Applicability of radiomics in interstitial lung disease associated with systemic sclerosis: proof of concept.

OBJECTIVE: To retrospectively evaluate if texture-based radiomics features are able to detect interstitial lung disease (ILD) and to distinguish between the different disease stages in patients with systemic sclerosis (SSc) in comparison with mere visual analysis of high-resolution computed tomography (HRCT). METHODS: Sixty patients (46 females, median age 56 years) with SSc who underwent HRCT of the thorax were retrospectively analyzed. Visual analysis was performed by two radiologists for the presence of ILD features. Gender, age, and pulmonary function (GAP) stage was calculated from clinical data (gender, age, pulmonary function test). Data augmentation was performed and the balanced dataset was split into a training (70%) and a testing dataset (30%). For selecting variables that allow classification of the GAP stage, single and multiple logistic regression models were fitted and compared by using the Akaike information criterion (AIC). Diagnostic accuracy was evaluated from the area under the curve (AUC) from receiver operating characteristic (ROC) analyses, and diagnostic sensitivity and specificity were calculated. RESULTS: Values for some radiomics features were significantly lower (p < 0.05) and those of other radiomics features were significantly higher (p = 0.001) in patients with GAP2 compared with those in patients with GAP1. The combination of two specific radiomics features in a multivariable model resulted in the lowest AIC of 10.73 with an AUC of 0.96, 84% sensitivity, and 99% specificity. Visual assessment of fibrosis was inferior in predicting individual GAP stages (AUC 0.86; 83% sensitivity; 74% specificity). CONCLUSION: The correlation of radiomics with GAP stage, but not with the visually defined features of ILD-HRCT, implies that radiomics might capture features indicating severity of SSc-ILD on HRCT, which are not recognized by visual analysis. KEY POINTS: • Radiomics features can predict GAP stage with a sensitivity of 84% and a specificity of almost 100%. • Extent of fibrosis on HRCT and a combined model of different visual HRCT-ILD features perform worse in predicting GAP stage. • The correlation of radiomics with GAP stage, but not with the visually defined features of ILD-HRCT, implies that radiomics might capture features on HRCT, which are not recognized by visual analysis.

Serum metabolites as biomarkers in systemic sclerosis-associated interstitial lung disease.

Systemic sclerosis (SSc) is a severe multi-organ disease with interstitial lung disease (ILD) being the major cause of death. While targeted therapies are emerging, biomarkers for sub-stratifying patients based on individual profiles are lacking. Herein, we investigated how levels of serum metabolites correlated with different stages of SSc and SSc-ILD. Serum samples of patients with SSc without ILD, stable and progressive SSc-ILD as well as of healthy controls (HC) were analysed using liquid targeted tandem mass spectrometry. The best discriminating profile consisted of 4 amino acids (AA) and 3 purine metabolites. L-tyrosine, L-tryptophan, and 1-methyl-adenosine distinguished HC from SSc patients. L-leucine, L-isoleucine, xanthosine, and adenosine monophosphate differentiated between progressing and stable SSc-ILD. In SSc-ILD, both, L-leucine and xanthosine negatively correlated with changes in FVC% predicted. Additionally, xanthosine was negatively correlated with changes in DLco% predicted and positively with the prognostic GAP index. Validation of L-leucine and L-isoleucine by an enzymatic assay confirmed both the sub-stratification of SSc-ILD patients and correlation with lung function and prognosis score. Serum metabolites may have potential as biomarkers for discriminating SSc patients based on the presence and severity of ILD. Confirmation in larger cohorts will be needed to appreciate their value for routine clinical care.

Evaluation of Intraoperative, Local Site Injections of Liposomal Bupivacaine as an Alternative to Standard Local Anesthetics in Patients Undergoing Total Hip Arthroplasty.

Background: Achieving postsurgical pain control after total hip arthroplasty (THA) is a critical factor for successful recovery because inadequately treated pain may lead to a delay in ambulation and hospital discharge and have an adverse impact on a patient's quality of life. Objective: This study compares the effectiveness of immediate-release local anesthetics for pain control in THA vs liposomal bupivacaine (LB) related to patient outcomes and costs of care. Methods: This is a retrospective cohort study of consecutive patients undergoing THA at 3 hospitals from January 2013 to July 2016. The control group received plain bupivacaine or ropivacaine while the study group received LB. Generalized linear models were used controlling for several patient factors. Primary measures included length of stay (LOS), hospitalization costs, pain relief, opioid use, and mobility. Secondary outcomes were discharge disposition and 30-, 60-, and 90-day readmissions. Results: One hundred and ninety-six patients were identified, with 103 as controls, 70 receiving LB, and 23 excluded. The LB group showed a decrease in LOS of 0.5 days (2.5 ± 2.6 vs 3.0 ± 2.1 days, P = .010), increased mobility on the day of surgery (27.6 ± 49.3 vs 12.5 ± 48.5 feet, P = .001) and the first day after surgery (186.8 ± 133.8 vs 155.2 ± 135.6, P = .039), and decreased hospital costs ($10 670 vs $11 351, P = .022). There were no significant differences in pain scores, opioid use, adverse events, discharge disposition, or readmissions. Study limitations include retrospective analysis, unblinded participants, and generalizability of results. Conclusions: LB provides an effective alternative to standard local anesthetics in patients undergoing THA based on improvements of inpatient parameters, LOS, and cost measures.

Use of vasoactive/vasodilating drugs for systemic sclerosis (SSc)-related digital ulcers (DUs) in expert tertiary centres: results from the analysis of the observational real-life DeSScipher study.

INTRODUCTION: DeSScipher is the first European multicentre study on management of systemic sclerosis (SSc), and its observational trial 1 (OT1) evaluated the efficacy of different drugs for digital ulcer (DU) prevention and healing. The aim of this study was to assess current use of vasoactive/vasodilating agents for SSc-related DU in the expert centres by analysing the baseline data of the DeSScipher OT1. METHOD: Baseline characteristics of patients enrolled in the OT1 and data regarding DU were analysed. RESULTS: The most commonly used drugs, in both patients with and without DU, were calcium channel blockers (CCBs) (71.6%), followed by intravenous iloprost (20.8%), endothelin receptor antagonists (ERAs) (20.4%) and phosphodiesterase 5 (PDE-5) inhibitors (16.5%). Of patients, 32.6% with DU and 12.8% without DU received two drugs (p < 0.001), while 11.5% with DU and 1.9% without DU were treated with a combination of three or more agents (p < 0.001). Sixty-five percent of the patients with recurrent DU were treated with bosentan and/or sildenafil. However, 64 out of 277 patients with current DU (23.1%) and 101 (23.6%) patients with recurrent DU were on CCBs alone. CONCLUSIONS: Our study shows that CCBs are still the most commonly used agents for DU management in SSc. The proportion of patients on combination therapy was low, even in patients with recurrent DU: almost one out of four patients with current and recurrent DU was on CCBs alone. Prospective analysis is planned to investigate the efficacy of different drugs/drug combinations on DU healing and prevention. Key Points • The analysis of DeSScipher, the first European multicentre study on management of SSc, has shown that the most commonly used vasoactive/vasodilating drugs for DU were CCBs, followed by intravenous Iloprost, ERAs and PDE-5 inhibitors. • More than half of the patients with recurrent DU received bosentan and/or sildenafil. • However, the proportion of patients on combination therapy of more than one vasoactive/vasodilating drug was low and almost one out of four patients with current and recurrent DU was on CCBs alone.

[Systemic sclerosis-clinical picture, diagnosis, and treatment]. / Systemische Sklerose ­ klinisches Bild, Diagnostik und Therapie.

Systemic sclerosis is a rare rheumatologic disease that is characterised by skin and organ fibrosis as well as vascular changes and the occurrence of specific autoantibodies. It has a high morbidity and mortality while its manifestations show significant heterogeneity in patients. Thus, diagnosis and follow-up of patients with systemic sclerosis has to be extensive, the more so because treatment must be adapted to organ manifestations. Although specific therapies for gastrointestinal, pulmonary or vascular complications exist, patients respond only partly to these and new therapeutic approaches are still needed.

[Systemic sclerosis-clinical picture, diagnosis, and treatment]. / Systemische Sklerose ­ klinisches Bild, Diagnostik und Therapie.

Systemic sclerosis is a rare rheumatologic disease that is characterised by skin and organ fibrosis as well as vascular changes and the occurrence of specific autoantibodies. It has a high morbidity and mortality while its manifestations show significant heterogeneity in patients. Thus, diagnosis and follow-up of patients with systemic sclerosis has to be extensive, the more so because treatment must adapted to organ manifestations. Although specific therapies for gastrointestinal, pulmonary or vascular complications exist, patients respond only partly to these and new therapeutic approaches are still needed.

Classification, categorization and essential items for digital ulcer evaluation in systemic sclerosis: a DeSScipher/European Scleroderma Trials and Research group (EUSTAR) survey.

BACKGROUND: A consensus on digital ulcer (DU) definition in systemic sclerosis (SSc) has been recently reached (Suliman et al., J Scleroderma Relat Disord 2:115-20, 2017), while for their evaluation, classification and categorisation, it is still missing. The aims of this study were to identify a set of essential items for digital ulcer (DU) evaluation, to assess if the existing DU classification was useful and feasible in clinical practice and to investigate if the new categorisation was preferred to the simple distinction of DU in recurrent and not recurrent, in patients with systemic sclerosis (SSc). METHODS: DeSScipher is the largest European multicentre study on SSc. It consists of five observational trials (OTs), and one of them, OT1, is focused on DU management. The DeSScipher OT1 items on DU that reached ≥ 60% of completion rate were administered to EUSTAR (European Scleroderma Trials and Research group) centres via online survey. Questions about feasibility and usefulness of the existing DU classification (DU due to digital pitting scars, to loss of tissue, derived from calcinosis and gangrene) and newly proposed categorisation (episodic, recurrent and chronic) were also asked. RESULTS: A total of 84/148 (56.8%) EUSTAR centres completed the questionnaire. DeSScipher items scored by ≥ 70% of the participants as essential and feasible for DU evaluation were the number of DU defined as a loss of tissue (level of agreement 92%), recurrent DU (84%) and number of new DU (74%). For 65% of the centres, the proposed classification of DU was considered useful and feasible in clinical practice. Moreover, 80% of the centres preferred the categorisation of DU in episodic, recurrent and chronic to simple distinction in recurrent/not recurrent DU. CONCLUSIONS: For clinical practice, EUSTAR centres identified only three essential items for DU evaluation and considered the proposed classification and categorisation as useful and feasible. The set of items needs to be validated while further implementation of DU classification and categorisation is warranted. TRIAL REGISTRATION: Observational trial on DU (OT1) is one of the five trials of the DeSScipher project (ClinicalTrials.gov; OT1 Identifier: NCT01836263 , posted on April 19, 2013).

Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL.

T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.

Assessment of liposome bupivacaine infiltration versus continuous femoral nerve block for postsurgical analgesia following total knee arthroplasty: a retrospective cohort study.

OBJECTIVE: Perioperative pain management is an important aspect of recovery from total knee arthroplasty (TKA) because severe pain can delay ambulation and hospital discharge. The objective of this retrospective sequential cohort study was to determine the impact of local infiltration analgesia using liposome bupivacaine (Exparel 1 ) when compared with a continuous femoral nerve block (FNB) following TKA. METHODS: This retrospective cohort study included consecutive patients who underwent TKA between April 2011 and April 2014, and received one of three interventions. Study Group A received adductor canal infiltration with bupivacaine HCl and knee infiltration with liposome bupivacaine. Study Group B received adductor canal infiltration with liposome bupivacaine and knee infiltration with liposome bupivacaine. The control group received a continuous FNB with ropivacaine HCl delivered via an elastomeric pump. Numeric pain rating scores (NPRS), distance walked, length of stay (LOS), and dose of narcotic medication were the key efficacy variables of interest. RESULTS: A total of 237 patients were included in this study: 98 in Group A, 34 in Group B, and 105 controls. On postoperative day (POD) 0, mean (standard deviation [SD]) NPRSs were similar between Group A (1.8 [1.7]), Group B (2.7 [1.8]), and the control group (2.3 [2.4]). Significantly (p < 0.05) more patients in Group A (58%) and Group B (44%) walked on POD0 than in the control group (0%); almost all patients walked on POD1. The mean (SD) distance walked was also significantly greater (p < 0.05) on POD1 in Group A (193 [203] feet) and Group B (211 [144] feet) than in the control group (46 [73] feet). Mean (SD) LOS was significantly (p < 0.05) shorter in Group B (2.2 [1.2] days), than in the control group (3.2 [0.7] days) and Group A (3.0 [1.7] days). CONCLUSIONS: Local infiltration analgesia using liposome bupivacaine was associated with improved ambulation and shorter LOS following TKA when compared with continuous FNB in this retrospective cohort study.

NOX4-driven ROS formation mediates PTP inactivation and cell transformation in FLT3ITD-positive AML cells.

Activating mutations of FMS-like tyrosine kinase 3 (FLT3), notably internal tandem duplications (ITDs), are associated with a grave prognosis in acute myeloid leukemia (AML). Transforming FLT3ITD signal transduction causes formation of reactive oxygen species (ROS) and inactivation of the protein-tyrosine phosphatase (PTP) DEP-1/PTPRJ, a negative regulator of FLT3 signaling. Here we addressed the underlying mechanisms and biological consequences. NADPH oxidase 4 (NOX4) messenger RNA and protein expression was found to be elevated in FLT3ITD-positive cells and to depend on FLT3ITD signaling and STAT5-mediated activation of the NOX4 promoter. NOX4 knockdown reduced ROS levels, restored DEP-1 PTP activity and attenuated FLT3ITD-driven transformation. Moreover, Nox4 knockout (Nox4(-/-)) murine hematopoietic progenitor cells were refractory to FLT3ITD-mediated transformation in vitro. Development of a myeloproliferative-like disease (MPD) caused by FLT3ITD-transformed 32D cells in C3H/HeJ mice, and of a leukemia-like disease in mice transplanted with MLL-AF9/ FLT3ITD-transformed murine hematopoietic stem cells were strongly attenuated by NOX4 downregulation. NOX4-targeting compounds were found to counteract proliferation of FLT3ITD-positive AML blasts and MPD development in mice. These findings reveal a previously unrecognized mechanism of oncoprotein-driven PTP oxidation, and suggest that interference with FLT3ITD-STAT5-NOX4-mediated overproduction of ROS and PTP inactivation may have therapeutic potential in a subset of AML.

[Early symptoms of dermatomyositis and antisynthetase syndrome]. / Frühsymptome der Dermatomyositis und des Antisynthetase-Syndroms.

INTRODUCTION: The early diagnosis of rheumatic diseases is becoming increasingly important. This particularly includes inflammatory myopathies which are multisystemic disorders with visceral involvement that are associated with high morbidity and mortality. Early diagnosis before the development of irreversible organ involvement is, therefore, of great importance. METHODS: This report provides information on early signs and symptoms of dermatomyositis and antisynthetase syndrome. Furthermore, screening methods which allow early diagnosis including involvement of internal organs are discussed. In addition, clinical and serological subtypes and their impact on prognosis are described.

A chick embryo with a yet unclassified type of cephalothoracopagus malformation and a hypothesis for explaining its genesis.

Cephalothoracopagus embryos are conjoined twins, who share parts of their heads, necks and bodies. Our study aims at presenting a detailed morphological analysis of a cephalothoracopagus chick embryo of developmental stage 31. Because none of the existing theories can explain the genesis of the phenotype of this embryo, we also suggest a hypothesis, which explains it. Beside the cephalothoracopagus embryo, we investigated five control embryos. With the aid of the high-resolution episcopic microscopy (HREM) technique, we created digital volume data and three-dimensional (3D) computer models of the organs and arteries of the embryos. We used the 3D models for topological analysis and for measuring the diameters of the great intrathoracic arteries. The malformed embryo showed two body backs, each containing a notochord, spinal cord and dorsal aorta. The body backs continued into separated lower bodies. The embryo had a single, four-chambered heart, single respiratory tract and single upper alimentary tract. The topology of the pharyngeal arch arteries was normal, and the diameters of these arteries were similar to that of the control embryos. We classified the embryo we investigated as a yet unknown malformation and suggest a hypothesis explaining its genesis.

Measurements of the diameters of the great arteries and semi-lunar valves of chick and mouse embryos.

The great arteries of embryos are small channels of a complex three-dimensional arrangement. Measurements of their diameters, as required for understanding cardiovascular morphogenesis and the genesis of malformations, cannot be performed in two-dimensional histological sections. We present and evaluate a quick and simple method for performing highly significant and objective measurements of the diameters of blood vessels in vertebrate embryos and used this method for providing statistics of the diameter of the semi-lunar valves and the lumina of the great arteries of early chick and mouse foetus. We employed the high-resolution episcopic microscopy technique for generating volume data and three-dimensional computer models of the arterial trees of 30 chick embryos (Hamburger Hamilton stage 34), 30 mouse embryos of the OF1 strain harvested on 14.5 dpc, 30 embryos of the OF1 strain harvested on 15.5 dpc and 28 mouse embryos of the PARKES strain harvested on 14.5 dpc. The three-dimensional models (voxel size 2 mum x 2 mum x 2 mum and 3 mum x 3 mum x 3 mum) were used for defining virtual resection planes perpendicular to the longitudinal axis of the blood vessels at comparable positions. In these planes, we measured the lumen areas and the lumen perimeters. We also calculated the lumen diameter and the true lumen area from the perimeter and present statistical analysis. Finally, we evaluate and discuss the reliability and reproducibility of our method and present all measurements in a form that minimizes the influence of specimen size variation, specimen processing and data generation methods.

[Systemic sclerosis. Objectives for the treatment]. / Systemische Sklerose. Zielkriterien der Behandlung.

Systemic sclerosis (SSc) is a multi-systemic fibrotic disorder with worldwide distribution and high morbidity and mortality. Characteristic features of this disease are widespread vasculopathy, inflammation, autoimmunity, and fibrosis. The better clinical outcome in recent years is mainly due to better management of organ complications. To date, there is no approved specific therapy to prevent or slow down the overall progression of the disease. So far, conventional disease-modifying antirheumatic drugs (DMARDs) have had no major impact on the disease course and have not prolonged survival. Based on recent studies of molecular pathomechanisms and various animal models, key molecules of fibrogenesis and vasculopathy in SSc could be identified. Therefore, to date, we have to reconsider and redefine the objectives of our treatment strategies. In this article, we discuss current and future therapeutic concepts as well as the objectives of new treatment strategies and of the evaluation of diagnostic tools with respect to pulmonary arterial hypertension, lung fibrosis and skin/systemic fibrosis.

Vitamin A-induced cholestatic hepatitis: a case report.

We report a case of intrahepatic cholestasis due to chronic vitamin A supplementation. A 70-year-old woman was admitted to the hospital for jaundice and reduced nutritional and general status with a 2-month history of increasing cholestasis. Some years previously she had suffered from breast and ovarian cancer with subsequent surgery and chemotherapy. Chemotherapy was terminated one month before elevated serum transaminase activities and cholestatic serum markers were noted. Following the chemotherapy, supportive care included weekly vitamin A injections (100,000 IU per injection). Liver biopsy showed an acute toxic liver injury with focal parenchymal necrosis, sinusoidal lesions, inflammatory infiltrate (round cells, macrophages), and activation and proliferation of stellate cells. The hepatic vitamin A concentration was found to be significantly elevated. There were no signs of intrahepatic metastasis or liver cirrhosis. Treatment with ursodeoxycholic acid rapidly improved the cholestasis and led to a total recovery after three weeks.

[Angiogenesis. Possibilities for therapeutic intervention in rheumatic diseases]. / Angiogenese. Therapeutische Interventionsmöglichkeiten bei rheumatischen Erkrankungen.

In contrast to vasculogenesis, angiogenesis is defined as the formation of new vessels from preexisting ones. Physiologically, this multistep process occurs in adults during the reproductive cycle and during pregnancy, pathophysiologically it can be found in wound healing, inflammation and carcinogenesis. The underlying mechanisms are vasodilatation and increasing permeability, destabilization of vessel walls and degradation of extracellular matrix, followed by the proliferation and migration of endothelial cells. Migrated endothelial cells form vascular tubes at sites of ischemia and these tubes are finally stabilized by pericytes and smooth muscle cells. This process is controlled by a complex interaction of angiogenic and angiostatic factors. In contrast to carcinogenesis, the role of angiogenesis for the pathogenesis and therapy of rheumatic diseases is less understood. Two examples for pathologically disturbed angiogenesis, rheumatoid arthritis and systemic sclerosis, are discussed in this review with respect to therapeutic options.

[Killing of cattle via electrical stunning]. / Töten von Rindern mittels Strom.

For disease control in the case of epidemics killing of cattle via electrical stunning is a method of choice. The official veterinarian is responsible for monitoring the adhesion to animal welfare principles during electrical stunning and killing. This requires specialised knowledge and experience as the symptoms of effective stunning are quite variable in cattle. Signs of effective and ineffective stunning are described below. In addition to suitable technical equipment, restraint of the animals and correct use of the equipment, neurophysiological processes have to be considered. Calm handling of the animals avoiding stress is a prerequisite for ensuring animal welfare and minimising pain especially when killing cattle using electrical methods.

The chronology of third molar mineralization in the Austrian population--a contribution to forensic age estimation.

The aim of the present study was to determine the chronology of third molar mineralization and to establish Austrian reference data. Therefore, a cross-sectional study was undertaken by evaluating 610 panoramic radiographs in order to assess the mineralization status of the mandibular third molars of Austrian male and female individuals (275 males and 335 females) between the ages of 12 and 24. The evaluation was carried out using the eight grade scheme of Demirjian et al. (1973). Mean ages, standard deviations, standard errors and percentile distributions are presented for each stage of development. Significant differences between the left and right mandibular third molars were not found. Males reach the developmental stages earlier than females, statistically significant differences were noted in stages E and F. Both mandibular third molars were observed in the majority of the individuals of the Austrian sample (477 individuals, 78.2%). For medicolegal purposes the likelihood of whether an Austrian individual is older than 18 years or not was determined.

Autologous haematopoietic stem cell transplantation for Behcet's disease with pulmonary involvement: analysis after 5 years of follow up.

BACKGROUND: Myeloablative chemotherapy and autologous haematopoietic stem cell transplantation (HSCT) may provide a therapeutic option in severe Behçet's disease (BD) with pulmonary involvement. CASE REPORTS: Two patients with BD with pulmonary involvement refractory to conventional immunosuppressive treatment underwent HSCT 1999. Stem cells were mobilised with cyclophosphamide (2 and 4 g/m(2)) and subsequently enriched ex vivo for CD34+ cells. The conditioning regimen used was melphalan (200 mg/m(2)). Outcome was measured by improvement of clinical features, function of affected organs, serological markers, need for immunosuppressive chemotherapy after transplant, and relapse. In both cases HSCT was successful, with good response and without serious complications. After 5 years of follow up one patient is in complete remission without immunosuppressive drugs and one has partial remission, needing low dose corticosteroids (8 mg/day). CONCLUSION: In these two patients myeloablative chemotherapy, followed by HSCT could be performed safely with marked improvement. In comparison with other observational studies the duration of more than 5 years of remission is remarkable, and its full duration is still unknown.