Spatial correlation between in vivo imaging and immunohistochemical biomarkers: A methodological study.

In this study, we present a method that enables voxel-by-voxel comparison of in vivo imaging to immunohistochemistry (IHC) biomarkers. As a proof of concept, we investigated the spatial correlation between dynamic contrast enhanced (DCE-)CT parameters and IHC biomarkers Ki-67 (proliferation), HIF-1α (hypoxia), and CD45 (immune cells). 54 whole-mount tumor slices of 15 laryngeal and hypopharyngeal carcinomas were immunohistochemically stained and digitized. Heatmaps of biomarker positivity were created and registered to DCE-CT parameter maps. The adiabatic approximation to the tissue homogeneity model was used to fit the following DCE parameters: Ktrans (transfer constant), Ve (extravascular and extracellular space), and Vi (intravascular space). Both IHC and DCE maps were downsampled to 4 × 4 × 3 mm[3] voxels. The mean values per tumor were used to calculate the between-subject correlations between parameters. For the within-subject (spatial) correlation, values of all voxels within a tumor were compared using the repeated measures correlation (rrm). No between-subject correlations were found between IHC biomarkers and DCE parameters, whereas we found multiple significant within-subject correlations: Ve and Ki-67 (rrm = -0.17, P < .001), Ve and HIF-1α (rrm = -0.12, P < .001), Ktrans and CD45 (rrm = 0.13, P < .001), Vi and CD45 (rrm = 0.16, P < .001), and Vi and Ki-67 (rrm = 0.08, P = .003). The strongest correlation was found between IHC biomarkers Ki-67 and HIF-1α (rrm = 0.35, P < .001). This study shows the technical feasibility of determining the 3 dimensional spatial correlation between histopathological biomarker heatmaps and in vivo imaging. It also shows that between-subject correlations do not reflect within-subject correlations of parameters.

Mind-body practices for people living with dementia and their family carers: a systematic review.

INTRODUCTION: People with dementia and their family carers may benefit from non-pharmacological interventions, including mind-body (MB-) practices, which can improve physical and mental health by inducing relaxation. This systematic review provides an overview of availability and effects of MB-practices. CONTENT: The authors performed a systematic search in PubMed, Embase, Emcare, Web of Science, Cochrane Library, PsycINFO, China National Knowledge Infrastructure and Academic Search Premier on February 1, 2024. Research papers on MB-practices for people with dementia and/or their family carers in English, Chinese, Japanese, German, French and Dutch were included if a full text was available. Selection of included articles, data extraction and methodological quality assessments were conducted by two researchers. SUMMARY: Of the 130 included studies, 100 (77 %) were of high quality. Traditional Chinese Medicine (TCM) and touch interventions for people with dementia, and meditations for family carers resulted in improvements in respectively cognition and neuropsychiatric symptoms, and mental health. Lack of evidence for other MB-practices is related to small numbers of studies, fragmented use of outcome measures and mixed findings. OUTLOOK: MB-practices showed promising results. We recommend implementation and further research of TCM- and touch interventions for people with dementia as well as meditations for family carers. We suggest a cross-over of the promising results of one group to be studied in the other group.

The Development and Characteristics of Planetary Health in Medical Education: A Scoping Review.

PURPOSE: Climate change, biodiversity loss, and other ecological crises threaten human health globally. The interrelation between human health and ecosystems is addressed in the emerging field of planetary health. Ecological crises have created an urgency to integrate planetary health, including sustainable health care, into medical education. To facilitate integration and guide future research, this review aims to provide an overview of the existing literature about planetary health in medical education. METHOD: The authors conducted a scoping review using the conventional methodological framework for scoping studies. They performed a comprehensive search in 7 databases without language restrictions in March 2022. Two researchers independently extracted data. The team analyzed the data using data-driven thematic analysis, content analysis, and qualitative summarizing. Data were structured according to the Curriculum Development for Medical Education: A Six-Step Approach. RESULTS: The authors identified 3,703 unique publications, of which 127 were included. Articles predominantly (71%, n = 90) covered the call to integrate planetary health in medical education (step 1: general needs assessment). Many publications (24%, n = 31) proposed learning objectives (step 3); these mainly concerned raising awareness while few concerned action perspectives. Publications limitedly reported on the final steps of curriculum development. Only 2 covered a full cycle of curriculum development. Most were published recently, with first authors mainly from Europe and North America. CONCLUSIONS: Planetary health in medical education is an urgent and hot topic. Literature focused predominantly on why planetary health should be integrated in medical education and what should be covered. The authors recommend future research and education development to shift to how to do so, especially in evaluation and feedback. Research and education development needs to be conducted and reported on systematically and underpinned by educational principles. Lastly, it would benefit from perspectives beyond 'Western-based' ones.

Inconsistent definitions of prolonged labor in international literature: a scoping review.

Objective: Prolonged labor is the commonest indication for intrapartum cesarean section, but definitions are inconsistent and some common definitions were recently found to overestimate the speed of physiological labor. The objective of this review is to establish an overview of synonyms and definitions used in the literature for prolonged labor, separated into first and second stages, and establish types of definitions used. Data sources: A systematic search was conducted in PubMed, Embase, Web of Science, Cochrane Library, Emcare, and Academic Search Premier. Study eligibility criteria: All articles in English that (1) attempted to define prolonged labor, (2) included a definition of prolonged labor, or (3) included any synonym for prolonged labor, were included. Methods: Data on study design, year of publication, country or region of origin, synonyms used, definition of prolonged first and/or second stage, and origin of provided definition (if not primarily established by the study) were collected into a database. Results: In total, 3402 abstracts and 536 full-text papers were screened, and 232 papers were included. Our search established 53 synonyms for prolonged labor. Forty-three studies defined prolonged labor and 189 studies adopted a definition of prolonged labor. Definitions for prolonged first stage of labor were categorized into: time-based (n=14), progress-based (n=12), clinician-based (n=5), or outcome-based (n=4). For the 33 studies defining prolonged second stage, the majority of definitions (n=25) were time-based, either based on total duration or duration of no descent of the presenting part. Conclusions: Despite efforts to arrive at uniform labor curves, there is still little uniformity in definitions of prolonged labor. Consensus on which definition to use is called for, in order to safely and respectfully allow physiological labor progress, ensure timely management, and assess and compare incidence of prolonged labor between settings.

Criteria for the diagnosis of extranodal extension detected on radiological imaging in head and neck cancer: Head and Neck Cancer International Group consensus recommendations.

Extranodal extension of tumour on histopathology is known to be a negative prognostic factor in head and neck cancer. Compelling evidence suggests that extranodal extension detected on radiological imaging is also a negative prognostic factor. Furthermore, if imaging detected extranodal extension could be identified reliably before the start of treatment, it could be used to guide treatment selection, as patients might be better managed with non-surgical approaches to avoid the toxicity and cost of trimodality therapy (surgery, chemotherapy, and radiotherapy together). There are many aspects of imaging detected extranodal extension that remain unresolved or are without consensus, such as the criteria to best diagnose them and the associated terminology. The Head and Neck Cancer International Group conducted a five-round modified Delphi process with a group of 18 international radiology experts, representing 14 national clinical research groups. We generated consensus recommendations on the terminology and diagnostic criteria for imaging detected extranodal extension to harmonise clinical practice and research. These recommendations have been endorsed by 19 national and international organisations, representing 34 countries. We propose a new classification system to aid diagnosis, which was supported by most of the participating experts over existing systems, and which will require validation in the future. Additionally, we have created an online educational resource for grading imaging detected extranodal extensions.

European randomized controlled trial evaluating differential target multiplexed spinal cord stimulation and conventional medical management in subjects with persistent back pain ineligible for spine surgery: 24-month results.

BACKGROUND: Differential target multiplexed spinal cord stimulation (DTM SCS) was shown to be superior to conventional SCS for treating chronic low back pain (CLBP) in subjects with persistent spinal pain syndrome with previous spinal surgery (PSPS-T2) or ineligible for it (PSPS-T1). This study reports 24-month efficacy and safety of DTM SCS vs. conventional medical management (CMM) in PSPS-T1 subjects across four European countries. METHODS: This is a prospective, multicenter, open-label, randomized, controlled trial with optional crossover. Subjects randomized 1:1 to DTM SCS or CMM. Primary endpoint was responder rate (% subjects reporting ≥50% CLBP relief) at 6 months. A superiority test compared responder rates between treatments. CLBP and leg pain levels, functional disability, quality of life (QoL), patient satisfaction and global impression of change were evaluated for 24 months. A Composite Responder Index (CRI) was obtained using CLBP relief, disability and QoL. Incidence of study-related adverse events evaluated safety. RESULTS: A total of 55 and 57 subjects were randomized to DTM SCS and CMM respectively. DTM SCS was superior, with CLBP responder rates ≥80% and CLBP relief >5.6 cm (>70% reduction) through the 24-month follow-up. Improvements with DTM SCS in other outcomes were sustained. The CRI was >80% for DTM SCS through 24 months. Opioid medication intake decreased in subjects treated with DTM SCS. Most patients treated with DTM SCS felt satisfied and improved at the end of the study. Safety was congruent with other studies. CONCLUSION: DTM SCS is efficacious and safe during 24 months for the treatment of CLBP and leg pain in PSPS-T1 patients ineligible for spine surgery. SIGNIFICANCE STATEMENT: This randomized controlled trial shows that Differential Target Multiplexed SCS (DTM SCS) is an effective and safe long-term treatment for PSPS type 1 patients suffering from axial low back pain with or without leg pain and who are ineligible for spinal surgery. Currently, CMM treatments are their only option and provide limited benefits. Besides superior pain relief, DTM SCS provides significant improvements in functional disability, quality of life, high levels of satisfaction and perceived impression of change.

Health behavior interventions among people with lower socio-economic position: a scoping review of behavior change techniques and effectiveness.

Background: Behavior change interventions can unintendedly widen existing socio-economic health inequalities. Understanding why interventions are (in)effective among people with lower socio-economic position (SEP) is essential. Therefore, this scoping review aims to describe what is reported about the behavior change techniques (BCTs) applied within interventions and their effectiveness in encouraging physical activity and healthy eating, and reducing smoking and alcohol consumption according to SEP. Methods: A systematic search was conducted in 12 electronic databases, and 151 studies meeting the eligibility criteria were included and coded for health behavioral outcomes, SEP-operationalization, BCTs (type and number) and effectiveness. Results: Findings suggest that approaches for measuring, defining and substantiating lower SEP vary. Current studies of behavior change interventions for people of different SEP do not systematically identify BCTs, making systematic evaluation of BCT effectiveness impossible. The effectiveness of interventions is mainly evaluated by overall intervention outcomes and SEP-moderation effects are mostly not assessed. Conclusion: Using different SEP-operationalizations and not specifying BCTs hampers systematic evidence accumulation regarding effective (combinations of) BCTs for the low SEP population. To learn which BCTs effectively improve health behaviors among people with lower SEP, future intervention developers should justify how SEP is operationalized and must systematically describe and examine BCTs.

Value-Based Healthcare: A Primer for the Dermatologist.

BACKGROUND: Value-based healthcare (VBHC) is an increasingly employed strategy to transform healthcare organizations into economically sustainable systems that deliver high-value care. In dermatology, the need for VBHC is evident as chronic skin diseases require long-term, often expensive treatments. This narrative review aims to introduce dermatologists to the principles and implementation of VBHC. SUMMARY: VBHC emphasizes maximizing outcomes that are directly relevant to patients. Key components of VBHC include a systematic assessment of standardized patient-relevant outcomes by using core outcome sets and measurement of healthcare cost for the individual patient. Systematic reporting and comparing of risk-adjusted outcomes across the full cycle of care for a specific condition provide benchmarked feedback and actionable insights to promote high-value care and reduce low-value care. VBHC aims to organize care around the patient in condition-specific and team-based integrated practice units with multidisciplinary collaboration, utilize information technology platforms to enable digital data monitoring, reduce cost, and eventually reform payment systems to support bundled payments for the overall care cycle. VBHC implementation in practice necessitates the establishment of a systematic framework for outcome-based quality improvement, the incorporation of value and outcomes in shared decision-making practices, and the cultivation of a value-centric culture among healthcare professionals through continuous training. KEY MESSAGES: Dermatologists can benefit from implementing VBHC principles in their practice. An essential step toward value-driven dermatological care is to start measuring outcomes relevant for patients for each patient, which is lacking partly due to the absence of core outcome sets developed for clinical practice. By reducing low-value care and emphasizing optimal patient-centered outcomes, VBHC has the potential to improve the quality of care and ensure cost containment. Efforts are needed to enhance the development and uptake of VBHC in dermatological clinical practice to realize these benefits.

The complete genome of "Candidatus Phytoplasma fraxini" AshY1 from the ash yellows group.

The complete genome of "Candidatus Phytoplasma fraxini" AshY1, originating from Fraxinus americana in North America, was assembled using long reads from single-molecule real-time sequencing technology. The chromosome of 598 kb provides insights into the effector repertoire of a phytopathogenic bacterium from the 16SrVII phytoplasma group.

Joint EANM-SNMMI guideline on the role of 2-[18F]FDG PET/CT in no special type breast cancer : (endorsed by the ACR, ESSO, ESTRO, EUSOBI/ESR, and EUSOMA).

INTRODUCTION: There is much literature about the role of 2-[18F]FDG PET/CT in patients with breast cancer (BC). However, there exists no international guideline with involvement of the nuclear medicine societies about this subject. PURPOSE: To provide an organized, international, state-of-the-art, and multidisciplinary guideline, led by experts of two nuclear medicine societies (EANM and SNMMI) and representation of important societies in the field of BC (ACR, ESSO, ESTRO, EUSOBI/ESR, and EUSOMA). METHODS: Literature review and expert discussion were performed with the aim of collecting updated information regarding the role of 2-[18F]FDG PET/CT in patients with no special type (NST) BC and summarizing its indications according to scientific evidence. Recommendations were scored according to the National Institute for Health and Care Excellence (NICE) criteria. RESULTS: Quantitative PET features (SUV, MTV, TLG) are valuable prognostic parameters. In baseline staging, 2-[18F]FDG PET/CT plays a role from stage IIB through stage IV. When assessing response to therapy, 2-[18F]FDG PET/CT should be performed on certified scanners, and reported either according to PERCIST, EORTC PET, or EANM immunotherapy response criteria, as appropriate. 2-[18F]FDG PET/CT may be useful to assess early metabolic response, particularly in non-metastatic triple-negative and HER2+ tumours. 2-[18F]FDG PET/CT is useful to detect the site and extent of recurrence when conventional imaging methods are equivocal and when there is clinical and/or laboratorial suspicion of relapse. Recent developments are promising. CONCLUSION: 2-[18F]FDG PET/CT is extremely useful in BC management, as supported by extensive evidence of its utility compared to other imaging modalities in several clinical scenarios.

Serum proteomics reveals hemophagocytic lymphohistiocytosis-like phenotype in a subset of patients with multisystem inflammatory syndrome in children.

Children with Multisystem Inflammatory Syndrome in Children (MIS-C) can present with thrombocytopenia, which is a key feature of hemophagocytic lymphohistiocytosis (HLH). We hypothesized that thrombocytopenic MIS-C patients have more features of HLH. Clinical characteristics and routine laboratory parameters were collected from 228 MIS-C patients, of whom 85 (37%) were thrombocytopenic. Thrombocytopenic patients had increased ferritin levels; reduced leukocyte subsets; and elevated levels of ASAT and ALAT. Soluble IL-2RA was higher in thrombocytopenic children than in non-thrombocytopenic children. T-cell activation, TNF-alpha and IFN-gamma signaling markers were inversely correlated with thrombocyte levels, consistent with a more pronounced cytokine storm syndrome. Thrombocytopenia was not associated with severity of MIS-C and no pathogenic variants were identified in HLH-related genes. This suggests that thrombocytopenia in MIS-C is not a feature of a more severe disease phenotype, but the consequence of a distinct hyperinflammatory immunopathological process in a subset of children.

Non-prime- and prime-side profiling of Pro-Pro endopeptidase specificity using synthetic combinatorial peptide libraries and mass spectrometry.

A group of bacterial proteases, the Pro-Pro endopeptidases (PPEPs), possess the unique ability to hydrolyze proline-proline bonds in proteins. Since a protease's function is largely determined by its substrate specificity, methods that can extensively characterize substrate specificity are valuable tools for protease research. Previously, we achieved an in-depth characterization of PPEP prime-side specificity. However, PPEP specificity is also determined by the non-prime-side residues in the substrate. To gain a more complete insight into the determinants of PPEP specificity, we characterized the non-prime- and prime-side specificity of various PPEPs using a combination of synthetic combinatorial peptide libraries and mass spectrometry. With this approach, we deepened our understanding of the P3-P3' specificities of PPEP-1 and PPEP-2, while identifying the endogenous substrate of PPEP-2 as the most optimal substrate in our library data. Furthermore, by employing the library approach, we investigated the altered specificity of mutants of PPEP-1 and PPEP-2. Additionally, we characterized a novel PPEP from Anoxybacillus tepidamans, which we termed PPEP-4. Based on structural comparisons, we hypothesized that PPEP-4 displays a PPEP-1-like prime-side specificity, which was substantiated by the experimental data. Intriguingly, another putative PPEP from Clostridioides difficile, CD1597, did not display Pro-Pro endoproteolytic activity. Collectively, we characterized PPEP specificity in detail using our robust peptide library method and, together with additional structural information, provide more insight into the intricate mechanisms that govern protease specificity.

Patient-clinician collaboration in making care fit: A qualitative analysis of clinical consultations in diabetes care.

OBJECTIVE: To confirm described dimensions of making care fit and explore how patients and clinicians collaborate to make care fit in clinical practice. METHODS: As part of an ongoing study, we audiotaped and transcribed patient-clinician consultations in diabetes care. We purposively selected consultations based on participants' demographical, biomedical and biographical characteristics. We analysed transcripts using reflexive thematic analysis. We combined a deductive and inductive approach, using the pre-described dimensions of making care fit and adding new (sub-)dimensions when pertinent. RESULTS: We analysed 24 clinical consultations. Our data confirmed eight previously described dimensions and provided new sub-dimensions of making care fit with examples from clinical practice (problematic situation, influence of devices, sense of options, shared agenda setting, clinician context, adapting to changing organization of care, and possibility to reconsider). CONCLUSION: Our study confirmed, specified and enriched the conceptualization of making care fit through practice examples. We observed patient-clinician collaboration in exploration of patients' context, and by responsively changing, adapting or maintaining care plans. PRACTICE IMPLICATIONS: Our findings support clinicians and researchers with insights in important aspects of patient-clinician collaboration. Ultimately, this would lead to optimal design of care plans that fit well in each patient life.

ALACEN: A Holistic Herbaceous Biomass Fractionation Process Attaining a Xylose-Rich Stream for Direct Microbial Conversion to Bioplastics.

Lignocellulose biorefining is a promising technology for the sustainable production of chemicals and biopolymers. Usually, when one component is focused on, the chemical nature and yield of the others are compromised. Thus, one of the bottlenecks in biomass biorefining is harnessing the maximum value from all of the lignocellulosic components. Here, we describe a mild stepwise process in a flow-through setup leading to separate flow-out streams containing cinnamic acid derivatives, glucose, xylose, and lignin as the main components from different herbaceous sources. The proposed process shows that minimal degradation of the individual components and conservation of their natural structure are possible. Under optimized conditions, the following fractions are produced from wheat straw based on their respective contents in the feed by the ALkaline ACid ENzyme process: (i) 78% ferulic acid from a mild ALkali step, (ii) 51% monomeric xylose free of fermentation inhibitors by mild ACidic treatment, (iii) 82% glucose from ENzymatic degradation of cellulose, and (iv) 55% native-like lignin. The benefits of using the flow-through setup are demonstrated. The retention of the lignin aryl ether structure was confirmed by HSQC NMR, and this allowed monomers to form from hydrogenolysis. More importantly, the crude xylose-rich fraction was shown to be suitable for producing polyhydroxybutyrate bioplastics. The direct use of the xylose-rich fraction by means of the thermophilic bacteria Schlegelella thermodepolymerans matched 91% of the PHA produced with commercial pure xylose, achieving 138.6 mgPHA/gxylose. Overall, the ALACEN fractionation method allows for a holistic valorization of the principal components of herbaceous biomasses.

Management of impacted fetal head at cesarean birth: A systematic review and meta-analysis.

INTRODUCTION: Despite increasing incidence of impacted fetal head at cesarean birth and associated injury, it is unclear which techniques are most effective for prevention and management. A high quality evidence review in accordance with international reporting standards is currently lacking. To address this gap, we aimed to identify, assess, and synthesize studies comparing techniques to prevent or manage impacted fetal head at cesarean birth prior to or at full cervical dilatation. MATERIAL AND METHODS: We searched MEDLINE, Emcare, Embase and Cochrane databases up to 1 January 2023 (PROSPERO: CRD420212750016). Included were randomized controlled trials (any size) and non-randomized comparative studies (n ≥ 30 in each arm) comparing techniques or adjunctive measures to prevent or manage impacted fetal head at cesarean birth. Following screening and data extraction, we assessed risk of bias for individual studies using RoB2 and ROBINS-I, and certainty of evidence using GRADE. We synthesized data using meta-analysis where appropriate, including sensitivity analyses excluding data published in potential predatory journals or at risk of retraction. RESULTS: We identified 24 eligible studies (11 randomized and 13 non-randomized) including 3558 women, that compared vaginal disimpaction, reverse breech extraction, the Patwardhan method and/or the Fetal Pillow®. GRADE certainty of evidence was low or very low for all 96 outcomes across seven reported comparisons. Pooled analysis mostly showed no or equivocal differences in outcomes across comparisons of techniques. Although some maternal outcomes suggested differences between techniques (e.g., risk ratio of 3.41 [95% CI: 2.50-4.66] for uterine incision extension with vaginal disimpaction vs. reverse breech extraction), these were based on unreliable pooled estimates given very low GRADE certainty and, in some cases, additional risk of bias introduced by data published in potential predatory journals or at risk of retraction. CONCLUSIONS: The current weaknesses in the evidence base mean that no firm recommendations can be made about the superiority of any one impacted fetal head technique over another, indicating that high quality training is needed across the range of techniques. Future studies to improve the evidence base are urgently required, using a standard definition of impacted fetal head, agreed maternal and neonatal outcome sets for impacted fetal head, and internationally recommended reporting standards.

Glutamine promotes human CD8+ T cells and counteracts imiquimod-induced T cell hyporesponsiveness.

T cells protect tissues from cancer. Although investigations in mice showed that amino acids (AA) critically regulate T cell immunity, this remains poorly understood in humans. Here, we describe the AA composition of interstitial fluids in keratinocyte-derived skin cancers (KDSCs) and study the effect of AA on T cells using models of primary human cells and tissues. Gln contributed to ∼15% of interstitial AAs and promoted interferon gamma (IFN-γ), but not granzyme B (GzB) expression, in CD8+ T cells. Furthermore, the Toll-like receptor 7 agonist imiquimod (IMQ), a common treatment for KDSCs, down-regulated the metabolic gatekeepers c-MYC and mTORC1, as well as the AA transporter ASCT2 and intracellular Gln, Asn, Ala, and Asp in T cells. Reduced proliferation and IFN-γ expression, yet increased GzB, paralleled IMQ effects on AA. Finally, Gln was sufficient to promote IFN-γ-production in IMQ-treated T cells. Our findings indicate that Gln metabolism can be harnessed for treating KDSCs.

EUNOS 2023 Practical Neuro-Ophthalmology Course: Groningen, The Netherlands, June 1st-2nd, 2023.

The European Neuro-Ophthalmology Society (EUNOS) practical neuro-ophthalmology course, henceforth referred to as the EUNOS course, took place in 2023 in Groningen, the Netherlands. This two-day international event featured a blend of plenary lecture sessions, workshops, and case reports, providing a practical update on fundamental neuro-ophthalmology topics for residents and young specialists in both neurology and ophthalmology.

Enhanced surface colonisation and competition during bacterial adaptation to a fungus.

Bacterial-fungal interactions influence microbial community performance of most ecosystems and elicit specific microbial behaviours, including stimulating specialised metabolite production. Here, we use a co-culture experimental evolution approach to investigate bacterial adaptation to the presence of a fungus, using a simple model of bacterial-fungal interactions encompassing the bacterium Bacillus subtilis and the fungus Aspergillus niger. We find in one evolving population that B. subtilis was selected for enhanced production of the lipopeptide surfactin and accelerated surface spreading ability, leading to inhibition of fungal expansion and acidification of the environment. These phenotypes were explained by specific mutations in the DegS-DegU two-component system. In the presence of surfactin, fungal hyphae exhibited bulging cells with delocalised secretory vesicles possibly provoking an RlmA-dependent cell wall stress. Thus, our results indicate that the presence of the fungus selects for increased surfactin production, which inhibits fungal growth and facilitates the competitive success of the bacterium.