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Objective To investigate whether intravenous immunoglobulin (IVIG) improves neurological outcomes in children with encephalitis when administered early in the illness.Design Phase 3b multicentre, double-blind, randomised placebo-controlled trial.Setting Twenty-one hospitals in the UK.Participants Children aged 6 months to 16 years with a diagnosis of acute or subacute encephalitis, with a planned sample size of 308.Intervention Two doses (1 g/kg/dose) of either IVIG or matching placebo given 24–36 hours apart, in addition to standard treatment.Main outcome measure The primary outcome was a ‘good recovery’ at 12 months after randomisation, defined as a score of≤2 on the Paediatric Glasgow Outcome Score Extended.Secondary outcome measures The secondary outcomes were clinical, neurological, neuroimaging and neuropsychological results, identification of the proportion of children with immune-mediated encephalitis, and IVIG safety data.Results 18 participants were recruited from 12 hospitals and randomised to receive either IVIG (n=10) or placebo (n=8) between 23 December 2015 and 26 September 2017. The study was terminated early following withdrawal of funding due to slower than anticipated recruitment, and therefore did not reach the predetermined sample size required to achieve the primary study objective; thus, the results are descriptive. At 12 months after randomisation, 9 of the 18 participants (IVIG n=5/10 (50%), placebo n=4/8 (50%)) made a good recovery and 5 participants (IVIG n=3/10 (30%), placebo n=2/8 (25%)) made a poor recovery. Three participants (IVIG n=1/10 (10%), placebo n=2/8 (25%)) had a new diagnosis of epilepsy during the study period. Two participants were found to have specific autoantibodies associated with autoimmune encephalitis. No serious adverse events were reported in participants receiving IVIG.Conclusions The IgNiTE (ImmunoglobuliN in the Treatment of Encephalitis) study findings support existing evidence of poor neurological outcomes in children with encephalitis. However, the study was halted prematurely and was therefore underpowered to evaluate the effect of early IVIG treatment compared with placebo in childhood encephalitis.Trial registration number Clinical Trials.gov NCT02308982; ICRCTN registry ISRCTN15791925.

BackgroundAccurate assessment of carotid stenosis severity is important for proper patient management. The present study aimed to compare the evaluation of carotid stenosis severity using four duplex sonography (DUS) measurements, including peak systolic velocity (PSV), PSV ratio in stenosis and distal to stenosis (PSVICA/ICA ratio), end-diastolic velocity (EDV), and B-mode, with computed tomography angiography (CTA), and to evaluate the impact of plaque morphology on correlation between DUS and CTA.MethodsConsecutive patients with carotid stenosis of ≥40% examined using DUS and CTA were included. Plaque morphology was also determined using magnetic resonance imaging. Spearman’s correlation and Kendall’s rank correlation were used to evaluate the results.ResultsA total of 143 cases of internal carotid artery stenosis of ≥40% based on DUS were analyzed. The PSVICA/ICA ratio showed the highest correlation [Spearman’s correlation r = 0.576) with CTA, followed by PSV (r = 0.526), B-mode measurement (r = 0.482), and EDV (r = 0.441; p 0.05 in all cases).ConclusionPSV, PSVICA/ICA ratio, EDV, and B-mode measurements showed comparable correlations with CTA in evaluation of carotid artery stenosis based on their correlation with CTA results. Heavy calcifications and plaque surface irregularity or ulceration negatively influenced the measurement accuracy.

We compiled a sampling of the treatment techniques of intensity-modulated total body irradiation, total marrow irradiation and total marrow and lymphoid irradiation utilized by several centers across North America and Europe. This manuscript does not serve as a consensus guideline, but rather is meant to serve as a convenient reference for centers that are considering starting an intensity-modulated program.

ABSTRACT The N4-like viruses, which were recently assigned to the novel viral family Schitoviridae in 2021, belong to a podoviral-like viral lineage and possess conserved genomic characteristics and a unique replication mechanism. Despite their significance, our understanding of N4-like viruses is primarily based on viral isolates. To address this knowledge gap, this study has established a comprehensive N4-like viral data sets comprising 342 high-quality N4-like viruses/proviruses (144 viral isolates, 158 uncultured viruses, and 40 integrated N4-like proviruses). These viruses were classified into 97 subfamilies (89 of which are newly identified), 148 genera (100 of which are newly identified), and 253 species (177 of which are newly identified). The study reveals that N4-like viruses inhibit the polar region, oligotrophic open oceans, and the human gut, where they infect various bacterial lineages, such as Alpha/Beta/Gamma/Epsilon-proteobacteria in the Proteobacteria phylum. Although N4-like viral endogenization appears to be prevalent in Proteobacteria, it has also been observed in Firmicutes. Additionally, the phylogenetic analysis has identified evolutionary divergence within the hallmark genes of N4-like viruses, indicating a complex origin of the different conserved parts of viral genomes. Moreover, 1,101 putative auxiliary metabolic genes (AMGs) were identified in the N4-like viral pan-proteome, which mainly participate in nucleotide and cofactor/vitamin metabolisms. Of these AMGs, 27 were found to be associated with virulence, suggesting their potential involvement in the spread of bacterial pathogenicity. Importance The findings of this study are significant, as N4-like viruses represent a unique viral lineage with a distinct replication mechanism and a conserved core genome. This work has resulted in a comprehensive global map of the entire N4-like viral lineage, including information on their distribution in different biomes, evolutionary divergence, genomic diversity, and the potential for viral-mediated host metabolic reprogramming. As such, this work significantly contributes to our understanding of the ecological function and viral-host interactions of bacteriophages.

Abstract A growth mode of pentacene thin films deposited by high vacuum sublimation where the morphology versus thickness h “rings” back and forth between rough 3D films with pyramid islands and smooth 2D films with ziqqurat islands is discovered. The roughness σ versus h exhibits seamless coherent oscillations whose amplitude and wavelength increase as integer multiples of 1.5 ML thickness. The quantized oscillations are reconducted to dynamic wetting/dewetting transitions involving the upper layers of pentacene film. Importantly, the transconductance of organic field effect transistors, either in solid state or electrolyte‐gated, exhibits antiphase oscillations with one‐decade swing. Charge mobilities in the wetting regime reach 0.1 cm2 V−1 s−1, in line with high‐end values reported for thin‐film pentacene transistors. Controlling this growth mode enables the limitations of charge transport imposed by the roughening transition to be overcome, a universal feature of high vacuum growth to date.

Summary: Recent work suggests that serial dependence, where perceptual decisions are biased toward previous stimuli, arises from the prior that sensory input is temporally correlated. However, existing studies have mostly used random stimulus sequences that do not involve such temporal consistencies. Here, we manipulated the temporal statistics of visual stimuli to examine the role of true temporal correlations in serial dependence. In two experiments, observers reproduced the orientation of the last stimulus in a sequence, while we varied temporal correlations in the stimulus features at two timescales: stimulus history within the trial and decision history across trials. We found a clear dissociation: increasing temporal correlation in the stimulus history led to adaptation-like repulsive biases, whereas increasing temporal correlation in the decision history reduced attractive biases. Thus, we suggest that temporal correlation enhances the discriminative ability of the visual system, revealing the fundamental role of the broader temporal context.

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health.

Summary: Low-carbon technology adoption is an essential element of energy transitions toward net-zero emissions around the world. To exploit the full potential of low-carbon technologies, households should ideally co-adopt multiple low-carbon technologies. Whereas previous research primarily investigated predictors of single-technology adoption in isolation, here we focus on the co-adoption of multiple low-carbon technologies, including solar photovoltaics, stationary batteries, heat pumps, and electric vehicles, to examine the interconnections between adoption decisions and the potential of certain technologies to serve as “entry points” for the co-adoption of multiple low-carbon technologies. Based on a sample of 1967 homeowners, we identified unique demographic and psychological variables associated with co-adoption. We moreover observed specific co-adoption patterns across time in that the adoption of one technology increased the likelihood of adopting another technology. This effect, however, was primarily driven by co-adoption in close temporal proximity, pointing to opportunities for targeted policies that support technology bundles.

Film mulching is widely used as an agronomic practice to counteract water scarcity in arid and semi-arid areas. Although crop models have emerged as powerful tools for system studies and scenarios analysis, they have been rarely used in areas with severe drought and salinization and where mulching is being used as a management practice. An earlier study shown great modelling potential under severe salinity in southern Xinjiang, China. The model is WAVES (the WAter Vegetation Energy and Solute), while evaporation was overestimated in the earlier study without considering the mulching effect. In this study, we used a modified WAVES model by incorporating three functions working on potential evaporation, underlying surface albedo, and soil resistance into it to represent the mulching effect. Calibration and validation were conducted using cotton field experiments from 2 different years. Of the 3 functions evaluated, the one representing potential evaporation reduction exerted the highest modification effect on soil water status. The modified model better simulated evaporation, soil-water content, soil-salt content, leaf area index (LAI), and yield than the original model, decreasing normalized root mean square error (NRMSE) by 173%, 15%, 14%, 9%, and 35%, respectively. The modification effects were most significant during the seedling stage. In addition, the modified model produced a higher realistic evaporation (E)/evapotranspiration (ET) under the film mulching environment. These findings suggest that the modified WAVES model can be applied for crop management under film mulching, particularly in areas with low rainfall and high salinization.

Effective weed management in pastures is critical for maintaining the productivity of grazing land. Autonomous ground vehicles (AGVs) are increasingly being considered for weed localization and treatment in agricultural land. Weeds, however, can be difficult to distinguish from background plants, due to similarities in colour, shape and texture. While deep learning approaches can be used to solve the localization issue, they are computationally expensive, and require a large volume of training images in order to combat overfitting. In this paper we present a novel Extreme Learning Machine based network for segmenting weeds from the background pasture. The proposed method utilizes a combination of LBP, HOG and colour features, and is tested on four small datasets, achieving a high mean Intersection over Union of 87.1, 79.5, 81.6 and 87.6 for Bathurst burr, horehound, thistle and serrated tussock respectively.

Future agricultural systems should increase productivity and sustainability of food production and supply. For this, integrated and efficient capture, management, sharing, and use of agricultural and environmental data from multiple sources is essential. However, there are challenges to understand and efficiently use different types of agricultural and environmental data from multiple sources, which differ in format and time interval. In this regard, the role of emerging technologies is considered to be significant for integrated data gathering, analyses and efficient use. In this study, a concept was developed to facilitate the full integration of digital technologies to enhance future smart and sustainable agricultural systems. The concept has been developed based on the results of a literature review and diverse experiences and expertise which enabled the identification of stat-of-the-art smart technologies, challenges and knowledge gaps. The features of the proposed solution include: data collection methodologies using smart digital tools; platforms for data handling and sharing; application of Artificial Intelligent for data integration and analysis; edge and cloud computing; application of Blockchain, decision support system; and a governance and data security system. The study identified the potential positive implications i.e. the implementation of the concept could increase data value, farm productivity, effectiveness in monitoring of farm operations and decision making, and provide innovative farm business models. The concept could contribute to an overall increase in the competitiveness, sustainability, and resilience of the agricultural sector as well as digital transformation in agriculture and rural areas. This study also provided future research direction in relation to the proposed concept. The results will benefit researchers, practitioners, developers of smart tools, and policy makers supporting the transition to smarter and more sustainable agriculture systems.

Several craniofacial pathologies are present in an early adolescent from a cemetery (n = 22) associated with a Neolithic Funnel Beaker culture in Modřice, Czechia. The objective of the study was to document anomalies on the Modřice 3871 cranium, with an emphasis on investigating whether the mid-sagittal suture exhibited synostosis or bridging to account for the visible scaphocephaly. All available cranial and postcranial elements of the Modřice 3871 early adolescent were examined macroscopically. The cranial vault was subjected to radiography and compared to macroscopic views. Modřice 3871 is estimated to age to 12–14 years. Macroscopic examination and radiography support a diagnosis of mid-sagittal bridging rather than synostosis for this slender and anteroposteriorly elongated cranium. In comparison, the anterior sagittal, coronal and lambdoidal sutures are completely unfused. Craniofacial asymmetry, cribra orbitalia, porotic hyperostosis of the temporal and the presence of multiple wormian bones indicate additional maturational disruptions. The scaphocephaly observed in Modřice 3871 is not severe compared to modern clinical manifestations of craniosynostosis. Radiocarbon dated to 3,700–3,600 years BCE, Modřice 3871 presents one of the oldest recorded cases of scaphocephaly. The elongated vault is probably not the result of head-binding given the dearth of anthropogenic cranial reshaping in the Neolithic of Europe. This study adds to the growing recognition of prehistoric and historic craniofacial anomalies which will likely continue as additional human remains are excavated. In addition, the study increases the understanding of the lived experience of prehistoric individuals experiencing visible craniofacial pathologies such as cranial asymmetry and scaphocephaly.

Abstract Background Isolated ACL reconstructions (ACLR) demonstrate limitations in restoring native knee kinematics. This study investigates the knee mechanics of ACLR plus various anterolateral augmentations using a patient-specific musculoskeletal knee model. Materials and methods A patient-specific knee model was developed in OpenSim using contact surfaces and ligament details derived from MRI and CT data. The contact geometry and ligament parameters were varied until the predicted knee angles for intact and ACL-sectioned models were validated against cadaveric test data for that same specimen. Musculoskeletal models of the ACLR combined with various anterolateral augmentations were then simulated. Knee angles were compared between these reconstruction models to determine which technique best matched the intact kinematics. Also, ligament strains calculated by the validated knee model were compared to those of the OpenSim model driven by experimental data. The accuracy of the results was assessed by calculating the normalised RMS error (NRMSE); an NRMSE 60%). Similar errors were observed between ACL strain results (NRMSE > 60%). Other ligament comparisons were acceptable. All ACLR plus anterolateral augmentation models restored kinematics toward the intact state, with ACLR plus anterolateral ligament reconstruction (ACLR + ALLR) achieving the best match and the greatest strain reduction in ACL, PCL, MCL, and DMCL. Conclusion The intact and ACL-sectioned models were validated against cadaveric experimental results for all rotations. It is acknowledged that the validation criteria are very lenient; further refinement is required for improved validation. The results indicate that anterolateral augmentation moves the kinematics closer to the intact knee state; combined ACLR and ALLR provide the best outcome for this specimen.

One of the main sources of uncertainty in carbon budgets is that continental landscapes are made up of a heterogeneous mosaic of ecosystems. Here the authors put forward an integrative framework to improve estimates of land-atmosphere carbon exchange based on the accumulation of carbon in the landscape as constrained by its lateral export through rivers.

Everettians generally argue that their view recommends just the same rational choices as orthodoxy. In this note, however, we will show that Everettians should advocate non-standard choices in one specific kind of situation, namely situations where different people have unequal claims to an indivisible good.

How cells respond to denaturation of extracellular protein domains remained largely unknown. Here, authors describe an aggregation-dependent endocytosis pathway, facilitating uptake and degradation of antibody- and stress-induced protein aggregates.

El hemangioma fusocelular es un tumor vascular benigno poco frecuente. Se ha relacionado con el síndrome de Maffucci, el síndrome de Klippel-Trenaunay y otras malformaciones venosas. Habitualmente son nódulos dérmicos de color violáceo en las extremidades distales de niños y adultos jóvenes, sin predilección por ningún sexo. Se presenta el caso de una paciente de 22 años que padecía un nódulo subcutáneo, doloroso a la presión, en la pierna derecha. A la exploración física se observó una tumoración redondeada violácea de 1,5 cm. Se sospechó la presencia de un hemangioma. Se realizó una escisión simple y se envió al departamento de anatomía patológica. Se describió la muestra como nódulo intraluminal constituido por una proliferación de células de aspecto fusiforme con moderada atipia y aisladas figuras de mitosis y se confirmó el diagnóstico de hemangioma fusocelular de localización intravascular. El diagnóstico del hemangioma fusocelular es anatomopatológico y como tratamiento suele bastar la escisión simple, aunque frecuentemente recidivan. Dado que el hemangioma fusocelular es una entidad poco conocida y puede ser confundida con otras lesiones vasculares, se considera interesante la comunicación del presente caso. El conocimiento de este tipo de lesión puede aumentar los casos notificados.

When fuel materials for high-temperature gas-cooled nuclear reactors are quantification tested, significant analysis is required to establish their stability under various proposed accident scenarios, as well as to assess degradation over time. Typically, samples are examined by lab assistants trained to capture micrograph images used to analyze the degradation of a material. Analysis of these micrographs still require manual intervention which is time-consuming and can introduce human-error. While machine learning and computer vision models would be useful to this analysis, data for training such models is limited due to physical experiment costs, including lab hours and materials. This collaborative research are: 1) establishes an open dataset of micrographs and semantic labels named Graphite-23; 2) analyzes semantic segmentation architectures against the new data; and 3) contributes open source code for the community to progress research in degradation analysis of materials. A U-Net architecture with various backbones demonstrates competitive performance on the proposed dataset, with an mIoU up to 0.83, establishing a clear baseline for future research in this intersection of fields.

Enzymes are potent catalysts with high specificity and selectivity. To leverage nature’s synthetic potential for industrial applications, various protein engineering techniques have emerged which allow to tailor the catalytic, biophysical, and molecular recognition properties of enzymes. However, the many possible ways a protein can be altered forces researchers to carefully balance between the exhaustiveness of an enzyme screening campaign and the required resources. Consequently, the optimal engineering strategy is often defined on a case-by-case basis. Strikingly, while predicting mutations that lead to an improved target function is challenging, here we show that the prediction and exclusion of deleterious mutations is a much more straightforward task as analyzed for an engineered carbonic acid anhydrase, a transaminase, a squalene-hopene cyclase and a Kemp eliminase. Combining such a pre-selection of allowed residues with advanced gene synthesis methods opens a path toward an efficient and generalizable library construction approach for protein engineering. To give researchers easy access to this methodology, we provide the website LibGENiE containing the bioinformatic tools for the library design workflow.

Osteoporosis (OP) is a debilitating skeletal abnormality involving bone remodeling and bone cell homeostasis characterized by decreased bone strength and high fracture risk. A novel therapeutic intervention for OP by manipulating cellular autophagy–apoptosis processes to promote skeletal homeostasis is presented. Protective effects of the naturally occurring plant extract Liquiritigenin (LG) were demonstrated in an ovariectomy (OVX)-OP mouse model and preosteoblast MC3T3-E1 cells. Micro-CT and histological staining assessments of skeletal phenotype were applied alongside detection of autophagy activity in osteocytes and MC3T3-E1 cells by transmission electron microscopy (TEM). The effects of LG on chloroquine (CQ)- and the apoptosis-inducing TS-treated osteogenic differentiations and status of lysosomes within MC3T3-E1 cells were analyzed by Neutral red, Alizarin red S and alkaline phosphatase (ALP) staining and Western blot assays. Treatment with LG prevented bone loss, increased osteogenic differentiation in vivo and in vitro, and inhibited osteoclast formation to some extent. TEM analyses revealed that LG can improve auto-lysosomal degradation within osteocytes from OVX mice and MC3T3-E1 cells. The abnormal status of lysosomes associated with CQ and TS treatments was notably alleviated by LG which also reduced levels of apoptosis-induced inhibition of osteogenic differentiation and averted abnormal osteogenic differentiation as a consequence of a blockage in autolysosome degradation. Overall, LG stimulates bone growth in OVX mice through increased osteogenic differentiation and regulation of autophagy-apoptosis mechanisms, presenting an auspicious natural therapy for OP.

A novel manufacturing strategy for the detailed fabrication of complex and mechanically robust microwave components is presented. Additive printing of the full wax positive model with a multijet printer allows free shaping on the one hand, while metal casting provides mechanical stability for a variety of applications on the other. In addition to that a slotted waveguide model is used to improve the post-processing and performance. This combination is used with a rectangular waveguide for the E-band to demonstrate the performance of this manufacturing method at higher frequencies than previous publications. Measurements on the samples show comparable attenuation coefficients to the milled split-block counterpart, i.e., less than 5dB/m, a good root mean square (RMS) surface roughness of the inner surfaces with $S_{\textrm {q}}$ = $5.85\; {\mathrm { \mu \text {m} }}$ and astonishingly fine tolerances of 8.8±40.3 ${\mathrm { \mu \text {m} }}$ overall. Comparisons are also made between other published additive manufacturing processes.

In this work, the authors show that metamorphism in the post-translationally modified TDP-43 prion-like domain encodes determinants that command mechanisms with major relevance in disease and stress the relevance of post-translationally modified chains as the targets for disease intervention.

miRNA-125b, a translational repressor of p53, undergoes initial HuR-mediated exosomal export in response to DNA damage, leading to p53 upregulation, which in turn induces transcription and processing of miR-125b causing inhibition of p53 expression.

Background: Identifying mechanisms of major depressive disorder that continue into remission is critical, as these mechanisms may contribute to subsequent depressive episodes. Biobehavioral markers related to depressogenic self-referential processing biases have been identified in adults with depression. Thus, we investigated whether these risk factors persisted during remission as well as contributed to the occurrence of stress and depressive symptoms over time. Methods: At baseline, adults with remitted depression (n = 33) and healthy control subjects (n = 33) were administered diagnostic and stress interviews as well as self-report symptom measures. In addition, participants completed a self-referential encoding task while electroencephalography data were acquired. Stress interviews and self-report symptom measures were readministered at the 6-month follow-up assessment. Results: Drift diffusion modeling showed that compared with healthy individuals, adults with remitted depression exhibited a slower drift rate to negative stimuli, indicating a slower tendency to reject negative stimuli as self-relevant. At the 6-month follow-up assessment, a slower drift rate to negative stimuli predicted greater interpersonal stress severity among individuals with remitted depression but not healthy individuals while controlling for both baseline depression symptoms and interpersonal stress severity. Highlighting the specificity of this effect, results were nonsignificant when predicting noninterpersonal stress. For self-relevant positive words endorsed, adults with remitted depression exhibited smaller left- than right-hemisphere late positive potential amplitudes; healthy control subjects did not show hemispheric differences. Conclusions: Self-referential processing deficits persist into remission. In line with the stress generation framework, these biases predicted the occurrence of interpersonal stress, which may provide insight about a potential pathway for the re-emergence of depressive symptoms.

Abstract Background After the emergence of the first vaccines against the COVID-19, public health authorities have promoted mass vaccination in order to achieve herd immunity and reduce the effects of the disease. Vaccination rates have differed between countries, depending on supply (availability of resources) and demand (altruism and resistance to vaccination) factors. Methods This work considers the hypothesis that individuals’ health altruism has been an important factor to explain the different levels of vaccination between countries, using the number of transplants as a proxy for altruism. Taking European Union’s countries to remove, as far as possible, supply factors that might affect vaccination, we carry out cross-sectional regressions for the most favorable date of the vaccination process (maximum vaccination speed) and for each month during the vaccination campaign. Results Our findings confirm that altruism has affected vaccination rates against the COVID-19. We find a direct relationship between transplants rates (proxy variable) and vaccination rates during periods in which the decision to be vaccinated depended on the individual’s choice, without supply restrictions. The results show that other demand factors have worked against vaccination: political polarization and belonging to the group of countries of the former Eastern bloc. Conclusions Altruism is a useful tool to define future vaccination strategies, since it favors the individuals’ awareness for vaccination.

Background and Aims: Primary sclerosing cholangitis (PSC) is a probable autoimmune liver disease characterized by persistent and progressive biliary inflammation that leads to biliary infection, cirrhosis, or cholangiocarcinoma. Genome-wide omics data are scarce regarding this severe disease. Methods: MEDLINE database gene prioritization by text mining (biliary inflammation, biliary fibrosis, biliary stasis) was integrated in distinct omics data: (1) PSC liver transcriptome training and validation cohorts, (2) farnesoid X receptor (FXR) mice liver transcriptome subjected to an FXR agonist or FXR knockout mice; (3) liver single-cell transcriptome of the Abcb4−/− mice model of PSC. Results: A liver molecular network highlighted the involvement of nuclear receptor subfamily 0 group B member 2 (NR0B2) and its associated nuclear receptor FXR in a metabolic cascade that may influence the immune response. NR0B2 upregulation in PSC liver was independent of gender, age, body mass index, liver fibrosis, and PSC complications. Heterogeneity of NR0B2 upregulation was found in cholangiocyte cell types in which the NR0B2-based cell fate decision revealed the involvement of several metabolic pathways for detoxification (sulfur, glutathione derivative, and monocarboxylic acid metabolisms). Genes potentially implicated in carcinogenesis were also discovered on this cholangiocyte trajectory: GSTA3, inhibitor of DNA binding 2, and above all, TMEM45A, a transmembrane molecule from the Golgi apparatus considered as oncogenic in several cancers. Conclusion: By revisiting PSC through PubMed data mining, we evidenced the early cholangiocyte deregulation of NR0B2, highlighting a metabolic and premalignant reprogramming of the cholangiocyte cell type. The therapeutic targeting of NR0B2 could potentiate that of FXR and enable action on early events of the disease and prevent its progression.

Effective and practical measurement methods for assessing field inoculation experiments are needed to identify inoculants that could improve lucerne establishment. In this study, assessment potential of different existing measurement methods (plant height, Dualex 4 Scientific leaf-clip meter, GreenSeeker handheld crop sensor, drone-acquired orthomosaic calculation, yield, nutrient analysis and nodule assessment) were compared across 12 inoculation treatments applied to lucerne (Medicago sativa L.) at 3 sites. F-values were used to compare the potential of different methods to separate inoculation treatments. The handheld GreenSeeker measuring normalised difference vegetation index (NDVI) showed the greatest potential for separating inoculation treatments in fields where lucerne had not previously been cultivated, followed by visible atmospherically resistant index (VARI) and green-red vegetation index (GRVI) from drone-acquired orthomosaics. These methods are non-destructive, low cost, require low labour input, fast, and do not require sample preparation, and thus are efficient measurement methods for disaggregating treatments in field inoculation experiments.

Future climate change will affect many human activities and sectors. Among those, the built environment will face several challenges about the varying climate conditions, including increased demand for summer cooling and related heat stress indoor conditions. In this framework, the paper presents the results of a recent study that investigated the global warming impacts on energy demand and indoor climate comfort for an office building in Stockholm over the next 50-60 years. The future climate conditions were investigated in 2070 and 2080 with different climate morphing approaches. Three different passive cooling solutions to decrease the cooling demand (such as external roller shade, electrochromic glazing, and internally ventilated shading) have been preliminarily assessed about thermal and optical properties, then integrated into the building energy simulation software IDA-ICE to evaluate the building energy performances regarding different Swedish climates, and finally economically estimated with a simplified LCC analysis. The results indicated that an increment of the cooling demand from 3 up to 24 kWh/m2 and a reduction of the heating usage of 20-50 % will be experienced in 50-60 years. The different weather data morphing approaches displayed the inherent uncertainties when future evaluations are performed, although similar weather patterns were found. The improvement of the solar and optical properties indicated a lower cooling and ventilation usage with reductions of about 10-16 %. The electrochromic technology reported the lowest cooling demand (decrease up to 24 %), while the internally ventilated shading option outperformed the others with anannual energy consumption 4-9 % lower and the lowest LCC.

Abstract The extent of elective nodal irradiation (ENI) in patients undergoing definitive chemoradiotherapy (dCRT) for esophageal squamous cell carcinoma (ESCC) remains unclear. The aim of this dosimetric study was to evaluate the extent of incidental nodal irradiation using modern radiation techniques. A planning target volume (PTV) was generated for 30 patients with node-negative esophageal carcinoma (13 cervical/upper third, 7 middle third, 10 lower third/abdomen). Thereby, no elective nodal irradiation (ENI) was intended. Both three-dimensional conformal radiotherapy (3D-CRT) and volumetric-modulated arc therapy (VMAT) treatment plans (50 Gy in 25 fractions) were calculated for all patients. Fifteen nodal stations were contoured according to the definitions of the AJCC and investigated in regard to dosimetric parameters. Compared to 3D-CRT, VMAT was associated with lower dose distribution to the organs at risk (lower Dmean, V20 and V30 for the lungs and lower Dmean and V30 for the heart). For both techniques, the median Dmean surpassed 40 Gy in 12 of 15 (80%) nodal stations. However, VMAT resulted in significantly lower Dmeans and equivalent uniform doses (EUD) compared to 3D-CRT for eight nodal stations (1L, 2L, 2R, 4L, 7, 8L, 10L, 15), while differences did not reach significance for seven nodal station (1R, 4R, 8U, 8M, 10R, 16). For dCRT of ESCC, the use of VMAT was associated with significantly lower median (incidental) doses to eight of 15 regional lymph node areas compared to 3D-CRT. However, given the small absolute differences, these differences probably do not impair (regional) tumor control rates.

Abstract Purpose Soft tissue injury and soft tissue injury as risk factors for nonunion following trochanteric femur fractures (TFF) are marginally investigated. The aim of this study was to identify risk factors for impaired fracture healing in geriatric trauma patients with TFF following surgical treatment with a femoral nail. Methods This retrospective cohort study included geriatric trauma patients (aged > 70 years) with TFF who were treated with femoral nailing. Fractures were classified according to AO/OTA. Nonunion was defined as lack of callus-formation after 6 months, material breakage, and requirement of revision surgery. Risk factors for nonunion included variables of clinical interest (injury pattern, demographics, comorbidities), as well as type of approach (open versus closed) and were assessed with uni- and multivariate regression analyses. Results This study included 225 geriatric trauma patients. Nonunion was significantly more frequently following AO/OTA 31A3 fractures (N = 10, 23.3%) compared with AO/OTA type 31A2 (N = 6, 6.9%) or AO/OTA 31A1 (N = 3, 3.2%, p

Abstract Monitoring the emergence of new SARS-CoV-2 variants is important to detect potential risks of increased transmission or disease severity. We investigated the identification of SARS-CoV-2 variants from real-time reverse transcriptase polymerase chain reaction (RT-PCR) routine diagnostics data. Cycle threshold (Ct) values of positive samples were collected from April 2021 to January 2022 in the Northern Metropolitan Area of Barcelona (n = 15,254). Viral lineage identification from whole genome sequencing (WGS) was available for 4618 (30.3%) of these samples. Pairwise differences in the Ct values between gene targets (ΔCt) were analyzed for variants of concern or interest circulating in our area. A specific delay in the Ct of the N-gene compared to the RdRp-gene (ΔCtNR) was observed for Alpha, Delta, Eta and Omicron. Temporal differences in ΔCtNR correlated with the dynamics of viral replacement of Alpha by Delta and of Delta by Omicron according to WGS results. Using ΔCtNR, prediction of new variants of concern at early stages of circulation was achieved with high sensitivity and specificity (91.1% and 97.8% for Delta; 98.5% and 90.8% for Omicron). Thus, tracking population-wide trends in ΔCt values obtained from routine diagnostics testing in combination with WGS could be useful for real-time management and response to local epidemics.

Abstract Background Large-scale trials have shown that hypofractionated adjuvant breast radiotherapy was as effective in terms of survival and local control as conventional fractionated radiotherapy, and acute toxicity was reduced with hypofractionated radiotherapy. However, there is a lack of data about the toxicity of breast with regional nodal irradiation (RNI). The aim of this study was to assess the effect of fractionation on radiation-related acute skin toxicity in patients receiving RNI in addition to whole-breast or chest wall irradiation, using real-life data. Methods We conducted a prospective, multicenter cohort study with systematic computerized data collection integrated into Mosaiq®. Three comprehensive cancer centers used a standardized form to prospectively collect patient characteristics, treatment characteristics and toxicity. Results Between November 2016 and January 2022, 1727 patients were assessed; 1419 (82.2%) and 308 (17.8%) patients respectively received conventional fractionated and hypofractionated radiation therapy. Overall, the incidence of acute grade 2 or higher dermatitis was 28.4% (490 patients). Incidence was lower with hypofractionated than with conventional fractioned radiation therapy (odds ratio (OR) 0.34 [0.29;0.41]). Two prognostic factors were found to increase the risk of acute dermatitis, namely 3D (vs IMRT) and breast irradiation (vs chest wall). Conclusion Using real-life data from unselected patients with regional nodal irradiation, our findings confirm the decreased risk of dermatitis previously reported with hypofractionated radiation therapy in clinical trials. Expansion of systematic data collection systems to include additional centers as well as dosimetric data is warranted to further evaluate the short- and long-term effects of fractionation in real life.

Abstract Background SARS-CoV-2 infection is associated with a significant risk of hospitalisation, death, and prolonged impact on quality of life. Evaluation of new treatment options and optimising therapeutic management of people hospitalised with SARS-CoV-2 infection remains essential, but rapid changes in pandemic conditions and potential therapies have limited the utility of traditional approaches to randomised controlled trials. Methods ASCOT ADAPT is an international, investigator-initiated, adaptive platform, randomised controlled trial of therapeutics for non-critically ill patients hospitalised with COVID-19. The study design is open label and pragmatic. Potential participants are hospitalised adults with PCR confirmed, symptomatic, SARS-CoV-2 infection, within 14 days of symptom onset. Domains include antiviral, antibody and anticoagulant interventions, with a composite primary outcome of 28-day mortality or progression to intensive-care level respiratory or haemodynamic support. Initial interventions include intravenous nafamostat and variable dose anticoagulation. A range of secondary endpoints, and substudies for specific domains and interventions are outlined. Discussion This paper presents the trial protocol and management structure, including international governance, remote site monitoring and biobanking activities and provides commentary on ethical and pragmatic considerations in establishing the ASCOT ADAPT trial under pandemic conditions. Trial registration Australian and New Zealand Clinical Trials Registry (ACTRN12620000445976) and ClinicalTrials.gov (NCT04483960).

This Guide for Living Donor Kidney Transplantation (LDKT) has been prepared with the sponsorship of the Spanish Society of Nephrology (SEN), the Spanish Transplant Society (SET), and the Spanish National Transplant Organization (ONT). It updates evidence to offer the best chronic renal failure treatment when a potential living donor is available. The core aim of this Guide is to supply clinicians who evaluate living donors and transplant recipients with the best decision-making tools, to optimise their outcomes.Moreover, the role of living donors in the current KT context should recover the level of importance it had until recently. To this end the new forms of incompatible HLA and/or ABO donation, as well as the paired donation which is possible in several hospitals with experience in LDKT, offer additional ways to treat renal patients with an incompatible donor.Good results in terms of patient and graft survival have expanded the range of circumstances under which living renal donors are accepted. Older donors are now accepted, as are others with factors that affect the decision, such as a borderline clinical history or alterations, which when evaluated may lead to an additional number of transplantations.This Guide does not forget that LDKT may lead to risk for the donor. Pre-donation evaluation has to centre on the problems which may arise over the short or long-term, and these have to be described to the potential donor so that they are able take them into account. Experience over recent years has led to progress in risk analysis, to protect donors’ health. This aspect always has to be taken into account by LDKT programmes when evaluating potential donors.Finally, this Guide has been designed to aid decision-making, with recommendations and suggestions when uncertainties arise in pre-donation studies. Its overarching aim is to ensure that informed consent is based on high quality studies and information supplied to donors and recipients, offering the strongest possible guarantees. Resumen: Esta guía de recomendaciones para el TR de donante vivo (TRDV) es un documento elaborado con el patrocinio de la Sociedad Española de Nefrología, la Sociedad Española de Trasplantes y la Organización Nacional de Trasplantes que actualiza la calidad de la evidencia disponible para ofrecer el mejor tratamiento de la insuficiencia renal crónica cuando se disponga de un donante vivo potencial. El objetivo principal de esta guía es proporcionar a los profesionales con responsabilidad en los estudios previos del donante vivo y del receptor trasplantado, las mejores herramientas para tomar decisiones en beneficio del donante vivo y del receptor del trasplante.Además, en el contexto actual del TR, el donante vivo debe recuperar el protagonismo que alcanzó en un pasado reciente. Para ello, las nuevas modalidades de donación HLA y/o ABO incompatible, así como la donación cruzada disponibles en diversos centros con experiencia en TRDV, son oportunidades adicionales para el tratamiento de enfermos renales que tienen un donante incompatible.Los buenos resultados en supervivencia del paciente y del injerto están ampliando las circunstancias de aceptación de donantes vivos de riñón, incluyendo donantes de mayor edad y otros con algunos condicionantes que incluyen antecedentes o alteraciones límite que, cuando son evaluados con criterios objetivos, pueden aportar un numero adicional de trasplantes.No se ha obviado en esta guía que el TRDV puede representar algún riesgo para el que dona. Estos problemas que pueden aparecer a corto o largo plazo tienen que ser objeto principal de valoración previa a la donación y presentados al potencial donante para que en ejercicio de su autonomía los asuma o rechace. La experiencia acumulada en los últimos años ha permitido avanzar en el análisis de riesgos para preservar la salud de los donantes, aspecto que debe estar siempre presente en los responsables de programas de TRDV cuando se procede al estudio de idoneidad de un potencial donante.Finalmente, esta guía ha sido estructurada para facilitar la toma de decisiones con recomendaciones y sugerencias ante incertidumbres derivadas de los resultados en los exhaustivos estudios predonación. Y todo ello, con el objetivo de que el consentimiento informado que debe certificar la calidad de los estudios y la información proporcionada a donante y receptor, alcancen las mayores garantías posibles.

Federated ML (FL) provides an alternative to train accurate and generalizable ML models, by only sharing numerical model updates. Here, the authors present the largest FL study to-date to generate an automatic tumor boundary detector for glioblastoma.

Abstract In Western‐democratic countries, it is widely accepted that affected communities should be involved in natural resource planning and decisions. This is especially so when the well‐being of diverse communities is directly involved, and where alternative future options are being considered. Although there is an agreement that ‘values’ and ‘well‐being’, in some form, guide decisions, there is no consensus on the well‐being framework(s) that might be used in participatory planning. To assist a multicultural group in assessing alternative future development scenarios for the Martuwarra (Fitzroy River) in Western Australia, we developed a well‐being framework that culturally diverse communities could share and use to discuss and assess scenarios. In this paper, we aim to evaluate the effectiveness of the well‐being framework used to assess the potential impacts of scenarios by (i) analysing how effectively participants used the well‐being framework; (ii) verifying whether the well‐being framework was sensitive to the cultural diversity of participants and (iii) direct evaluation by workshop participants. Our analysis shows that participants effectively applied most well‐being categories, and the framework was sensitive to the cross‐cultural context of the application by capturing Aboriginal cultural elements. However, the approach can be improved by including principles of behaviour; producing a more complete system model; and reviewing and amending the well‐being categories in more extensive community consultation. We conclude that the interaction among different worldviews generated valuable knowledge and that, with further adaptation, the framework shows promise for applications involving similar tasks in culturally diverse contexts. Read the free Plain Language Summary for this article on the Journal blog.

The digital revolution has brought ethical crossroads of technology and behavior, especially in the realm of sustainable cities. The need for a comprehensive and constructive ethical framework is emerging as digital platforms encounter trouble to articulate the transformations required to accomplish the sustainable development goal (SDG) 11 (on sustainable cities), and the remainder of the related SDGs. The unequal structure of the global system leads to dynamic and systemic problems, which have a more significant impact on those that are most vulnerable. Ethical frameworks based only on the individual level are no longer sufficient as they lack the necessary articulation to provide solutions to the new systemic challenges. A new ethical vision of digitalization must comprise the understanding of the scales and complex interconnections among SDGs and the ongoing socioeconomic and industrial revolutions. Many of the current social systems are internally fragile and very sensitive to external factors and threats, which lead to unethical situations. Furthermore, the multilayered net-like social tissue generates clusters of influence and leadership that prevent communities from a proper development. Digital technology has also had an impact at the individual level, posing several risks including a more homogeneous and predictable humankind. To preserve the core of humanity, we propose an ethical framework to empower individuals centered on the cities and interconnected with the socioeconomic ecosystem and the environment through the complex relationships of the SDGs. Only by combining human-centered and collectiveness-oriented digital development will it be possible to construct new social models and interactions that are ethical. Thus, it is necessary to combine ethical principles with the digital innovation undergoing in all the dimensions of sustainability.

Abstract Background Primary treatment of central neurocytomas is surgical resection. Gamma Knife surgery is considered a valuable therapeutic option in case of residual (after subtotal resection) or recurrent central neurocytomas. Here, we focused on the role of F-18 fluroethyltyrosine as a marker to document tumor progression after initial resection, in the context of an atypical central neurocytoma. We also describe MIB-1’s role in evaluating therapeutic decision-making. Case presentation Two patients with central neurocytomas were treated by Gamma Knife surgery in our center. The first case (31-year-old Caucasian male) had atypical central neurocytoma. Four and a half years after surgical resection, magnetic resonance imaging and F-18 fluroethyltyrosine documented clear progression of residual central neurocytoma, further treated by Gamma Knife surgery (18 Gy at 50%, target volume 1.4 cc, and prescription isodose volume 1.8 cc). The initial post-Gamma Knife surgery clinical course was uneventful, with progressive volumetric reduction of residual tumor up to 4.5 years, when out-of-field recurrence was suspected and confirmed by local F-18 fluroethyltyrosine hyperactivity. Second single-fraction Gamma Knife surgery was performed (18 Gy at 50%, target volume 0.49 cc, prescription isodose volume 0.72 cc). The second (32-year-old Caucasian female) had previous subtotal resection and typical central neurocytoma. Seven years later, she had residual tumor progression. Single-fraction Gamma Knife surgery was performed (16 Gy at 50% isodose line, target volume 1.7 cc, and prescription isodose volume 2.5 cc). Last follow-up showed tumor volume reduction. Follow-up magnetic resonance imaging showed important volumetric reduction of both treated lesions. Conclusions In atypical central neurocytomas, F-18 fluroethyltyrosine could be used as postoperative examination to detect small tumor remnants, follow-up evaluation following the Gamma Knife surgery or, in select cases, following surgical resection. The role of MIB-1 is important in therapeutic decision-making, as tumors with MIB-1 exceeding 2% are characterized by more aggressive clinical course. Single-fraction Gamma Knife surgery remains a valuable therapeutic option for postoperative residual atypical central neurocytomas and central neurocytoma recurrences.

The extension of biology with a more data-centric component offers new opportunities for discovery. To enable investigations that rely on third-party data, the infrastructure that retains data and allows their re-use should, arguably, enable transactions that relate to any and all biological processes. The assembly of such a service-oriented and enabling infrastructure is challenging. Part of the challenge is to factor in the scope and scale of biological processes. From this foundation can emerge an estimate of the number of discipline-specific centres which will gather data in their given area of interest and prepare them for a path that will lead to trusted, persistent data repositories which will make fit-for-purpose data available for re-use. A simple model is presented for the scope and scale of life sciences. It can accommodate all known processes conducted by or caused by any and all organisms. It is depicted on a grid, the axes of which are (x) the durations of the processes and (y) the sizes of participants involved. Both axes are presented in log10 scales, and the grid is divided into decadal blocks with ten fold increments of time and size. Processes range in duration from 10-17 seconds to 3.5 billion years or more, and the sizes of participants range from 10-15 to 1.3 107 metres. Examples are given to illustrate the diversity of biological processes and their often inexact character. About half of the blocks within the grid do not contain known processes. The blocks that include biological processes amount to ‘Nature’s envelope’, a valuable rhetorical device onto which subdisciplines and existing initiatives may be mapped, and from which can be derived some key requirements for a comprehensive data infrastructure.

The SMC5/6 complex is critical for genome stability. Here, the authors identify mutations in SLF2 and SMC5 as cause of Atelís Syndrome characterized by microcephaly, short stature, anemia, segmented chromosomes and mosaic variegated hyperploidy.

Abstract Background Squamous cell carcinoma is the most common malignancy of the oral cavity. Primary treatment involves surgical resection of the tumour with a surrounding margin. Historically, the most commonly accepted margin clearance is 5 mm. This distance is controversial, with recent publications suggesting closer margins do not impact local recurrence and survival. The objective of this study is to determine the closest surgical margin that does not impact local recurrence and overall survival. Methods A retrospective review of the London Health Sciences Centre Head and Neck Multidisciplinary Clinic between 2010 and 2018 was performed. Demographic data, subsite, tumour staging, treatment modality, margins, and survival outcomes were analyzed. The primary endpoint was local recurrence free survival. Secondary endpoints included recurrence-free survival and overall survival. Descriptive statistics, as well as univariable and multivariable Cox proportional hazards regression modelling were performed for all patients. Results Four-hundred and twelve patients were included in the study, with a median follow-up of 3.3 years. On univariable analysis, positive margins and margins 5 mm. Patients with surgical margins > 1 mm experienced similar outcomes to those with margins > 5 mm. Multivariable analysis identified age of diagnosis, alcohol consumption, pathological tumour and nodal category as predictors of local recurrence free survival. Conclusions Although historical margins for head and neck surgery are 5 mm, similar outcomes were observed for margins greater than 1 mm in our cohort. These findings require validation through multi-institutional collaborative efforts. Graphical abstract

Abstract Background Empirical estimates of health system opportunity costs have been suggested as a basis for the cost-effectiveness threshold to use in Health Technology Assessment. Econometric methods have been used to estimate these in several countries based on data on spending and mortality. This study examines empirical evidence on four issues: non-linearity of the relationship between spending and mortality; the inclusion of outcomes other than mortality; variation in the efficiency with which expenditures generate health outcomes; and the relationship among efficiency, mortality rates and outcome elasticities. Methods Quantile Regression is used to examine non-linearities in the relationship between mortality and health expenditures along the mortality distribution. Data Envelopment Analysis extends the approach, using multiple measures of health outcomes to measure efficiency. These are applied to health expenditure data from 151 geographical units (Primary Care Trusts) of the National Health Service in England, across eight different clinical areas (Programme Budget Categories), for 3 fiscal years from 2010/11 to 2012/13. Results The results suggest differences in efficiency levels across geographical units and clinical areas as to how health resources generate outcomes, which indicates the capacity to adjust to a decrease in health expenditure without affecting health outcomes. Moreover, efficient units have lower absolute levels of mortality elasticity to health expenditure than inefficient ones. Conclusions The policy of adopting thresholds based on estimates of a single system-wide cost-effectiveness threshold assumes a relationship between expenditure and health outcomes that generates an opportunity cost estimate which applies to the whole system. Our evidence of variations in that relationship and therefore in opportunity costs suggests that adopting a single threshold may exacerbate the efficiency and equity concerns that such thresholds are designed to counter. In most health care systems, many decisions about provision are not made centrally. Our analytical approach to understanding variability in opportunity cost can help policy makers target efficiency improvements and set realistic targets for local and clinical area health improvements from increased expenditure.

Studies the nature and economic significance of knowledge. Ways in which the concepts of tacitness and codification have come to be employed by economists; Reconceptualization of the aspects of knowledge production and distribution activities; Alternative framework for the study of knowledge codification activities.

Community and citizen science (CCS) projects – initiatives that involve public participation in scientific research – can both sustain and expand long-term monitoring of large dam removal projects. In this article, we discuss our perspectives on CCS associated with the Elwha River dam removals. We summarize how the public has been or could be involved in monitoring and distill lessons learned for other large dam removal projects. Much of the Elwha monitoring involved technical field work requiring training and incurring potential liability risks, guiding projects towards smaller-scale public involvement. Partnering with organizations that have capacity for volunteer management expanded CCS opportunities and provided logistical support to project managers committed to public engagement. We found that many projects engaged with students and/or with paid or unpaid interns; compensating participants in various ways can help to create reciprocal relationships that support long-term monitoring. In the future, other large dam removals could consider planning ahead for community involvement in dam removal monitoring to accommodate the technical and potentially hazardous nature of the work – broadening who may be able to participate. In addition, involving community members in setting research agendas could be an important first step in engaging them in long-term monitoring, in turn facilitating multi-generational research at the timescale of landscape-level changes. Finally, explicit relationship-building with Indigenous communities can enhance the benefits of community engagement in dam removal science for all involved.

BackgroundIntensity-modulated conformal radiotherapy (IMRT) has become the technique of choice for the treatment of locally advanced or inoperable non-small cell lung cancer (NSCLC). Nevertheless, this technique presents dosimetric uncertainties, particularly in treating moving targets such as pulmonary neoplasms. Moreover, it theoretically increases the risk of isolated nodal failure (INF) due to reduced incidental irradiation.ObjectiveThe objective of this study was to evaluate the efficacy and safety of IMRT in patients with inoperable NSCLC and to describe the pattern of relapses.MethodsPatients with locally advanced NSCLC treated with radiotherapy and chemotherapy between 2015 and 2018 at the Oscar Lambret Center were retrospectively included in the study. Overall and progression-free survival were estimated using the Kaplan–Meier method. The cumulative incidence of the different components of relapse was estimated using the Kalbfleisch and Prentice method. Prognostic factors for relapse/death were investigated using the Cox model. A comparison with literature data was performed using a one-sample log-rank test.ResultsSeventy patients were included, and 65 patients (93%) had stage III disease. All the patients received chemotherapy, most frequently with cisplatin and navelbine. The dose received was 66 Gy administered in 33 fractions. The median follow-up and survival were 49.1 and 39.1 months, respectively. A total of 35 deaths and 43 relapses, including 29 with metastatic components, were reported. The overall survival rates at 1 and 2 years were 80.2% (95% confidence interval 68.3%-88.0%) and 67.2% (95% confidence interval 54.2%-77.3%), respectively. Locoregional relapse was observed in 14 patients, including two INF, one of which was located in the lymph node area adjacent to the clinical target volume. Median relapse-free survival was 15.2 months. No variable was statistically associated with the risk of relapse/death in multivariate analysis. Seven patients (10%) experienced grade 3 or higher toxicity.ConclusionThe use of IMRT for locally advanced or inoperable NSCLC led to favorable long-term clinical outcomes. The rate of locoregional relapse, particularly isolated lymph node failure, was low and comparable with that of the three-dimensional radiotherapy series, as was the rate of early and late toxicities.