clinical work and observations with First World War soldiers with brain injuries, pay unprecedented attention to chronicity as a particular form of the pathological, capable of stabilizing in forms of health. From this stems a concept of holistic care which pays attention to the person as a whole and to the possibilities for restructuring his or her relationship with the milieu. While the directions he took in his clinical approach of brain-injured patients make him a pioneer of Physical and Rehabilitation Medicine, his reflection on norms and normality, and on the limits of medical action, rooted in a conception of health as “latitude de vie”, nevertheless distinguish him from the rehabilitation paradigm as it is sometimes described and criticized. In this respect, Goldstein’s conceptions seem to be fruitfully extended to the care and support of chronic illnesses and certain situations of disability today.

Abstract Background The delivery of high-quality services in chronically underfunded social or long-term care systems is a major challenge internationally. National guidelines, developed by the National Institute for Health and Care Excellence, set out how local authorities in England and Wales should fund and provide care based on best available evidence. Theoretical and participatory approaches can usefully inform the design and evaluation of implementation strategies for guidelines. The aim of the study is to develop a Theory-of-Change for how the implementation of these guidelines is expected to lead to impacts from a local authority perspective. Methods As part of a comparative case study (The ‘Valuing Care Guidelines’ study; February 2022 to April 2024) with three local authority sites in England and Wales, we involved altogether 17 participants in two Theory-of-Change online workshops per site, each of 2 hours. Additional data gathered from the same participants as part of the overall study were used to conceptualise and enrich information from the workshops. Results Participants described the Theory-of-Change map as follows: A wide range of activities (categorised in stages of ‘pre-implementation’, ‘implementation’, ‘sustainment and scaling’) and skills were required to implement guidelines, and achieve long-term organisational sustainability and service delivery outcomes, leading to final impacts for service users and carers. Participants described a co-creation implementation model, led by ‘Implementation Support Practitioners’, who utilised relational skills to achieve motivation, trust, and confidence at different organisational levels, addressing contextual barriers such as inadequate staffing, lack of resources and of organisational support systems. Consistent use of guidelines by frontline staff could only be achieved if the value of guideline implementation was promoted widely, and if consideration was given to the roles of stakeholders, such as the inspection body, local health care providers, users and carers. Conclusions Our study is the first to investigate the implementation of national social care guidelines by local authorities in England and Wales. It generates insights that can guide implementation practice as well as inform the evaluation of future implementation strategies.

Abstract Background Understanding the resistance mechanisms of tumor is crucial for advancing cancer therapies. The prospective MATCH-R trial (NCT02517892), led by Gustave Roussy, aimed to characterize resistance mechanisms to cancer treatments through molecular analysis of fresh tumor biopsies. This report presents the genomic data analysis of the MATCH-R study conducted from 2015 to 2022 and focuses on targeted therapies. Methods The study included resistant metastatic patients (pts) who accepted an image-guided tumor biopsy. After evaluation of tumor content (TC) in frozen tissue biopsies, targeted NGS (10 30%) were performed before and/or after the anticancer therapy. Patient-derived xenografts (PDX) were established by implanting tumor fragments into NOD scid gamma mice and amplified up to five passages. Results A total of 1,120 biopsies were collected from 857 pts with the most frequent tumor types being lung (38.8%), digestive (16.3%) and prostate (14.1%) cancer. Molecular targetable driver were identified in 30.9% (n = 265/857) of the patients, with EGFR (41.5%), FGFR2/3 (15.5%), ALK (11.7%), BRAF (6.8%), and KRAS (5.7%) being the most common altered genes. Furthermore, 66.0% (n = 175/265) had a biopsy at progression on targeted therapy. Among resistant cases, 41.1% (n = 72/175) had no identified molecular mechanism, 32.0% (n = 56/175) showed on-target resistance, and 25.1% (n = 44/175) exhibited a by-pass resistance mechanism. Molecular profiling of the 44 patients with by-pass resistance identified 51 variants, with KRAS (13.7%), PIK3CA (11.8%), PTEN (11.8%), NF2 (7.8%), AKT1 (5.9%), and NF1 (5.9%) being the most altered genes. Treatment was tailored for 45% of the patients with a resistance mechanism identified leading to an 11 months median extension of clinical benefit. A total of 341 biopsies were implanted in mice, successfully establishing 136 PDX models achieving a 39.9% success rate. PDX models are available for EGFR (n = 31), FGFR2/3 (n = 26), KRAS (n = 18), ALK (n = 16), BRAF (n = 6) and NTRK (n = 2) driven cancers. These models closely recapitulate the biology of the original tumors in term of molecular alterations and pharmacological status, and served as valuable models to validate overcoming treatment strategies. Conclusion The MATCH-R study highlights the feasibility of on purpose image guided tumor biopsies and PDX establishment to characterize resistance mechanisms and guide personalized therapies to improve outcomes in pre-treated metastatic patients. Graphical Abstract

Abstract Smart textiles that promise to become sensors and actuators for multiple applications are an active area of research. Conductive textiles formed by coating a fabric with a conductive film will play a key role in such applications. Here we present contactless mapping of the terahertz (THz) conductivity of thin conductive films deposited on textiles. These conductivity maps enable non-destructive assessment of the conductivity of such layers and therefore the identification and localization of non-uniformities in local conductivity. The THz measurements are quantitatively consistent with four-point probe measurements of the same areas.

Abstract Sepia melanin, a biopigment extracted from the ink sac of cuttlefish, is relevant to sustainable organic electronics. In this work, we flexographically print films from an ink of Sepia melanin including shellac as a bio-sourced binder on silver electrode-patterned paper. We examine the electrical response in high humidity and ambient conditions (here the electronic conductivity is as high as 10−4 S/cm). Additionally, we study the biodegradation of the printed films and their individual constituents based on their mineralization into CO2 under composting conditions. The printed films exhibit biodegradation levels of about 97 ± 25% in 85 d. We observe microorganism colonization on the printed film’s surface. The analysis of the microbial community on the compost reveals that bacterial species within the Acidimicrobiia class, specifically Actinomarinales order, are potentially responsible for the biodegradation of the printed film. Meanwhile, ecotoxicity tests conducted by germinating Lolium multiflorum and Tagetes erecta suggest that printed films have negligible phytotoxicity.

Abstract Background Post-intensive care syndrome could be responsible for inability to receive proper cancer treatment after ICU stay in patients with solid tumors (ST). Our purpose was to determine the factors associated with cancer treatment resumption and the impact of cancer treatment on the outcome of patients with ST after ICU stay. Methods We conducted a retrospective study including all patients with ST admitted to the ICU between 2014 and 2019 in a French University-affiliated Hospital. Results A total of 219 patients were included. Median SAPS II at ICU admission was 44.0 [IQR 32.8, 66.3]. Among the 136 patients who survived the ICU stay, 81 (59.6%) received cancer treatment after ICU discharge. There was an important increase in patients with poor performance status (PS) of 3 or 4 after ICU stay (16.2% at admission vs. 44.5% of patients who survived), with significant PS decline following the ICU stay (median difference − 1.5, 95% confidence interval [-1.5-1.0], p

Service-learning has become widespread in universities worldwide, implying an increased number of involved faculty. Many studies document service-learning's impact on students, but only a handful of exploratory studies examine impact on faculty. We offer a focused investigation of positive and negative impacts of service-learning on faculty from an Asian context, based on interviews with 24 faculty members from diverse academic disciplines in a university in Hong Kong. Phenomenological methods are used to summarize the essences of firsthand experiences. Participants' valenced views about service-learning's impact are categorized as dominant positive, mixed, and negative stances. Service-learning contributed to faculty teaching, civic-mindedness, person/values, professional development, and research. Findings suggest that service-learning involvement can benefit more diverse faculty than previously identified. Service-learning is recommended as a strategy for faculty development, and as a means for universities to fulfill their social responsibility and contribute to sustainable development goals outlined by the United Nations.

A two reaction synthesis of a urea, using triphosgene, was studied. The objective was to transpose the process from laboratory scale to pre-industrial plant. The whole study was performed in a continuous process, adapting the characteristic dimensions and length of the reactor. In this paper, the development of the process is presented, and the choices about safety and operating conditions constraints are discussed. The final operation allows a 70% global yield in a 7 week study. Furthermore, the use of microreactors not only permits an exhaustive study of the process operating parameters, but also provides feedback on the developed chemistry itself. The results obtained are a demonstration of the use of continuous processes in small scale reactors for complex molecule development. The mg·h-1 to kg·h-1 is a key transposition in the pharmaceutical industries project development, as it can help to accelerate the first lot production used in toxicological or pre-clinic stages.

Objectives: Fitusiran is an investigational, subcutaneous small interfering RNA therapeutic in development for hemophilia A and B, with and without inhibitors that aims to rebalance hemostasis by targeting antithrombin (AT) mRNA to lower AT levels and restore sufficient thrombin generation. To further enhance the benefit-risk profile of fitusiran, the revised AT-based dosing regimen was designed to target AT activity levels of 15-35%. The objective of this study was to evaluate and compare AT activity measurements in hemostasis laboratories using commercially available in vitro diagnostic AT activity assays across countries. Material and methods: AT immunodepleted and normal pooled plasma were mixed to generate 100%, 36%, 14% and 9% (IU/dL) AT activity levels, based on the Siemens Innovance® AT activity assay. Forty-eight Hemostasis Laboratories in 16 countries, blinded to AT activity levels, tested plasma samples in triplicates on three different days. Labs used their routine chromogenic AT activity assays, which evaluate the effectiveness of AT in inhibiting human or bovine factor IIa or Xa. Pre-defined acceptable recovery criteria was set at ± 20% of assigned value with intra-assay coefficient of variation (CV) < 20%. Results and discussion: Siemens Innovance® AT (human FXa based) assay can reliably measure antithrombin across all activity levels (CV 20%) with the highest reproducibility at 14% and 36% (CV 10%). Siemens Berichrom® and STA® -Stachrom® (bovine IIa based) assays could reliably measure 100% and 36% samples but showed lab-to-lab variability for ≤ 15% AT activity. Siemens Berichrom® had a CV > 20% for 14% and 9% samples. For Stachrom®, only 8/12 labs reported a value for the 14% sample and all labs failed to measure the 9% sample. The HemosIL® (bovine FXa based) assay significantly underestimated AT activity levels ≤ 36%. Most labs using HemosIL® failed to report any values for 14% and 9% AT samples. Clear inference regarding rarely used AT assays (each N < 4) could not be made. Conclusion: This study provides important data regarding the performance of commercially available, regulatory cleared AT activity assays across a range of AT activity levels. Siemens Innovance® AT (human FXa) assay can reliably measure AT activity at clinical decision points of 15%–35% (CV 10%) and is recommended for fitusiran monitoring. This assay was used for all fitusiran phase 1,2,3 clinical trials for measuring AT activity. Berichrom® and Stachrom® (bovine FIIa) assays can only be used for fitusiran monitoring after extra validation for ≤ 15% AT (CV < 20%). HemosIL® (bovine FXa) assay significantly underestimates AT activity ≤ 36% and should not be recommended for fitusiran patient management.

A captive sand tiger shark (Carcharias taurus) presented with progressive, hard, raised, miliary skin lesions localized to the lateral trunk and peduncle. Histopathologic evaluation of biopsy samples revealed dysplastic proliferation of odontogenic epithelium with the production of collagenous material. Inclusion bodies and viral particles were not observed with light or transmission electron microscopy, respectively. However, using next generation sequencing with Illumina MiSeq and PCR followed by Sanger sequencing, the complete genome of a novel adomavirus, tentatively named sand tiger shark adomavirus (STAdoV), was obtained from the affected tissue. The genome was circular and 18.5 kilobases with bidirectionally transcribed genes, namely EO1, EO2 & 4, EO3, LO4, LO5, LO6, LO7, LO8, and SET. In situ hybridization using RNAscope® technology and a STAdoV specific probe localized viral DNA to the nuclei of proliferating epithelial cells. Adomaviruses are an emerging viral group with structural and replicative genes sharing a complex evolutionary history with adenoviruses and small circular DNA tumor viruses including papillomaviruses and polyomaviruses. Adomaviruses are described in a number of fish species in association with both necrotizing and proliferative diseases. BLAST analysis of the viral genome revealed greatest nucleotide identity (71.29%) to guitarfish adomavirus (GAdoV), another elasmobranch virus associated with proliferative (epidermal) skin lesions. Lesions in the index animal persisted for approximately 1 year during which time four conspecifics developed similar proliferations. Ultimately, lesions in all sharks regressed spontaneously without recurrence for 2 years.

Abstract Background Primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) are distinct hematological malignancies of B-cell origin that share many biological, molecular, and clinical characteristics. In particular, the JAK/STAT signaling pathway is a driver of tumor development due to multiple recurrent mutations, particularly in STAT6. Furthermore, the XPO1 gene that encodes exportin 1 (XPO1) shows a frequent point mutation (E571K) resulting in an altered export of hundreds of cargo proteins, which may impact the success of future therapies in PMBL and cHL. Therefore, targeted therapies have been envisioned for these signaling pathways and mutations. Methods To identify novel molecular targets that could overcome the treatment resistance that occurs in PMBL and cHL patients, we have explored the efficacy of a first-in-class HSP110 inhibitor (iHSP110-33) alone and in combination with selinexor, a XPO1 specific inhibitor, both in vitro and in vivo. Results We show that iHSP110-33 decreased the survival of several PMBL and cHL cell lines and the size of tumor xenografts. We demonstrate that HSP110 is a cargo of XPO1wt as well as of XPO1E571K. Using immunoprecipitation, proximity ligation, thermophoresis and kinase assays, we showed that HSP110 directly interacts with STAT6 and favors its phosphorylation. The combination of iHSP110-33 and selinexor induces a synergistic reduction of STAT6 phosphorylation and of lymphoma cell growth in vitro and in vivo. In biopsies from PMBL patients, we show a correlation between HSP110 and STAT6 phosphorylation levels. Conclusions These findings suggest that HSP110 could be proposed as a novel target in PMBL and cHL therapy.

Abstract Long-chain fatty acids with antimicrobial properties are abundant on the skin and mucosal surfaces, where they are essential to restrict the proliferation of opportunistic pathogens such as Staphylococcus aureus. These antimicrobial fatty acids (AFAs) elicit bacterial adaptation strategies, which have yet to be fully elucidated. Characterizing the pervasive mechanisms used by S. aureus to resist AFAs could open new avenues to prevent pathogen colonization. Here, we identify the S. aureus lipase Lip2 as a novel resistance factor against AFAs. Lip2 detoxifies AFAs via esterification with cholesterol. This is reminiscent of the activity of the fatty acid-modifying enzyme (FAME), whose identity has remained elusive for over three decades. In vitro, Lip2-dependent AFA-detoxification was apparent during planktonic growth and biofilm formation. Our genomic analysis revealed that prophage-mediated inactivation of Lip2 was rare in blood, nose, and skin strains, suggesting a particularly important role of Lip2 for host – microbe interactions. In a mouse model of S. aureus skin colonization, bacteria were protected from sapienic acid (a human-specific AFA) in a cholesterol- and lipase-dependent manner. These results suggest Lip2 is the long-sought FAME that exquisitely manipulates environmental lipids to promote bacterial growth in otherwise inhospitable niches.

Abstract The prognostic value of radiomic quantitative features measured on pre-treatment 18F-FDG PET/CT was investigated in patients with follicular lymphoma (FL). We conducted a retrospective study of 126 FL patients (grade 1-3a) diagnosed between 2006 and 2020. A dozen of PET/CT-derived features were extracted via a software (Oncometer3D) from baseline 18F-FDG PET/CT images. The receiver operating characteristic (ROC) curve, Kaplan–Meier method and Cox analysis were used to assess the prognostic factors for progression of disease within 24 months (POD24) and progression-free survival at 24 months. Four different clusters were identified among the twelve PET parameters analyzed: activity, tumor burden, fragmentation-massiveness and dispersion. On ROC analyses, TMTV, the total metabolic tumor volume, had the highest AUC (0.734) followed by medPCD, the median distance between the centroid of the tumors and their periphery (AUC: 0.733). Patients with high TMTV (HR = 4.341; p

Purpose: To investigate and compare the anatomic and functional outcomes of chandelier-assisted scleral buckling (CASB) surgery using contact versus non-contact lens-based wide-angle viewing systems (WAVSs) in rhegmatogenous retinal detachment (RRD) patients. Methods: This was a retrospective, multicenter study evaluating the anatomic (reattachment rate) and visual acuity (VA) outcomes at 6 months post-CASB for primary RRD. Results: Forty-seven RRD patients underwent CASB with a non-contact WAVS (Group C1) and 90 with a contact lens WAVS (Group C2). Preoperative parameters including myopia, macula-off RRD, posterior vitreous detachment, number of retinal breaks, and retinal dialysis as the etiology of RRD did not differ significantly between the two groups. The outcomes of retinal attachment (85.11% of C1 patients and 76.67% of C2 patients, P = 0.34) and final visual outcome (VA ≥6/12: C1 = 61.7%; C2 = 46.67%, P = 0.13) were also comparable. Furthermore, no significant difference in postoperative complications such as cataracts, glaucoma, infection, buckle exposure, and buckle failure was observed. Finally, both groups were comparable in terms of re-detachment rates (10.64% in C1 and 23.33% in C2, P = 0.11). Conclusion: The two WAVS approaches used in CASB surgery have comparable surgical and functional outcomes and postoperative complications. The operating surgeon can freely choose between these viewing platforms during the contemporary scleral bucking (SB) surgery without impacting the outcome.

Abstract Terahertz imaging is unlocking unique capabilities for the analysis of cultural heritage artifacts. This paper uses terahertz time-domain imaging for the study of a gilded wooden artifact, providing a means to perform stratigraphic analysis, yielding information about the composition of the artifact, presence of certain materials identifiable through their THz spectral fingerprint, as well as alterations that have been performed over time. Due to the limited information that is available for many historic artifacts, the data that can be obtained through the presented technique can guide proper stewardship of the artifact, informing its long-term preservation.

IntroductionThe honey bee ectoparasitic mite, Varroa destructor, is one of the main causes of honey bee colony loss worldwide. Synthetic acaricides are the most commonly used strategy for varroa control, however, resistance to these acaricides has emerged. Consequently, the use of organic acids for varroa control is gaining more interest among beekeepers. For example, oxalic acid (OA) is a natural compound that has been shown to be an effective acaricide against varroa mites, however, the potential toxicity of OA to adult bees and queens is poorly understood. The objective of the study was to evaluate the toxicity of incremental doses of vaporized OA on honey bee workers and queens.MethodsWe exposed 32 colonies to incremental doses (0, 5, 10 or 20 g per colony) of vaporized OA once per week over four consecutive weeks and we monitored the acute and long-term toxicity. We investigated the short-term effects of OA administration by evaluating adult bee mortality, brood production, and population size. Next, we evaluated the long-term effects of OA application on both worker bees and queens. Regarding workers, we investigated their ability to rear new queens. As for queens, we measured acceptance, performance, and sperm quality.ResultsWe found that colonies treated with 20 g OA (20 times the label dose) had a statistically significant increase in worker bee mortality, with a non-significant, 23% decrease in brood relative to controls. No significant differences were observed in queen performance nor sperm quality.DiscussionWe found that repeated application of vaporized OA, at up to 20 times the label dose, had no significant short-term nor long-term, negative effects on colony or queen health, with the exception of a short-term increase in adult bee mortality in the 20 g OA-treated group. The results of this study support the safety of higher-than-label doses of OA for honey bee colonies. The observed increase in adult bee mortality in the 20 g OA dose group in this study suggests that OA doses should be maintained below 20 g per brood chamber.

Abstract Predicting the risk of establishment and spread of populations outside their native range represents a major challenge in evolutionary biology. Various methods have recently been developed to estimate population (mal)adaptation to a new environment with genomic data via so‐called Genomic Offset (GO) statistics. These approaches are particularly promising for studying invasive species but have still rarely been used in this context. Here, we evaluated the relationship between GO and the establishment probability of a population in a new environment using both in silico and empirical data. First, we designed invasion simulations to evaluate the ability to predict establishment probability of two GO computation methods (Geometric GO and Gradient Forest) under several conditions. Additionally, we aimed to evaluate the interpretability of absolute Geometric GO values, which theoretically represent the adaptive genetic distance between populations from distinct environments. Second, utilizing public empirical data from the crop pest species Bactrocera tryoni, a fruit fly native from Northern Australia, we computed GO between “source” populations and a diverse range of locations within invaded areas. This practical application of GO within the context of a biological invasion underscores its potential in providing insights and guiding recommendations for future invasion risk assessment. Overall, our results suggest that GO statistics represent good predictors of the establishment probability and may thus inform invasion risk, although the influence of several factors on prediction performance (e.g., propagule pressure or admixture) will need further investigation.

Abstract Pulmonary fibrosis is an interstitial scarring disease of the lung characterized by poor prognosis and limited treatment options. Tissue transglutaminase 2 (TG2) is believed to promote lung fibrosis by crosslinking extracellular matrix components and activating latent TGFβ. This study assessed physiologic pulmonary function and metabolic alterations in the mouse bleomycin model with TG2 genetic deletion. TG2‐deficient mice demonstrated attenuated the fibrosis and preservation of lung function, with significant reduction in elastance and increases in compliance and inspiratory capacity compared to control mice treated with bleomycin. Bleomycin induced metabolic changes in the mouse lung that were consistent with increased aerobic glycolysis, including increased expression of lactate dehydrogenase A and increased production of lactate, as well as increased glutamine, glutamate, and aspartate. TG2‐deficient mice treated with bleomycin exhibited similar metabolic changes but with reduced magnitude. Our results demonstrate that TG2 is required for a typical fibrosis response to injury. In the absence of TG2, the fibrotic response is biochemically similar to wild‐type, but lesions are smaller and lung function is preserved. We also show for the first time that profibrotic pathways of tissue stiffening and metabolic reprogramming are interconnected, and that metabolic disruptions in fibrosis go beyond glycolysis.

Storm surges are the most important driver of flooding in many coastal areas. Understanding the spatial extent of storm surge events has important financial and practical implications for flood risk management, reinsurance, infrastructure reliability and emergency response. In this paper, we apply a new tracking algorithm to a high-resolution surge hindcast (CODEC, 1980–2017) to characterize the spatial dependence and temporal evolution of extreme surge events along the coastline of the UK and Ireland. We quantify the severity of each spatial event based on its footprint extremity to select and rank the collection of events. Several surge footprint types are obtained based on the most impacted coastal stretch from each particular event, and these are linked to the driving storm tracks. Using the collection of the extreme surge events, we assess the spatial distribution and interannual variability of the duration, size, severity, and type. We find that the northeast coastline is most impacted by the longest and largest storm surge events, while the English Channel experiences the shortest and smallest storm surge events. The interannual variability indicates that the winter seasons of 1989-90 and 2013–14 were the most serious in terms of the number of events and their severity, based on the return period along the affected coastlines. The most extreme surge event and the highest number of events occurred in the winter season 1989–90, while the proportion of events with larger severities was higher during the winter season 2013–14. This new spatial analysis approach of surge extremes allows us to distinguish several categories of spatial footprints of events around the UK/Ireland coast and link these to distinct storm tracks. The spatial dependence structures detected can improve multivariate statistical methods which are crucial inputs to coastal flooding assessments.

Abstract Background Drug resistance in tuberculosis (TB) poses a major ongoing challenge to public health. The recent inclusion of bedaquiline into TB drug regimens has improved treatment outcomes, but this advance is threatened by the emergence of strains of Mycobacterium tuberculosis (Mtb) resistant to bedaquiline. Clinical bedaquiline resistance is most frequently conferred by off-target resistance-associated variants (RAVs) in the mmpR5 gene (Rv0678), the regulator of an efflux pump, which can also confer cross-resistance to clofazimine, another TB drug. Methods We compiled a dataset of 3682 Mtb genomes, including 180 carrying variants in mmpR5, and its immediate background (i.e. mmpR5 promoter and adjacent mmpL5 gene), that have been associated to borderline (henceforth intermediate) or confirmed resistance to bedaquiline. We characterised the occurrence of all nonsynonymous mutations in mmpR5 in this dataset and estimated, using time-resolved phylogenetic methods, the age of their emergence. Results We identified eight cases where RAVs were present in the genomes of strains collected prior to the use of bedaquiline in TB treatment regimes. Phylogenetic reconstruction points to multiple emergence events and circulation of RAVs in mmpR5, some estimated to predate the introduction of bedaquiline. However, epistatic interactions can complicate bedaquiline drug-susceptibility prediction from genetic sequence data. Indeed, in one clade, Ile67fs (a RAV when considered in isolation) was estimated to have emerged prior to the antibiotic era, together with a resistance reverting mmpL5 mutation. Conclusions The presence of a pre-existing reservoir of Mtb strains carrying bedaquiline RAVs prior to its clinical use augments the need for rapid drug susceptibility testing and individualised regimen selection to safeguard the use of bedaquiline in TB care and control.

La ONU prevé que para el 2060, el uso de recursos primarios se duplicará, y que el acero y el cemento serán los principales responsables de las emisiones de gases de efecto invernadero. En ese contexto de agotamiento y sobreconsumo planetario, definir el lugar del material –es decir, dónde y cuánto colocar– como parte del proceso de diseño y fabricación del entorno construido cobra una nueva y urgente relevancia. Este ensayo discute cuál es el lugar del material, específicamente el del hormigón –como uno de los materiales más masificados y contaminantes– a partir de dos perspectivas históricas, la formal y la económica; y una perspectiva futura, la ecológica. Mientras las dos primeras han dominado durante el último siglo las decisiones de diseño y la conformación de lo que conocemos como “industria de la construcción”, el inminente colapso ambiental nos exige repensar la relación entre técnica, material y diseño a través de la incorporación de la variable ecológica como clave para responder a esa pregunta inicial.

Abstract Biliary tract cancers (BTCs) are heterogeneous malignancies with dismal prognosis due to tumor aggressiveness and poor response to limited current therapeutic options. Tumor exome profiling has allowed to successfully establish targeted therapeutic strategies in the clinical management of cholangiocarcinoma (CCA). Still, whether liquid biopsy profiling could inform on BTC biology and patient management is unknown. In order to test this and generate novel insight into BTC biology, we analyzed the molecular landscape of 128 CCA patients, using a 394-gene NGS panel (Foundation Medicine). Among them, 32 patients had matched circulating tumor (ct) DNA and tumor DNA samples, where both samples were profiled. In both tumor and liquid biopsies, we identified an increased frequency of alterations in genes involved in genome integrity or chromatin remodeling, including ARID1A (15%), PBRM1 (9%), and BAP1 (14%), which were validated using an in-house-developed immunohistochemistry panel. ctDNA and tumor DNA showed variable concordance, with a significant correlation in the total number of detected variants, but some heterogeneity in the detection of actionable mutations. FGFR2 mutations were more frequently identified in liquid biopsies, whereas KRAS alterations were mostly found in tumors. All IDH1 mutations detected in tumor DNA were also identified in liquid biopsies. These findings provide novel insights in the concordance between the tumor and liquid biopsies genomic landscape in a large cohort of patients with BTC and highlight the complementarity of both analyses when guiding therapeutic prescription.