Polyethylene glycol-coated collagen patch (hemopatch®) in open partial nephrectomy.

PURPOSE: To describe the results of a polyethylene glycol-coated collagen patch, Hemopatch® on blood loss, surgical time and renal function in partial nephrectomy (PN) for renal cell carcinoma (RCC). METHODS: Out of a single surgeon cohort of n = 565 patients undergoing conventional open PN (CPN) between 01/2015 and 12/2017 at the University of Munich a consecutive subgroup (n = 42) was operated on using a polyethylene glycol-coated collagen-based sealant Hemopatch® (Baxter International Inc., Deerfield, IL, USA) (HPN). RESULTS: Median age was 65.2 years (range 12.7-95.2) with median follow-up of 9.43 months (0.03-49.15). Baseline renal function (CKD-EPI) was 78.56 ml/min/1.73 m2 (range 20.38-143.09) with a non-significant decline to 74.78 ml/min/1.73 m2 (range 3.75-167.74) at follow-up. In CPN 46% had low complexity, 33% moderate complexity and 20% high complexity lesions with 33% low, 40% moderate and 27% high complexity masses in HPN. Median tumor size was 4.3 cm (range 1-38 cm) in CPN with 4.8 cm (range 3.8-18.3 cm) with HPN, p = 0.293. Median blood loss and duration of surgery was significantly lower in the HPN group vs. CPN (146 ml ± 195 vs. 114 ml ± 159 ml; p = 0.021; 43 min ± 27 for HPN vs. 53 min ± 49; p = 0.035) with no difference in clamping time (12.6 min ± 8.6 for HPN vs. 12.0 min ± 9.5; p = 0.701). CONCLUSIONS: Hemopatch® supported renoraphy shows promising results compared to standard renoraphy in PN. No side effects were seen. Further studies should evaluate the prevention of arterio-venous or urinary fistulas. In complex partial nephrectomies Hemopatch® supported renoraphy should be considered.

Validation of a clinicopathological and gene expression profile model for sentinel lymph node metastasis in primary cutaneous melanoma.

BACKGROUND: The Clinicopathological and Gene Expression Profile (CP-GEP) model was developed to accurately identify patients with T1-T3 primary cutaneous melanoma at low risk for nodal metastasis. OBJECTIVES: To validate the CP-GEP model in an independent Dutch cohort of patients with melanoma. METHODS: Patients (aged ≥ 18 years) with primary cutaneous melanoma who underwent sentinel lymph node biopsy (SLNB) between 2007 and 2017 at the Erasmus Medical Centre Cancer Institute were eligible. The CP-GEP model combines clinicopathological features (age and Breslow thickness) with the expression of eight target genes involved in melanoma metastasis (ITGB3, PLAT, SERPINE2, GDF15, TGFBR1, LOXL4, CXCL8 and MLANA). Using the pathology result of SLNB as the gold standard, performance measures of the CP-GEP model were calculated, resulting in CP-GEP high risk or low risk for nodal metastasis. RESULTS: In total, 210 patients were included in the study. Most patients presented with T2 (n = 94, 45%) or T3 (n = 70, 33%) melanoma. Of all patients, 27% (n = 56) had a positive SLNB, with nodal metastasis in 0%, 30%, 54% and 16% of patients with T1, T2, T3 and T4 melanoma, respectively. Overall, the CP-GEP model had a negative predictive value (NPV) of 90·5% [95% confidence interval (CI) 77·9-96.2], with an NPV of 100% (95% CI 72·2-100) in T1, 89·3% (95% CI 72·8-96·3) in T2 and 75·0% (95% CI 30·1-95·4) in T3 melanomas. The CP-GEP indicated high risk in all T4 melanomas. CONCLUSIONS: The CP-GEP model is a noninvasive and validated tool that accurately identified patients with primary cutaneous melanoma at low risk for nodal metastasis. In this validation cohort, the CP-GEP model has shown the potential to reduce SLNB procedures in patients with melanoma.

[The development of anorexia nervosa in people with an autism spectrum disorder; a qualitative, retrospective study]. / Het ontstaan van anorexia nervosa bij mensen met een autismespectrum-stoornis; een kwalitatief en retrospectief onderzoek.

BACKGROUND: To improve treatment options for women with autism spectrum disorder (ASD) in combination with anorexia nervosa (an), it is necessary to better understand which risk factors are involved in the development of an in this target audience.
AIM: To identify risk factors for the development of an in people with ASD.
METHOD: Six women with ASD who are, or have been suffering from an, were interviewed about the development of their eating disorder. The data were analyzed using the thematic analysis method.
RESULTS: Regarding these participants, the generally accepted risk factors for developing an also appear to play a role, where it is possible that people with ASD form a vulnerable group for these risk factors. Characteristics specific for ASD were found to also contribute to the development of an in these participants.
CONCLUSION: For women with ASD it is important to be aware of a vulnerability to develop an. Extra support in areas where they experience difficulties is therefore necessary. The ASD specific characteristics can be aggravating or sustaining factors for an and should therefore be included in the treatment.

Implementation of the 2015 European Society of Cardiology guidelines for the management of infective endocarditis in the Netherlands.

Because the occurrence of infective endocarditis (IE) continues to be associated with high mortality, a working group was created by the Dutch Society of Cardiology to examine how the most recent European Society of Cardiology (ESC) guidelines for IE management could be implemented most effectively in the Netherlands. In order to investigate current Dutch IE practices, the working group conducted a country-wide survey. Based on the results obtained, it was concluded that most ESC recommendations could be endorsed, albeit with some adjustments. For instance, the suggested pre-operative screening and treatment of nasal carriers of Staphylococcus aureus as formulated in the ESC guideline was found to be dissimilar to current Dutch practice, and was therefore made less restrictive. The recently adapted ESC diagnostic criteria for IE were endorsed, while the practical employment of the relevant diagnostic techniques was simplified in an adapted flowchart. In addition, the presence of a multidisciplinary, so-called 'endocarditis team' in tertiary centres was proposed as a quality indicator. An adapted flowchart specifically tailored to Dutch practice for microbiological diagnostic purposes was constructed. Lastly, the working group recommended the Stichting Werkgroep Antibioticabeleid (SWAB; Dutch Working Party on Antibiotic Policy) guidelines for IE treatment instead of the antibiotic regimens proposed by the ESC.

Clinical Usage of Different Guidelines in Routine Management, Therapy and Follow-Up of Patients with Renal Cell Cancer in Germany.

OBJECTIVES: To evaluate the usage of different guidelines and to estimate the impact of changed recommendation in routine management, therapy and follow-up of patients with renal cell cancer (RCC). METHODS: An anonymous questionnaire was sent to 600 urologists in Germany. Twenty-seven percent of them were included in the analysis. The questions were about the practice setting, surgical and medical treatment of RCC, follow-up modalities, knowledge and usage of RCC guidelines. Results were correlated with the recommendations of the EAU-guideline. RESULTS: Sixty-eight percent of the urologists were office based. Sixty percent were located in bigger cities. Ninety-eight percent of the colleagues reported to be knowledgeable about the EAU-guidelines, 62% reported to know the American Urological Association, 59% DGU/AWMF, 19% National Comprehensive Cancer Network, 19% European Society for Medical Oncology, 13% Onkopedia, and 3% British Association of Urological Surgeons-guidelines. Eighty-seven percent reported that partial nephrectomy (Nx) was performed in tumours with diameter <4 cm. Forty-one percent performed a radical Nx for tumours that were 4-7 cm. Follow-up of RCC was done in 99%. Fifty-nine percent underwent an abdominal CT scan after 6 months. Thirty-nine percent got a chest X-ray done. Among those with metastatic RCC, only 84% were offered systemic therapy. First-line therapy was predominantly advocated using sunitinib. CONCLUSION: Almost all urologists know and use the EAU-guidelines. Other guidelines are rarely used. Follow-up is performed in discordance with the EAU-recommendations. Interestingly, only 84% with metastatic disease are introduced to systemic therapy.

Dual energy can accurately differentiate uric acid-containing urinary calculi from calcium stones.

PURPOSE: To retrospectively evaluate the accuracy of dual-energy CT (DECT) in the detection of the chemical composition of urinary calculi in correlation with infrared spectroscopic stone analysis. METHODS: We reviewed the CT scans of 255 patients who underwent DECT due to a clinical suspicion of urolithiasis. Out of this group, we included 64 patients with clinically symptomatic urolithiasis requiring stone removal. After surgical removal of the stone by ureterorenoscopy, chemical composition was analyzed with infrared spectroscopy. We correlated DECT stone characterization results with chemical stone composition based on dual-energy indices (DEI). A total of 213 renal and ureteral stones could be removed and chemically analyzed. RESULTS: A total of 213 calculi were evaluated. Thirty eight out of sixty four (59 %) patients had >1 stone. DECT was used to differentiate stones by using DEI. Stones harboring calcium (CA) were color-coded in blue, while stones containing uric acid (UA) were colored red. Median DEI in UA-containing stones were 0.001. Non-UA-containing stones had a DEI between 0.073 for pure CA stones and 0.077 containing CA and other substances (p = 0.001; p = 0.03, respectively). Sensitivity of DECT was 98.4 % for differentiation of UA from non-UA-containing calculi. Specificity was 98.1 %. Mean effective radiation dose of DECT was 4.18 mSv (0.44-14.27 mSv), thus comparable to conventional CT scans of the abdomen. Conventional measurement of Hounsfield units did not correlate with stone composition. CONCLUSION: DECT with image post-processing reliably discriminates UA-containing calculi from all other stones, but the study offered limitations. Discrimination within the non-UA stones cannot be reliably achieved but is clinically insignificant.

Phylogenetic analysis of highly pathogenic avian influenza A(H5N8) virus outbreak strains provides evidence for four separate introductions and one between-poultry farm transmission in the Netherlands, November 2014.

Phylogenetic analysis of highly pathogenic avian influenza A(H5N8) virus strains causing outbreaks in Dutch poultry farms in 2014 provides evidence for separate introduction of the virus in four outbreaks in farms located 16-112 km from each other and for between-farm transmission between the third and fourth outbreak in farms located 550 m from each other. In addition, the analysis showed that all European and two Japanese H5N8 virus strains are very closely related and seem to originate from a calculated common ancestor, which arose between July and September 2014. Our findings suggest that the Dutch outbreak virus strain 'Ter Aar' and the first German outbreak strain from 2014 shared a common ancestor. In addition, the data indicate that the Dutch outbreak viruses descended from an H5N8 virus that circulated around 2009 in Asia, possibly China, and subsequently spread to South Korea and Japan and finally also to Europe. Evolution of the virus seemed to follow a parallel track in Japan and Europe, which supports the hypothesis that H5N8 virus was exchanged between migratory wild waterfowl at their breeding grounds in Siberia and from there was carried by migrating waterfowl to Europe.

[Eating problems in individuals with autism spectrum disorder (ASD) but no intellectual impairment]. / Eetproblemen bij mensen met een autismespectrumstoornis zonder intellectuele beperking.

BACKGROUND: Little is known about the co-occurrence--in individuals--of autism spectrum disorder (ASD) and eating disorders and eating problems. Consequently, clinicians do not have enough information about how to diagnose or treat the combination of ASD and eating problems. AIM: To discuss the scientific literature and clinical experiences relating to eating disorders and eating problems in people who have ASD but no intellectual impairment. METHOD: The scientific literature was searched by means of PubMed, Medline and PsycINFO, and clinical experiences were discussed. RESULTS: The combination of ASS and anorexia nervosa seems to be a strong predictor that the eating disorder will follow a chronic course. It is not clear how often bulimia nervosa occurs in persons with ASD. Eating problems in persons with ASD often seem to be related to sensory sensitivity, eating preferences and motor problems. So far, little is known about the treatment of eating disorders and eating problems in individuals with ASD. CONCLUSION: When diagnosing and treating eating disorders and eating problems in individuals with ASD, it is important to take information processing and behaviour characteristics of ASD into account. Further research is needed, particularly in order to cast more light on treatment possibilities.

Genetic and epigenetic determinants mediate proneness of oncogene breakpoint sites for involvement in TCR translocations.

T-cell receptor (TCR) translocations are a genetic hallmark of T-cell acute lymphoblastic leukemia and lead to juxtaposition of oncogene and TCR loci. Oncogene loci become involved in translocations because they are accessible to the V(D)J recombination machinery. Such accessibility is predicted at cryptic recombination signal sequence (cRSS) sites ('Type 1') as well as other sites that are subject to DNA double-strand breaks (DSBs) ('Type 2') during early stages of thymocyte development. As chromatin accessibility markers have not been analyzed in the context of TCR-associated translocations, various genetic and epigenetic determinants of LMO2, TAL1 and TLX1 translocation breakpoint (BP) sites and BP cluster regions (BCRs) were examined in human thymocytes to establish DSB proneness and heterogeneity of BP site involvement in TCR translocations. Our data show that DSBs in BCRs are primarily induced in the presence of a genetic element of sequence vulnerability (cRSSs, transposable elements), whereas breaks at single BP sites lacking such elements are more likely induced by chance or perhaps because of patient-specific genetic vulnerability. Vulnerability to obtain DSBs is increased by features that determine chromatin organization, such as methylation status and nucleosome occupancy, although at different levels at different BP sites.

[The influence of genes and environment on the development of autism spectrum disorders]. / De invloed van genen en omgeving op het ontstaan van autismespectrumstoornissen.

BACKGROUND: Autism spectrum disorders (asd) occur in 0,6% of the general population. On the basis of research in the 70s, 80s and 90s many experts came to the conclusion that asd were in fact genetically determined and were linked only slightly to environmental factors. Recent research, however, indicates that environmental factors really do play an important role. AIM: To describe and identify the main trends in current research into the causes of asd. METHOD: The literature was studied with the help of Medline, Cochrane, Web of Science and ScienceDirect. RESULTS: Recent studies indicate that there is an underlying genetic cause in 35 to 60% of the cases of asd. Environmental factors play a greater role than previously thought and trigger the development of asd in people with a genetic vulnerability to asd. Not only is there evidence of risk factors for asd, but there is also evidence that certain factors protect against asd, for instance the use of folic acid before and during pregnancy. CONCLUSION: asd are probably related to a combination of gene mutations and environmental factors and to the interactions between the two. Further research is needed into the genetic and environmental causes of asd.

Cytomegalovirus contributes partly to uraemia-associated premature immunological ageing of the T cell compartment.

Cytomegalovirus (CMV) infection has been implicated in accelerated T cell ageing. End-stage renal disease (ESRD) patients have a severely immunologically aged T cell compartment but also a high prevalence of CMV infection. We investigated whether CMV infection contributes to T cell ageing in ESRD patients. We determined the thymic output by the T cell receptor excision circle (TREC) content and percentage of CD31+ naïve T cells. The proliferative history of the T cell compartment by determination of the relative telomere length (RTL) and the T cell differentiation status was determined by immunophenotyping. It appeared that CMV infection did not affect thymic output but reduced RTL of CD8+ T cells in ESRD patients. Moreover, increased T cell differentiation was observed with higher percentages of CD57+ and CD28null CD4+ and CD8+ memory T cells. These CD28null T cells had significantly shorter telomeres compared to CD28+ T cells. Therefore we concluded that CMV infection does not affect the decreased thymic output but increases T cell differentiation as observed in ESRD-related premature T cell ageing.

Molecular recognition and self-assembly special feature: Self-assembled biomimetic [2Fe2S]-hydrogenase-based photocatalyst for molecular hydrogen evolution.

The large-scale production of clean energy is one of the major challenges society is currently facing. Molecular hydrogen is envisaged as a key green fuel for the future, but it becomes a sustainable alternative for classical fuels only if it is also produced in a clean fashion. Here, we report a supramolecular biomimetic approach to form a catalyst that produces molecular hydrogen using light as the energy source. It is composed of an assembly of chromophores to a bis(thiolate)-bridged diiron ([2Fe2S]) based hydrogenase catalyst. The supramolecular building block approach introduced in this article enabled the easy formation of a series of complexes, which are all thoroughly characterized, revealing that the photoactivity of the catalyst assembly strongly depends on its nature. The active species, formed from different complexes, appears to be the [Fe(2)(micro-pdt)(CO)(4){PPh(2)(4-py)}(2)] (3) with 2 different types of porphyrins (5a and 5b) coordinated to it. The modular supramolecular approach was important in this study as with a limited number of building blocks several different complexes were generated.

[Suicidality in people with autism without intellectual impairment]. / Suïcidaliteit bij mensen met autisme zonder verstandelijke beperking.

People with autism spectrum disorders (ASD) relatively often experience suicidality. This seems partly related to comorbid disorders such as depression, ADHD and addiction. In addition, people with ASD are relatively vulnerable due to limitations in social communication, for example for bullying behavior of others. This, too, plays a role in suicidality, as well as having a strong tendency to ruminate and difficulty regulating emotions. Particularly in women with ASD, we see increased suicidality; possibly because they have more comorbid disorders, but also because of their tendency to camouflage and compensate. Social support and a sense of belonging do not protect people with ASD against suicidality. Practical help does seemtobe a protective factor. In clinical practice, health professionals should be aware of possible suicidality in people with ASD. Treatment of comorbidity and emotion regulation problems, as well as the practical guidance and the use of good anti-bullying programs can play an important role in this.

Universal screening for thyroid disease SHOULD NOT be recommended before and during pregnancy.

Thyroid dysfunction in pregnancy is strongly associated with adverse maternal and foetal outcomes. The effects of treatment are less clear. There is ongoing discussion on whom to treat, when to treat and whether treatment is beneficial. Although universal screening for thyroid disease during pregnancy increases diagnosis and treatment of thyroid dysfunction, there is currently insufficient evidence demonstrating a positive effect of screening on maternal and foetal outcomes. We therefore, at present, recommend against universal screening for thyroid disease before and during pregnancy.

Single-fraction image-guided robotic radiosurgery efficiently controls local prostate cancer recurrence after radical prostatectomy.

Purpose: To assess the therapeutic potential of single-fraction robotic stereotactic ablative body radiotherapy (SABR) in patients with locally recurrent prostate cancer (PC) after radical prostatectomy (RP). Materials and methods: We included 35 patients with biochemical failure after RP with single-site local recurrence in the prostate bed diagnosed by PSMA PET/CT. About 20/35 pts had previously received post-surgical adjuvant radiation therapy.High-resolution multiparametric magnetic resonance imaging (mpMRI) for exact visualization of tumor tissue was performed at 1.5 (n = 23; Siemens Magnetom Aera) or 3 Tesla (n = 12; Siemens Magnetom VIDA, Siemens Healthineers, Erlangen, Germany). Using the MRI and PET/CT dataset for planning, SABR was carried out after ultrasound-guided placement of a single gold fiducial marker at the site of tumor recurrence using a CyberKnife M6 unit (Accuray Inc., Sunnyvale, USA). Due to the high diagnostic accuracy of PSMA PET/CT and mpMRI, pre-SABR biopsy of tumor tissue was not deemed necessary. PSMA PET/CT performed in median 88 days before SABR confirmed the absence of distant metastases. MpMRI was performed at a median of 22 days prior to the intervention. SABR was performed in a single fraction with a dose of 20 (5/35), 21 (27/35) or 22 (3/35) Gy. Follow-up serum PSA was measured every 3 months thereafter. Results: Median patient age was 72 years (57-80 years) and median time from RP to SABR was 96.8 months (IQR, 69.3-160.2). Median serum PSA before SABR was 1.38 ng/mL (IQR 0.75-2.72). At 3 months, median PSA had dropped significantly in 27/35 patients to a median of 0.35 ng/mL (IQR 0.25-0.68). At 6 months, 30/35 patients showed biochemical response to SABR, while five patients were progressing: three had systemic disease on PSMA PET/CT, while two patients had rising PSA values without a visible correlate on PET/CT. The median follow-up time was 16 months. Grade 1 genitourinary (GU) toxicity was reported in 3/35 patients (9%) and grade 1 gastrointestinal (GI) toxicity in 2/35 patients (6%), respectively. Conclusion: SABR is an efficient new treatment option in the management of single-site local recurrent PC without the evidence of systemic disease; due to its very low toxicity, it is an alternative to surgical re-treatment or other focal therapies. It can significantly delay the onset of androgen deprivation therapy (ADT) in biochemical failure after radical prostatectomy.

Performance of clinical signs to detect bluetongue virus serotype 8 outbreaks in cattle and sheep during the 2006-epidemic in The Netherlands.

The performance of clinical signs as a diagnostic test for the detection of BTV-8 outbreaks during the 2006-epidemic in The Netherlands was evaluated by constructing and analysing receiver operating characteristic (ROC) curves. The area under the ROC curve of the BT-associated clinical signs in cattle was 0.77. An optimal efficient test (maximising both sensitivity and specificity) in cattle herds combined a sensitivity (Se) of 67% with a specificity (Sp) of 72%, comprising the following clinical signs: ulcerations and/or erosions of oral mucosa or erosions of lips/crusts in or around nostrils or oedema of the nose or hyperaemic/purple coloration of tongue, tongue protrusion or coronitis or apathy/tiredness or muscle necrosis, stiffness of limbs or loathing or refusal to move, prostration or torticollis or anoestrus. The area under the ROC curve of the BT-associated clinical signs in sheep was 0.81. The optimal efficient test in sheep flocks combined a Se of 76% with a Sp of 72%, comprising the following clinical signs: ulcerations of oral mucosa or serous nasal discharge or erosions/ulceration of tongue mucosa or hypersensitivity of the skin or muscle necrosis, stiffness of limbs or coronitis or grinding of teeth or salivation or weakness/paresis.

[Epidemiology and diagnostic assessment of small renal masses]. / Epidemiologie und Diagnostik kleiner Nierentumoren.

BACKGROUND: The incidence of small renal masses has been rising over the last few decades. At the same time, mortality of renal cell carcinoma (RCC) is decreasing. These trends can be explained by the availability of improved therapeutic measures and the good prognosis of small renal masses (SRM) turning out to be histopathologically benign or of low malignancy in many cases. OBJECTIVES: The aim of this article is to present epidemiology and diagnostic assessment of SRM. MATERIALS AND METHODS: Statistics, basic research, guidelines. RESULTS: The incidence of SRM is rising due to the widespread use of imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), and contrast-enhanced ultrasound (CEUS). Sensitivity is excellent for CEUS and for CECT in the characterization of SRM, while good specificity values can be reached by MRI. For characterization of complex cystic renal masses, CEUS has good diagnostic accuracy. CONCLUSIONS: Due to improved diagnostic possibilities, SRMs can be diagnosed in early asymptomatic stages. As SRM have a good prognosis and often are of low malignancy therapy, options should be carefully considered; especially in older patients, active surveillance should considered.

[Radical prostatectomy as part of a multimodal concept for patients with prostate cancer and bone metastases at initial diagnosis]. / Die radikale Prostatektomie als Teil eines multimodalen Konzepts für Patienten mit Prostatakarzinom- und Knochenmetastasen bei der Erstdiagnose.

In patients with metastatic prostate cancer presenting with synchronous bone metastases, the surgical removal of the primary is an experimental treatment approach. In the following article, we evaluate the rationale for this approach.

[Cytoreductive, radical prostatectomy in metastatic prostate cancer]. / Die zytoreduktive radikale Prostatektomie beim metastasierten Prostatakarzinom.

The resection of the primary tumor in patients with metastatic prostate cancer is controversially debated. Retrospective clinical studies indicate survival benefits and prevention of secondary, locoregional complications; however, results of ongoing multicenter prospective studies are still lacking. This review highlights the rationale behind the cytoreductive prostatectomy and summarizes current clinical study results.

Cognitive disturbances in old dogs suffering from the canine counterpart of Alzheimer's disease.

In geriatric dogs, Alzheimer-like behavior is frequently observed. This behavior has been classified by several authors using questionnaires and a correlation has been described between cognitive dysfunctions and Alzheimer-like pathology. In the present study, cognitive performance was correlated with brain pathology for 30 dogs of varying ages. Within these animals, two age-matched groups of old dogs with and without behavioral changes were compared. The behavioral changes were analyzed and scored with questionnaires and necropsy was performed to rule out any other cause for changed behavior. Measurements, (immuno)-histochemical staining and fluorescence microscopy were used to detect cortex atrophy, amyloid, rest-products of oxidative damage, demyelination and accumulations of macrophages in the brains of these dogs. Spearman rank correlation coefficients (r) were calculated and adjusted according to Bonferonni. In the whole group (young to very old dogs), the age of the animal showed a significant correlation with various behavioral changes (r = 0.7 to 0.9, P < 0.01). The dementia score correlated significantly (r = 0.6 to 0.8, P < 0.01) with all the brain lesions studied, except one, i.e. demyelination (r = -0.4, P > 0.05). These results suggest that a questionnaire can be used to diagnose Alzheimer-like changes in canine practice. Oxidative damage on a cellular and a nuclear level plays an important role in behavior changes.