Dupilumab-Associated Lymphoid Reactions in Patients With Atopic Dermatitis.

Importance: Since the increased use of dupilumab for atopic dermatitis (AD) in daily practice, several cases have been reported on the development of cutaneous T-cell lymphomas (CTCL) and lymphoid infiltrates. Objective: To provide insight in the clinical and histopathologic features of patients with AD clinically suspected for CTCL during dupilumab treatment. Design, Setting, and Participants: This retrospective observational case series included adult (≥18 years) patients with AD treated with dupilumab between October 2017 and July 2022 at the University Medical Center Utrecht in the Netherlands. Main outcomes and measures: Relevant patient, disease, and treatment characteristics were evaluated. Skin biopsies before, during, and after treatment were collected and reassessed. Results: Fourteen patients (54.5% male) with a median (IQR) age of 56 (36-66) years suspected for CTCL with deterioration of symptoms during dupilumab treatment were included. Of 14 patients, 3 were retrospectively diagnosed with preexistent mycosis fungoides (MF). Eleven patients with AD were eventually diagnosed with a lymphoid reaction (LR). These patients showed MF-like symptoms; however, histopathologic findings were different, and included sprinkled distribution of small hyperchromatic lymphocytes in the upper epidermal section, a dysregulated CD4:CD8 ratio, and CD30 overexpression, without loss of CD2/CD3/CD5. The median time to clinical worsening was 4.0 months (IQR, 1.4-10.0). Posttreatment biopsies showed complete clearance of the LR in all patients. Conclusions and relevance: This study found that dupilumab treatment can cause a reversible and benign LR, which mimics a CTCL, though has distinctive histopathologic features.

Artificial intelligence in digital pathology of cutaneous lymphomas: A review of the current state and future perspectives.

Primary cutaneous lymphomas (CLs) represent a heterogeneous group of T-cell lymphomas and B-cell lymphomas that present in the skin without evidence of extracutaneous involvement at time of diagnosis. CLs are largely distinct from their systemic counterparts in clinical presentation, histopathology, and biological behavior and, therefore, require different therapeutic management. Additional diagnostic burden is added by the fact that several benign inflammatory dermatoses mimic CL subtypes, requiring clinicopathological correlation for definitive diagnosis. Due to the heterogeneity and rarity of CL, adjunct diagnostic tools are welcomed, especially by pathologists without expertise in this field or with limited access to a centralized specialist panel. The transition into digital pathology workflows enables artificial intelligence (AI)-based analysis of patients' whole-slide pathology images (WSIs). AI can be used to automate manual processes in histopathology but, more importantly, can be applied to complex diagnostic tasks, especially suitable for rare disease like CL. To date, AI-based applications for CL have been minimally explored in literature. However, in other skin cancers and systemic lymphomas, disciplines that are recognized here as the building blocks for CLs, several studies demonstrated promising results using AI for disease diagnosis and subclassification, cancer detection, specimen triaging, and outcome prediction. Additionally, AI allows discovery of novel biomarkers or may help to quantify established biomarkers. This review summarizes and blends applications of AI in pathology of skin cancer and lymphoma and proposes how these findings can be applied to diagnostics of CL.

Association of endothelial to mesenchymal transition and cellular senescence with fibrosis in skin biopsies of systemic sclerosis patients: a cross-sectional study.

OBJECTIVES: Fibrosis is the dominant hallmark of systemic sclerosis (SSc). Several mechanisms have been proposed to drive the disease process, but how these relate to skin fibrosis is poorly understood. METHODS: We performed a cross-sectional study on archival skin biopsies from 18 SSc patients and four controls. Dermal fibrosis and inflammatory cell infiltration were scored in HE and Masson's Trichrome-stained sections. The presence of senescence was defined by P21 and/or P16 positivity in Ki-67 negative cells. Endothelial to mesenchymal transition (EndMT) was identified by co-localisation of CD31 and α-SMA in immunofluorescent double-stained sections, and by an enclosure of ERG positive endothelial cell nuclei by α-SMA stained cytoplasm in immunohistochemical double staining. RESULTS: The histological dermal fibrosis score of SSc skin biopsies was correlated with the modified Rodnan skin score (rho 0.55, p=0.042). Staining for markers of cellular senescence on fibroblasts was correlated with fibrosis score, inflammatory score, and CCN2 staining on fibroblasts. Moreover, EndMT was more abundant in skin from patients with SSc (p<0.01) but did not differ between groups with different fibrosis severity. The frequency of these EndMT features increased with the abundance of senescence markers and CCN2 on fibroblasts and dermal inflammation. CONCLUSIONS: EndMT and fibroblast senescence were more abundant in skin biopsies from SSc patients. This finding indicates that both senescence and EndMT are involved in the pathway leading to skin fibrosis and might be valuable biomarkers and/or possible targets for novel therapeutic interventions.

Microbubble-Assisted Ultrasound for Drug Delivery to the Retina in an Ex Vivo Eye Model.

Drug delivery to the retina is one of the major challenges in ophthalmology due to the biological barriers that protect it from harmful substances in the body. Despite the advancement in ocular therapeutics, there are many unmet needs for the treatment of retinal diseases. Ultrasound combined with microbubbles (USMB) was proposed as a minimally invasive method for improving delivery of drugs in the retina from the blood circulation. This study aimed to investigate the applicability of USMB for the delivery of model drugs (molecular weight varying from 600 Da to 20 kDa) in the retina of ex vivo porcine eyes. A clinical ultrasound system, in combination with microbubbles approved for clinical ultrasound imaging, was used for the treatment. Intracellular accumulation of model drugs was observed in the cells lining blood vessels in the retina and choroid of eyes treated with USMB but not in eyes that received ultrasound only. Specifically, 25.6 ± 2.9% of cells had intracellular uptake at mechanical index (MI) 0.2 and 34.5 ± 6.0% at MI 0.4. Histological examination of retinal and choroid tissues revealed that at these USMB conditions, no irreversible alterations were induced at the USMB conditions used. These results indicate that USMB can be used as a minimally invasive targeted means to induce intracellular accumulation of drugs for the treatment of retinal diseases.

Lack of concentration-dependent local toxicity of highly concentrated (5%) versus conventional 0.5% bupivacaine following musculoskeletal surgery in a rat model.

PURPOSE: Various sustained-release formulations incorporate high bupivacaine concentrations but data on local toxicity is lacking. This study explores local toxic effects of highly concentrated (5%) bupivacaine compared to clinically used concentrations in vivo following skeletal surgery, to assess the safety of sustained-release formulations with high bupivacaine concentrations. METHODS: Sixteen rats underwent surgery, in which screws with catheters affixed were implanted in the spine or femur in a factorial experimental design, allowing single-shot or continuous 72 h local administration of 0.5%, 2.5% or 5.0% bupivacaine hydrochloride. During the 30-day follow-up, animal weight was recorded and blood samples were obtained. Implantation sites underwent histopathological scoring for muscle damage, inflammation, necrosis, periosteal reaction/thickening and osteoblast activity. Effects of bupivacaine concentration, administration mode and implantation site on local toxicity scores were analyzed. RESULTS: Chi-squared tests for score frequencies revealed a concentration-dependent decrease in osteoblast count. Moreover, spinal screw implantation led to significantly more muscle fibrosis but less bone damage than femoral screw implantation, reflecting the more invasive muscle dissection and shorter drilling times related to the spinal procedure. No differences between bupivacaine administration modes regarding histological scoring or body weight changes were observed. Weight increased, while CK levels and leukocyte counts decreased significantly during follow-up, reflecting postoperative recovery. No significant differences in weight, leukocyte count and CK were found between interventional groups. CONCLUSION: This pilot study found limited concentration-dependent local tissue effects of bupivacaine solutions concentrated up to 5.0% following musculoskeletal surgery in the rat study population.

Towards diagnostic criteria for malignant deep penetrating melanocytic tumors using single nucleotide polymorphism array and next-generation sequencing.

Cutaneous deep penetrating melanocytic neoplasms frequently simulate melanoma and might occasionally progress to metastatic melanoma. Distinguishing deep penetrating nevi (DPN) and deep penetrating melanocytomas (DPM) from malignant deep penetrating tumors (MDPT) is difficult based on histopathology alone, and diagnostic criteria for MDPT are currently lacking. Using a molecular workup, we aimed to provide readily available diagnostic tools for classification of deep penetrating tumors. We used clinical follow-up and Single Nucleotide Polymorphism (SNP) array for tumor classification of 20 deep penetrating neoplasms to identify associations with histopathological, immunohistochemistry, and NGS findings. Ten neoplasms were classified as MDPT, four as DPM, and six as DPN. Two MDPT showed metastases. The following parameters were statistically significantly associated with MDPT: severe nuclear atypia (risk ratio [RR] 2.9, p < 0.05), absence of a nevus component (RR 10.0, p = 0.04), positive PRAME expression (RR 9.0, p = 0.02), complete loss of p16 expression (RR 3.5, p = 0.003), TERT-p and APC mutations (RR 11.0, p = 0.01 and RR 2.7, p = 0.002, respectively), and ≥1 additional pathogenic mutation (RR 9.0, p = 0.02). Ki-67 expression ≥ 5% was not significantly associated with MDPTs, although it was <5% in all DPNs. Three MDPT did not show nuclear ß-catenin expression despite having a CTNNB1 (n = 2) or an APC mutation (n = 1). Our findings suggest that complete loss of p16 and positive PRAME expression, a driver mutation in APC, ≥ 1 additional pathogenic mutation, especially in TERT-p, support an MDPT diagnosis in deep penetrating neoplasms. Besides severe nuclear atypia and possibly severe inflammation, we did not identify specific histopathological criteria for malignancy. Non-aberrant nuclear ß-catenin expression might not exclude a deep penetrating signature in MDPT.

Diagnosis of Sweet's syndrome in otolaryngology.

Sweet's syndrome (acute febrile neutrophilic dermatosis) consists of acute onset of painful cutaneous erythematous lesions, mostly found in the upper extremities followed by the head and neck region, particularly in patients with underlying malignancies. We describe the case of a woman in her mid-30s, who was treated for acute myeloid leukaemia and presented with a severe painful and progressive erythematous lesion of the retroauricular skin. Clinical features, laboratory tests, blood cultures and histological biopsy yielded a diagnosis of Sweet's syndrome. The treatment consisted of oral and topical corticosteroids and her signs and symptoms resolved within 1 week. Although Sweet's syndrome is uncommon, awareness among otolaryngologists is crucial to ensure a prompt diagnosis, cure and referral to an oncologist (if not already involved) for patients with Sweet's syndrome in the head and neck area.

Systemic and local evidence for complement involvement in chronic spontaneous urticaria.

BACKGROUND: The pathogenesis of chronic spontaneous urticaria (CSU), including the mechanism of action of omalizumab, remain unclear. We hypothesized complement system involvement given the often fast clinical response induced by treatment, including omalizumab. Therefore, we assessed the role of various complement factors surrounding omalizumab treatment. METHODS: Thirty CSU patients (median age 42 [range 21-70]; 73 % female) with a median once daily Urticaria Activity Score over 7 days (UAS7) score at baseline of 31.5 points were enrolled. Treatment consisted of six administrations of 300 mg omalizumab every 4 weeks succeeded by a follow-up period of 12 weeks. Four punch skin biopsies were taken per patient; at baseline from lesional skin, at baseline from nonlesional skin, and after 1 and 7 days from formerly lesional skin. Complement activity, including C1q, C3, C3bc/C3, C4, C4bc/C4, C5a, and Membrane Attack Complex in peripheral blood were analyzed and complement activation in the skin was determined by the analysis of C4d deposition. Results were related to the clinical response to omalizumab. RESULTS: Fifteen patients showed a UAS7 score of 6 or lower (median 0) at Week 24, 15 patients did not (median 16). Lesional skin biopsies at baseline revealed complement deposition (C4d) in blood vessels in the papillary dermis of 53% (16/30) of the patients, which suggests involvement of immune complexes in the pathogenesis of urticaria. Moreover, indication of increased complement activation in CSU was substantiated by increased C5a levels in peripheral blood compared to healthy controls (p = 0.010). The clinical effect of omalizumab could not be linked to the variation of complement components. CONCLUSIONS: Both C4d deposition in lesional skin and elevated C5a levels in peripheral blood indicate the involvement of complement activation in the pathogenesis of CSU. No correlation was found between omalizumab and activation of complement indicative of independent processes in the immunopathogenesis of CSU.

Getting it Right the First Time: Frozen Sections for Diagnosing Necrotizing Soft Tissue Infections.

BACKGROUND: The aim of this study was to investigate which histopathologic findings are most indicative for necrotizing soft tissue infections (NSTIs) in ambivalent cases. METHODS: Patients undergoing surgical exploration for suspected NSTIs with obtainment of incisional biopsies for histopathological assessment were included from January 2013 until August 2019. The frozen sections and formalin-fixed paraffin-embedded (FFPE) samples were retrospectively re-assessed. The primary outcome was the discharge diagnosis. RESULTS: Twenty-seven (69%) biopsies of the 39 included samples were from patients with NSTIs. Microscopic bullae (p = 0.043), severe fascial inflammation (p < 0.001) and fascial necrosis (p < 0.001) were significantly more often present in the NSTI group compared to the non-NSTI group. Muscle edema (n = 5), severe muscle inflammation (n = 5), muscle necrosis (n = 8), thrombosis (n = 10) and vasculitis (n = 5) were most frequently only seen in the NSTI group. In thirteen tissues samples, there were some discrepancies between the severity of findings in the frozen section and the FFPE samples. None of these discrepancies resulted in a different diagnosis or treatment strategy. CONCLUSION: Microscopic bullae, severe fascial or muscle inflammation, fascial or muscle necrosis, muscle edema, thrombosis and vasculitis upon histopathological evaluation all indicate a high probability of a NSTI. At our institution, diagnosing NSTIs is aided by using intra-operative frozen section as part of triple diagnostics in ambivalent cases. Based on the relation between histopathologic findings and final presence of NSTI, we recommend frozen section for diagnosing NSTIs in ambivalent cases.

Digital pathology in the time of corona.

The 2020 COVID-19 crisis has had and will have many implications for healthcare, including pathology. Rising number of infections create staffing shortages and other hospital departments might require pathology employees to fill more urgent positions. Furthermore, lockdown measures and social distancing cause many people to work from home. During this crisis, it became clearer than ever what an asset digital diagnostics is to keep pathologists, residents, molecular biologists and pathology assistants engaged in the diagnostic process, allowing social distancing and a 'need to be there' on-the-premises policy, while working effectively from home. This paper provides an overview of our way of working during the 2020 COVID-19 crisis with emphasis on the virtues of digital pathology.

Social Identification with the Medical Profession in the Transition from Student to Practitioner.

Phenomenon: This study explores professional identity formation during a final year of medical school designed to ease the transition from student to practitioner. Although still part of the undergraduate curriculum, this "transitional year" gives trainees more clinical responsibilities than in earlier rotations. Trainees are no longer regarded as regular clerks but work in a unique position as "semi-physicians," performing similar tasks as a junior resident during extended rotations. Approach: We analyzed transcripts from interviews with 21 transitional-year medical trainees at University Medical Center Utrecht about workplace experiences that affect the development of professional identity. We used Social Identity Approach as a lens for analysis. This is a theoretical approach from social psychology that explores how group memberships constitute an important component of individual self-concepts in a process called 'social identification.' The transcripts were analyzed using thematic analysis, with a focus on how three dimensions of social identification with the professional group emerge in the context of a transitional year: cognitive centrality (the prominence of the group for self-definition), in-group affect (positivity of feelings associated with group membership) and in-group ties (perception of fit and ties with group members). Findings: Students were very aware of being a practitioner versus a student in the position of semi-physician and performing tasks successfully (i.e., cognitive centrality). Students experienced more continuity in patient care in transitional-year rotations than in previous clerkships and felt increased clinical responsibility. As a semi-physician they felt they could make a significant contribution to patient care. Students experienced a sense of pride and purpose when being more central to their patients' care (i.e., in-group affect). Finally, in extended rotations, the trainees became integrated into daily social routines with colleagues, and they had close contact with their supervisors who could confirm their fit with the group, giving them a sense of belonging (i.e., in-group ties). Insights: Using the three-dimension model of social identification revealed how students come to identify with the social group of practitioners in the context of a transitional year with extended rotations, increased clinical responsibilities, and being in the position of a "semi-physician." These findings shed light on the identity transition from student to practitioner within such a curricular structure.

Modifying Graft-versus-Host Disease in a Humanized Mouse Model by Targeting Macrophages or B-Cells.

Humanized mouse models can well be modified to study specific aspects of Graft-versus-Host Disease (GvHD). This paper shows the results of both macrophage depletion and (early) B-cell depletion in a humanized mouse model using RAG2-/- γc-/- mice injected with HuPBMCs. Macrophage depletion showed a significant decrease in survival and also lead to a change in the histomorphology of the xenogeneic reaction. Higher levels of infiltrating B-cells were observed in various organs of mice depleted for macrophages. With (early) B-cell depletion using Rituximab, a clear improvement on clinical symptoms was observed, even when probably only inactivated B-cells were deleted. However, the histological examinations only showed a significant morphological effect on liver fibrosis. This may be related to a difference in the mRNA levels of TGF-ß. Also, lower mRNA levels of Tregs in some organs were observed after Rituximab treatment, which contradicts that a higher number of Tregs would always be related to less severe GvHD. Our data show that both macrophage depletion and (early) B-cell depletion in a xenogeneic mouse model can influence the clinical, histological, and cytokine production of a GvHD response.

A 5-Year Evaluation of the Implementation of Triple Diagnostics for Early Detection of Severe Necrotizing Soft Tissue Disease: A Single-Center Cohort Study.

BACKGROUND: The standardized approach with triple diagnostics (surgical exploration with visual inspection, microbiological and histological examination) has been proposed as the golden standard for early diagnosis of severe necrotizing soft tissue disease (SNSTD, or necrotizing fasciitis) in ambivalent cases. This study's primary aim was to evaluate the protocolized approach after implementation for diagnosing (early) SNSTD and relate this to clinical outcome. METHODS: A cohort study analyzing a 5-year period was performed. All patients undergoing surgical exploration (with triple diagnostics) for suspected SNSTD since implementation were prospectively identified. Demographics, laboratory results and clinical outcomes were collected and analyzed. RESULT: Thirty-six patients underwent surgical exploration with eight (22%) negative explorations. The overall 30-day mortality rate was 25%, with an early, SNSTD-related mortality rate of 11% (n = 3). Of these, one patient (4%) underwent primary amputation, but died during surgery. No significant differences between baseline characteristics were found between patients diagnosed with SNSTD in early/indistinctive or late/obvious stage. Patient diagnosed at an early stage had a significantly shorter ICU stay (2 vs. 6 days, p = 0.031). Mortality did not differ between groups; patients who died were all ASA IV patients. CONCLUSION: Diagnosing SNSTD using the approach with triple diagnostics resulted in a low mortality rate and only a single amputation in a pre-terminal patient in the first 5 years after implementation. All deceased patients had multiple preexisting comorbidities consisting of severe systemic diseases, such as end-stage heart failure. Early detection proved to facilitate faster recovery with shorter ICU stay.

Occurrence of an Abscopal Radiation Recall Phenomenon in a Glioblastoma Patient Treated with Nivolumab and Re-Irradiation.

Glioblastoma multiforme is the most frequent primary brain tumor. The clinical course of glioblastoma is almost invariably fatal. Combined chemo-irradiation with temozolomide is currently the standard of care for newly diagnosed glioblastoma and concurrent Nivolumab, an anti-PD-1 monoclonal antibody is being studied for de novo glioblastoma. We present a 62-year old patient with glioblastoma, which was discovered during evaluation of sudden-onset moderate ataxia. Following craniotomy of the glial tumour he received chemo radiation. During this first-line treatment the patient participated in the CA209-548 phase III placebo controlled study investigating the addition of concurrent nivolumab. One month after the last administration of nivolumab after 60 weeks of study participation, magnetic resonance imaging scan showed progressive disease. Therefore stereotactic re-irradiation was given. Five days after completing radiation therapy and 50 days after his last nivolumab course he developed a mild diffuse generalized pruritic maculopapular exanthema. Skin biopsy was very indicative for a drug hypersensitivity reaction. The maculopapular rash and pruritus was successfully treated with moderate potency topical corticosteroids and prednisone. With the introduction of PD1/PD-L1 inhibitors and other immunotherapies tweaking the immune system to target cancer cells one can argue that once local radiation triggers a local immune mediated hypersensitivity reaction as seen in radiation recall dermatitis, the subsequent hypersensitivity reaction which would traditionally only be a local reaction is now possible to advance to more pronounced (systemic) reactions as seen in an abscopal effect. Therefore, we propose a combined name to coin this effect, the abscopal radiation recall phenomenon.

Ethical considerations for modern molecular pathology.

Molecular pathology is becoming an increasingly important discipline in oncology as molecular tumor characteristics will increasingly determine targeted clinical cancer care. In recent years, many technological advances have taken place that contributed to the development of molecular pathology. However, attention to ethical aspects has been lagging behind as illustrated by the lack of publications or professional guidelines. Existing guidelines or publications on ethical aspects of DNA sequencing are mostly aimed at germline or tumor sequencing in clinical genetics or biomedical research settings. As a result, large differences have been demonstrated in the process of tumor sequencing analysis between laboratories. In this perspective we discuss the ethical issues to consider in molecular pathology by following the process of tumor DNA sequencing analysis from the preanalytical to postanalytical phase. For the successful and responsible use of DNA sequencing in clinical cancer care, several moral requirements must be met, for example, those related to the interpretation and returning of genetic results, informed consent, and the retrospective as well as future use of genetic data for biomedical research. Many ethical issues are new to pathology or more stringent than in current practice because DNA sequencing could yield sensitive and potentially relevant data, such as clinically significant unsolicited findings. The context of molecular pathology is unique and complex, but many issues are similar to those applicable to clinical genetics. As such, existing scholarship in this discipline may be translated to molecular pathology with some adaptations and could serve as a basis for guideline development. For responsible use and further development of clinical cancer care, we recommend that pathologists take responsibility for the adequate use of molecular analyses and be fully aware and capable of dealing with the diverse, complex, and challenging aspects of tumor DNA sequencing, including its ethical issues. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Prospective evaluation of sequential treatment of sclerotic chronic graft versus host disease with rituximab and nilotinib.

Sclerotic chronic graft vs. host disease (cGVHD) still has a large impact on morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). We performed the first prospective study to test whether sequential therapy of the anti-CD20 antibody rituximab followed by 6 months treatment with tyrosine kinase inhibitor nilotinib is a favorable treatment strategy for patients with sclerotic cGVHD. Twenty-nine patients were included, 24 were available for analysis. We observed objective responses in 71% of patients (two patients CR, 15 patients PR). Moreover, two out of five patients suffering from severe ulcerations showed complete resolution of ulcers. Observed responses lasted until the end of study follow-up. The majority of responding patients could reduce daily corticosteroid dose with more than 50%. Furthermore, CD5+ B-cells are significantly lower (p = 0.007) in responding patients at baseline, proposing a new biomarker predictive for response. In conclusion, sequential treatment of rituximab followed by nilotinib associates with a very high response rate in this difficult to treat patient population. CD5+ B-cells could assist in guiding treatment choices and might be a first step toward more personalized cGVHD treatment. This trial was registered at the Dutch clinical trial registry as NTR1222.

The EPA-based Utrecht undergraduate clinical curriculum: Development and implementation.

AIM: As reports of the application of entrustable professional activities (EPAs) increase, not only for postgraduate but also for undergraduate medical education, there is a need for descriptions of what a UME curriculum with EPAs could look like. We provide such a description based on the experiences at University Medical Center Utrecht, the Netherlands, which can be used as an example by other curriculum developers. METHODS: In a three-year process, the UMC Utrecht Curriculum Committee developed a clinical workplace curriculum with an EPA structure, taking into account examples, such as the US Core EPAs for Entering Residency, and recommendations to integrate and increase the length of clerkships. RESULTS: In the resulting curriculum, operational from 2016, students train to be trusted with indirect supervision before graduation in five broad EPAs: the clinical consultation; general medical procedures; informing, advising and guiding patients and families; communicating and collaborating with colleagues; and extraordinary patient care. Each of these integrates smaller (nested) EPAs that receive focused training attention in integrated clerkships at various moments and must be signed off for entrustment with indirect supervision to complete the clerkship. DISCUSSION: The framework of EPAs went through many iterations before it was consolidated. Among the issues that required special attention was the application of a supervision levels scale for sign-off, the necessity to cover all relevant clinical content while not labeling too many small tasks each as a separate EPA, methods of EPA-focused assessment in the workplace and the creation of an e-portfolio model to serve assessment and entrustment.