Interobserver agreement on definition of the target volume in stereotactic radiotherapy for pancreatic adenocarcinoma using different imaging modalities.

PURPOSE: The aim of this study was to evaluate interobserver agreement (IOA) on target volume definition for pancreatic cancer (PACA) within the Radiosurgery and Stereotactic Radiotherapy Working Group of the German Society of Radiation Oncology (DEGRO) and to identify the influence of imaging modalities on the definition of the target volumes. METHODS: Two cases of locally advanced PACA and one local recurrence were selected from a large SBRT database. Delineation was based on either a planning 4D CT with or without (w/wo) IV contrast, w/wo PET/CT, and w/wo diagnostic MRI. Novel compared to other studies, a combination of four metrics was used to integrate several aspects of target volume segmentation: the Dice coefficient (DSC), the Hausdorff distance (HD), the probabilistic distance (PBD), and the volumetric similarity (VS). RESULTS: For all three GTVs, the median DSC was 0.75 (range 0.17-0.95), the median HD 15 (range 3.22-67.11) mm, the median PBD 0.33 (range 0.06-4.86), and the median VS was 0.88 (range 0.31-1). For ITVs and PTVs the results were similar. When comparing the imaging modalities for delineation, the best agreement for the GTV was achieved using PET/CT, and for the ITV and PTV using 4D PET/CT, in treatment position with abdominal compression. CONCLUSION: Overall, there was good GTV agreement (DSC). Combined metrics appeared to allow a more valid detection of interobserver variation. For SBRT, either 4D PET/CT or 3D PET/CT in treatment position with abdominal compression leads to better agreement and should be considered as a very useful imaging modality for the definition of treatment volumes in pancreatic SBRT. Contouring does not appear to be the weakest link in the treatment planning chain of SBRT for PACA.

Erratum: Formation of a Spin Texture in a Quantum Gas Coupled to a Cavity [Phys. Rev. Lett. 120, 223602 (2018)].

This corrects the article DOI: 10.1103/PhysRevLett.120.223602.

Formation of a Spin Texture in a Quantum Gas Coupled to a Cavity.

We observe cavity mediated spin-dependent interactions in an off-resonantly driven multilevel atomic Bose-Einstein condensate that is strongly coupled to an optical cavity. Applying a driving field with adjustable polarization, we identify the roles of the scalar and the vectorial components of the atomic polarizability tensor for single and multicomponent condensates. Beyond a critical strength of the vectorial coupling, we infer the formation of a spin texture in a condensate of two internal states from the analysis of the cavity output field. Our work provides perspectives for global dynamical gauge fields and self-consistently spin-orbit coupled gases.

[Prophylaxis of Recurrent Venous Leg Ulcer]. / Rezidivprophylaxe des Ulcus cruris venosum.

Venous leg ulcer (VLU) counts among the most common chronic wounds in Europe. Treatment is lengthy, cumbersome and costly, and there is a high rate of recurrence. This review shows the measures that should be offered to every patient with healed VLU to permanently prevent recurrence. To prevent VLU in case of varicose veins, the progression of chronic venous insufficiency (CVI) has to be stopped. There is convincing evidence that the effective treatment of varicose veins reduces the recurrence rate in patients with VLU. In patients with post-thrombotic syndrome (PTS), further thrombosis should be prevented through targeted prophylaxis of new thromboembolic events. The benefit of endovascular revascularization on the VLU recurrence rate in patients with post-thrombotic damage in the pelvic veins has not been proven in clinical studies. On the other hand, it has been clearly demonstrated in several studies that compression therapy is the basic procedure for the prevention of recurrent VLU in patients with varicose veins or PTS, regardless of whether other measures have been implemented or not. Good adherence in patients with compression therapy is more important than choosing the highest possible compression class. Future efforts for patients with VLU must aim to provide therapists with tools and treatment strategies to guide their patients and to increase patients' acceptance and understanding of the importance of self-management, in particular regarding compression therapy for the prevention of recurrent VLU.

Acute outcome of chronic total occlusion (CTO) recanalizsation in the elderly.

OBJECTIVES: Percutaneous coronary intervention (PCI) of total chronic total occlusion (CTO) still remains a major challenge in interventional cardiology. There is only insignificant knowledge reported in the literature about age differences in CTO recanalization. We analyzed in this study the issue of the impact of age on procedural characteristics, complications and short-term outcome. METHODS: Between 2012-2016 we included 440 patients. They underwent PCI for at least one CTO. Antegrade and retrograde CTO techniques were applied. The retrograde approach was used only after failed antegrade intervention. Continuous data are presented as the mean ± standard deviation; categorical data are presented as numbers and percentages unless otherwise specified. We used Twosamplet- t-test with equal variance to test the significant differences of the variables between the two cohorts. RESULTS: Procedural success proved independently of age. There was no significant interaction between age and procedural success (p=0.5). Complication rates were low in both groups (2.7% vs. 4%; p=0,4) with no difference in statistical significance. CONCLUSIONS: Our study suggests that in an aging society patients with severe coronary artery disease and chronical total occlusions an interventional therapy should be used more intensively. It can be performed safe and feasible.

[Options and Limitations in Endovascular Therapy for Acute and Chronic Mesenteric Arterial Occlusions]. / Endovaskuläre Möglichkeiten und Grenzen bei akuten und chronischen mesenterialen Verschlussprozessen.

BACKGROUND: The significance of endovascular therapy for mesenteric ischaemia (MI) is being debated. Despite initially lower mortality and morbidity, inconsistent early and late results led to questions concerning indications and technical applications of the procedure. METHODS: 91 patients with MI underwent endovascular treatment in a period of 11 years. In 78 (85.7 %) patients a stent was deployed and in 13 (14.3 %) an angioplasty was performed, principally of the superior mesenteric artery (n = 81/91, 89 %). Follow-up consisted of a clinical and an ultrasound examination in all cases. Mean follow-up was 4.2 years. Our results were compared to those in the literature. RESULTS: Endovascular treatment of the intestinal arteries accounted for 0.6 % of all vascular procedures. Seven of 91 patients (7.7 %) died after an initial PTA/stenting. The overall peri-interventional morbidity was 6.6 % (n = 6/91). Medium- to long-term complications were encountered in 20 patients (22 %), primarily during the first year (85 %). Six of 91 patients developed an in-stent stenosis (6.6 %) and 14/91 patients (15.4 %) stent occlusion. Additionally 2 dislocated stents (2.2 %) and an arterial perforation with bleeding into the mesentery (1.1 %) were seen. Although 3 of these 20 patients were successfully treated with an additional PTA or stenting (15.0 %; n = 3/91, 3.3 %), surgical conversion was necessary in 9 (n = 9/20, 45 %; n = 9/91, 9.9 %). The postoperative mortality was respectively 22.2 % (n = 2/9; n = 2/91, 2.2 %). In the case of acute MI, endovascular procedures are only indicated for patients without peritonitis. In chronic MI, the indication for endovascular treatment depends on the type of occlusion and the vascular anatomy. Despite favourable early results, the outcome of endovascular treatment deteriorates with time reaching a 1-year patency rate of 63 % in a multicentre analysis. This leads to secondary procedures in 30 %. A surgical conversion carries a high mortality. CONCLUSION: The endovascular treatment of intestinal artery disease cannot be considered the treatment of choice, it is rather an alternative method in patients with functional or local contraindications to surgery. Life-long follow-up is necessary to prevent stent complications with fatal consequences. A prospective randomised study concerning the evaluation of the advantages and disadvantages of surgical and endovascular therapy of intestinal artery occlusive disease is required.

[The future of vascular medicine]. / Die Zukunft der Gefäßmedizin.

In the future vascular medicine will still have a great impact on health of people. It should be noted that the aging of the population does not lead to a dramatic increase in patient numbers, but will be associated with a changing spectrum of co-morbidities. In addition, vascular medical research has to include the intensive care special features of vascular patients, the involvement of vascular medicine in a holistic concept of fast-track surgery, a geriatric-oriented intensive monitoring and early geriatric rehabilitation. For the future acceptance of vascular medicine as a separate subject area under delimitation of cardiology and radiology is important. On the other hand, the subject is so complex and will become more complex in future specialisations that mixing of surgery and angiology is desirable, with the aim to preserve the vascular surgical knowledge and skills on par with the medical and interventional measures and further develop them. Only large, interdisciplinary guided vascular centres will be able to provide timely diagnosis and therapy, to deal with the growing multi-morbidity of the patient, to perform complex therapies even in an acute emergency and due to sufficient number of cases to present with well-trained and experienced teams. These requirements are mandatory to decrease patients' mortality step by step.

Herpes simplex virus type 1 thymidine kinase sequence fused to the lacz gene increases levels of {beta}-galactosidase activity per genome of high-capacity but not first-generation adenoviral vectors in vitro and in vivo.

Increased transgene expression per vector genome is an important goal in the optimization of viral vectors for gene therapy. Herein we demonstrate that herpes simplex virus type 1 (HSV1) thymidine kinase (TK) gene sequences (1,131 bp) fused to the 3' end of lacZ increase transgene expression from high-capacity adenoviral vectors (HCAd), but not from first-generation (Ad) vectors. The woodchuck hepatitis virus posttranscriptional regulatory element (WPRE), in contrast, increased transgene expression levels from Ad but not HCAd vectors. The differential activity of the HSV1 TK gene and WPRE sequences was detected both in vitro and in vivo and suggests potentially different mechanisms of action or the interaction of these elements with vector genomic sequences.

A parent training model for toilet training children with autism.

BACKGROUND: Azrin & Foxx pioneered an intensive toilet training protocol for individuals with intellectual disability living in a residential setting. Since the development of the Rapid Toilet Training (RTT) protocol, many have replicated the efficacy, most notably in educational and outpatient treatment settings, but often training over longer periods of time. This study presents data from a parent training model that replicates Azrin and Foxx's results and training time. METHOD: This multiple baseline across subjects design study employs an ABA design where two boys diagnosed with autism were toilet trained using a modified Azrin & Foxx intensive teaching protocol. The first subject, a 4-year-old boy, did not have a history of attempted toilet training. The second subject, a 6-year-old boy, demonstrated a history of failed toilet training attempts in both the home and school settings. The trainings were conducted in the home setting where a novel parent-training approach was implemented. RESULTS: Participant 1 was continent at the end of the second day of training, and completely toilet trained (including initiation and communication) by day 10 of the intervention. Participant 2 was continent after day 1 and completely toilet trained by day 5 of the intervention. CONCLUSIONS: Long-term follow-up demonstrates maintenance of skills 3 years post training. Social validity via parent satisfaction was assessed. Limitations to the current study and recommendations for future research were discussed.

Worth a local treatment? - Analysis of modern radiotherapy concepts for oligometastatic prostate cancer.

BACKGROUND: Prostate cancer (PCA) is the most-prevalent non-skin cancer in men worldwide. Nevertheless, the treatment of oligometastatic, especially lymph-node (ln) recurrent, PCA remains elusive. The aim of our study was to provide insights in radiotherapy (RT)-treatment of recurrent PCA exhibiting ln- or osseous (oss)-oligometastases. METHODS: Between April 2012 and April 2017, 27 oligometastatic PCA patients (19 ln and 8 single oss) were treated with RT at our institution. RESULTS: The metastasis-free survival (MFS) was 24.8 m (22.0-36.0 m) and 25.4 m (23.9-28.1 m) for the ln- and oss-subgroup resulting in 1-year MFS of 75.4 and 100% and 2-year MFS of 58.7 and 83.3% for ln- and oss-metastatic patients, respectively. Of notice, none of the recurrences for ln-patients was in the RT-field, constituting a local control of 100%. Within the ln-group, pre-RT median-PSA was 2.6 ng/ml, median post-RT PSA was 0.3 ng/ml, which was significant (p = 0.003). Median biochemical-free survival (bfS) was 12.2 m. PCA that was initially confined to the prostate had a better bfS (p < 0.001) and MFS (p = 0.013). The oss-group had a median PSA of 4.9 ng/ml pre-treatment which dropped to a median value of 0.14 ng/ml (p = 0.004). Toxicities were moderate, with only 1 case of III° toxicity. There were no deaths in the ln-group, thus overall survial was 100% here. CONCLUSION: Our study points out the feasibility of RT as a treatment option in recurrent PCA and demonstrates an excellent local control with a low-toxicity profile.

A comparison of two group-delivered social skills programs for young children with autism.

A social skills group intervention was developed and evaluated for young children with autism. Twenty-five 4- to 6-year-old (diagnosed) children were assigned to one of two kinds of social skills groups: the direct teaching group or the play activities group. The direct teaching group used a video-modeling format to teach play and social skills over the course of the intervention, while the play activities group engaged in unstructured play during the sessions. Groups met for 5 weeks, three times per week, 1 h each time. Data were derived and coded from videotapes of pre- and post-treatment unstructured play sessions. Findings indicated that while members of both groups increased prosocial behaviors, the direct teaching group made more gains in social skills.

Depth of the vadose zone controls aquifer biogeochemical conditions and extent of anthropogenic nitrogen removal.

We investigated biogeochemical conditions and watershed features controlling the extent of nitrate removal through microbial dinitrogen (N2) production within the surficial glacial aquifer located on the north and south shores of Long Island, NY, USA. The extent of N2 production differs within portions of the aquifer, with greatest N2 production observed at the south shore of Long Island where the vadose zone is thinnest, while limited N2 production occurred under the thick vadose zones on the north shore. In areas with a shallow water table and thin vadose zone, low oxygen concentrations and sufficient DOC concentrations are conducive to N2 production. Results support the hypothesis that in aquifers without a significant supply of sediment-bound reducing potential, vadose zone thickness exerts an important control of the extent of N2 production. Since quantification of excess N2 relies on knowledge of equilibrium N2 concentration at recharge, calculated based on temperature at recharge, we further identify several features, such as land use and cover, seasonality of recharge, and climate change that should be considered to refine estimation of recharge temperature, its deviation from mean annual air temperature, and resulting deviation from expected equilibrium gas concentrations.

Validity of the J-CTO Score and the CL-Score for predicting successful CTO recanalization.

BACKGROUND: Percutaneous coronary intervention (PCI) of total chronic coronary occlusion (CTO) still remains a major challenge in interventional cardiology. To predict the probability of a successful intervention different scoring systems are available. We analyzed in this study the validity of two scoring systems, the Japanese CTO score (J-CTO score) and the newly developed Clinical and Lesion-related score (CL Score). METHODS: Between 2012 and 2015 we included 379 consecutive patients. They underwent PCI for at least one CTO. Antegrade and retrograde CTO techniques were applied. The retrograde approach was used only after failed antegrade intervention. RESULTS: Patients undergoing CTO PCI were mainly men (84%). The overall procedural success rate was 84% (±0.4). The mean J-CTO score was 2.9 (±1.3) and the mean CL score was 4.3 (±1.7). The CL score predicted more precisely the interventional results than the J-CTO score. CONCLUSIONS: Our study suggests that the previously presented CL score is superior to the J-CTO score in identifying CTO lesions with a likelihood for successful recanalization. Generally it appears to be a helpful tool for selecting patients and identifying the appropriate operator.

Quantification of high-capacity helper-dependent adenoviral vector genomes in vitro and in vivo, using quantitative TaqMan real-time polymerase chain reaction.

First-generation adenoviral (Ad) and high-capacity adenoviral (HC-Ad) vectors are efficient delivery vehicles for transferring therapeutic transgenes in vivo into tissues/organs. The initial successes reported with adenoviral vectors in preclinical trials have been limited by immune-related adverse side effects. This has been, in part, attributed to the use of poorly characterized preparations of adenoviral vectors and also to the untoward immune adverse side effects elicited when high doses of these vectors were used. HC-Ads have several advantages over Ads, including the lack of viral coding sequences, which after infection and uncoating, makes them invisible to the host's immune system. Another advantage is their large cloning capacity (up to approximately 35 kb). However, accurate characterization of HC-Ad vectors, and of contaminating replication-competent adenovirus (RCA) or helper virus, is necessary before these preparations can be used safely in clinical trials. Consequently, the development of accurate, simple, and reproducible methods to standardize and validate adenoviral preparations for the presence of contaminant genomes is required. By using a molecular method that allows accurate, reproducible, and simultaneous determination of HC-Ad, contaminating helper virus, and RCA genome copy numbers based on real-time quantitative PCR, we demonstrate accurate detection of these three genomic entities, within CsCl-purified vector stocks, total DNA isolated from cells transduced in vitro, and from brain tissue infected in vivo. This approach will allow accurate assessment of the levels and biodistribution of HC-Ad and improve the safety and efficacy of clinical trials.

Structures of a hemoglobin-based blood substitute: insights into the function of allosteric proteins.

BACKGROUND: . Potential blood substitutes can be based on hemoglobin. Two problems must be overcome with acellular hemoglobin-based blood substitutes, however: the oxygen affinity of purified human hemoglobin is too high for it to deliver oxygen to tissues, and hemoglobin tetramers dissociate into alphabeta dimers that can cause kidney damage. A modified form of hemoglobin, rHb 1.1, has reduced oxygen affinity as the result of an Asnbeta 108-->Lys mutation, and dimerization is prevented by the insertion of a glycine residue between the sequences of the normal alpha chains to produce one covalently continuous di-alpha-chain. Determination of the structure of rHb 1.1 would provide structure-based explanations for the altered properties of rHb 1.1. RESULTS: . We determined the structures of the deoxy form of rHb 1.1 at 2.0 resolution and of cyanomet-rHb 1.1 at 2.6 resolution. Deoxy-rHb 1.1 adopts the classic 'T state' quaternary structure, but cyanomet-rHb 1.1 adopts a novel quanternary structure, the B state. The most striking feature of the tertiary structures is a charged hydrogen bond involving Lysbeta 108 that is broken in the T-->B state transition. The glycine bridge within the di-alpha-chain is well defined in both structures and appears to cause adoption of the B state instead of the previously observed ligand-bound quaternary structures R or Y/R2. CONCLUSIONS: . A charged hydrogen bond between Lysbeta 108 and Tyrbeta35 is broken in the transition between the deoxy and ligand-bound forms of rHb 1.1. This structural change reduces the oxygen affinity of rHb 1.1 by changing the relative stability of deoxy and ligand-bound states. Furthermore, our observations highlight the importance of small conformational changes in allosteric proteins, even in their most rigid domains. Three ligand-bound quaternary structures of hemoglobin (R, Y/R2 and B) have now been described. In contrast, only one quaternary structure has been observed for deoxyhemoglobin (T). The structural degeneracy of the high oxygen affinity form of hemoglobin is an important reminder that allosteric proteins may have multiple quaternary structures that are functionally very similar. This degeneracy of quaternary structures has important implications for the regulation of allosteric proteins, because different quaternary structures may be stabilized by different allosteric effectors.

[Simultaneous manifestation of blue-rubber-bleb-nevus-syndrome and malignant melanoma]. / Gemeinsame Manifestation von Blue-Rubber-Bleb-Naevus-Syndrom und malignem Melanom.

Blue rubber bleb nevi (BRBN) are rare vascular malformations of the integument and mucous membranes. Little is known about coherence between these nevi and malignant diseases. We report on a young man with progressive BRBN syndrome representing a thitherto unknown malignant melanoma.

Impact of the -308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to disease.

A biallelic G (TNF1 allele) to A (TNF2 allele) polymorphism 308 nucleotides upstream from the transcription initiation site in the tumor necrosis factor (TNF) promoter is associated with elevated TNF levels and disease susceptibilities observed in human subjects. The TNF2 allele is strongly associated with the high-TNF-producing autoimmune MHC haplotype HLA-A1, B8, DR3, with elevated serum TNF levels and a more severe outcome in infectious diseases, such as cerebral malaria. A number of groups have set out to determine whether the -308 polymorphism could affect transcription factor binding and hence influence TNF transcription and expression levels. Although some studies have failed to show any functional difference between the two allelic forms, others have shown that the -308 polymorphism effected transcription factor binding to the region encompassing -308, with the region in the TNF2 allele showing altered binding characteristics. The -308 polymorphism also has been found by some groups to be functionally significant in reporter gene assays in Raji B cells, Jurkat T cells, and U937 pre-monocytic cells. Up to fivefold differences can be measured between TNF1 and TNF2 allelic constructs when the TNF 3'UTR is present, indicating a role in the expression of the polymorphism. Although controversial, the majority of the data support a direct role for the TNF2 -308 allele in the elevated TNF levels observed in TNF2 homozygotes and HLA-A1, B8, DR3 individuals. Elevated TNF levels due to the -308 polymorphism may alter the immune response such that it confers susceptibility to certain autoimmune and infectious diseases.

The -308 tumor necrosis factor-alpha promoter polymorphism effects transcription.

Since the tumor necrosis factor alpha (TNF-alpha) gene was found to be located in the central major histocompatibility complex (MHC) there has been much speculation concerning a genetic association between particular TNF alleles and disease susceptibility. A relationship between the MHC haplotype A1, B8, DR3, TNF-alpha expression levels and susceptibility to autoimmune disease has been suggested by several groups. The identification of the -308 polymorphism and its association with the HLA A1, B8, DR3 haplotype have led to speculation that the polymorphism may play a role in the altered expression of TNF-alpha. We have demonstrated that the region (-323 to -285) encompassing -308 in the TNF2 allele binds nuclear factors differently to the same region in the promoter of the more common TNF1 allele. The G/A -308 polymorphism affected the affinity of factor binding and resulted in a factor binding to TNF2 but not TNF1. The observed differential binding was shown to be functional, with the 38bp region from TNF2 causing a two-fold greater activity of a heterologous promoter over that due to the same region in TNF1. To further substantiate the functional consequences of the TNF-alpha -308 polymorphism, we analysed both allelic forms of the TNF-alpha promoter region (-993 to +110) in a transient transfection assay, using luciferase as a reporter gene. The results showed that when present with the 3'UTR the -308A allelic form gave a two-fold greater level of transcription than the 308G form in PMA-stimulated Jurkat and U937 cells. This suggests that the -308 G/A polymorphism may play a role in the altered TNF-alpha gene expression observed in individuals with the HLA A1, B8, DR3 haplotype.

Summary of the practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults.

This practice parameter describes treatment with stimulant medication. It uses an evidence-based medicine approach derived from a detailed literature review and expert consultation. Stimulant medications in clinical use include methylphenidate, dextroamphetamine, mixed salts of amphetamine, and pemoline. They carry U.S. Food and Drug Administration indications for the treatment of attention-deficit hyperactivity disorder.

Summary of the practice parameter for the prevention and management of aggressive behavior in child and adolescent psychiatric institutions with special reference to seclusion and restraint.

This parameter reviews the current state of the prevention and management of child and adolescent aggressive behavior in psychiatric institutions, with particular reference to the indications and use of seclusion and restraint. It also presents guidelines that have been developed in response to professional, regulatory, and public concern about the use of restrictive interventions with aggressive patients with regard to personal safety and patient rights. The literature on the use of seclusion, physical restraint, mechanical restraint, and chemical restraint is reviewed, and procedures for carrying out each of these interventions are described. Clinical and regulatory agency perspectives on these interventions are presented. Effectiveness, indications, contraindications, complications, and adverse effects of seclusion and restraint procedures are addressed. Interventions are presented to provide more opportunities to promote patient independence and satisfaction with treatment while diminishing the necessity of using restrictive procedures.