Increased visceral adipose tissue in male patients with non-clear cell renal cell carcinoma.

BACKGROUND: It is well known that there is a link between obesity and oncogenesis in many sites, including the kidney. Adiposopathy is characterized by an excessive accumulation of adipose tissue, principally visceral, which can lead to adipocyte and adipose tissue-related disorder, promoting metabolic syndrome. Visceral adipocytes secrete growth factors, proinflammatory cytokines and adipokines, regarded as mediating factors associated with the oncogenesis of obesity-related tumors. In this study, we evaluate the relationship between visceral adipose tissue (VAT) and non-clear cell renal cell carcinoma (nccRCC) in male patients. METHODS: In this retrospective study, two groups were included: nccRCC group and control group. Total adipose tissue (TAT) area, VAT area and subcutaneous adipose tissue (SAT) area were measured in both groups. VAT/SAT ratio was subsequently calculated. RESULTS: Statistically significant differences between the two groups were found in TAT area (p = 0.05), VAT area (p < 0.01) and VAT/SAT ratio (p < 0.05), while no significant difference was found in SAT area. CONCLUSIONS: This study demonstrates an increased visceral adipose tissue in male patients with nccRCC.

Using a mixed-methods approach to measure impact of a school-based nutrition and media education intervention study on fruit and vegetable intake of Italian children.

OBJECTIVE: The purpose of the present study was to investigate the impact of a school-based nutrition and media education intervention on the promotion of fruit and vegetable consumption to help prevent childhood obesity. DESIGN: The 10-week-long intervention included sessions on nutrition education and media literacy. It also included a health communication media-based campaign workshop during which the children created posters, newsletters and video commercials related to fruits and vegetables targeted to their parents. For evaluation purposes, the study utilized a mixed-methods approach, including a quasi-experimental study (with one intervention group and one control group) and a focus group study. SETTING: Four different elementary schools in Treviso (Veneto Region of Italy) agreed to participate in the research. SUBJECTS: The target population for the study included 10-year-old Italian children and their parents. RESULTS: Data indicate that this intervention was effective for children but not for parents. Evaluation results show that the intervention was effective in significantly increasing children's fruit and vegetable intake (P<0·05) and all psychosocial determinants (P<0·05). CONCLUSIONS: The study results confirm the efficacy of a school-based health and media education intervention to address the children's obesity issue and, in particular, to increase children's fruit and vegetable intake. The study also opens a new perspective on the theoretical constructs investigated, because the development of 'ability of expression' could be considered one of the most important factors to determine the efficacy of the intervention.

Multidisciplinary follow-up in a patient with Morgagni hernia leads to diagnosis of Marfan syndrome.

BACKGROUND: congenital diaphragmatic hernia (CDH) is a birth defect occurring in isolated or syndromic (chromosomal or monogenic) conditions. The diaphragmatic defect can be the most common one: left-sided posterolateral, named Bochdalek hernia; or it can be an anterior-retrosternal defect, named Morgagni hernia. Marfan syndrome (MFS) is a rare autosomal dominant inherited condition that affects connective tissue, caused by mutations in fibrillin-1 gene on chromosome 15. To date various types of diaphragmatic defects (about 30 types) have been reported in association with MFS, but they are heterogeneous, including CDH and paraesophageal hernia. CASE PRESENTATION: We describe the case of a child incidentally diagnosed with Morgagni hernia through a chest X-ray performed due to recurrent respiratory tract infections. Since the diagnosis of CDH, the patient underwent a clinical multidisciplinary follow-up leading to the diagnosis of MFS in accordance with revised Ghent Criteria: the child had typical clinical features and a novel heterozygous de novo single-base deletion in exon 26 of the FBN1 gene, identified by Whole-Exome Sequencing. MFS diagnosis permitted to look for cardiovascular complications and treat them, though asymptomatic, in order to prevent major cardiovascular life-threatening events. CONCLUSION: Our case shows the importance of a long-term and multidisciplinary follow-up in all children with diagnosis of CDH.

Oxidative stress in relation to serotonin under general anaesthesia in dogs undergoing ovariectomy.

Abdominal surgery such as ovariectomy is a traumatic event that can cause oxidative stress. The aim of the present study was to evaluate the concentration of serotonin in relation to ovariectomy-induced oxidative stress in dogs undergoing general anesthesia. Thirty-two female dogs, under general anesthesia, received meloxicam before surgery (0.2 mgkg-1 SC) and after surgery (0.1 mgkg-1 OS every 24 h). The physiological, hematological, and biochemical parameters: glycemia, aspartate transaminase (AST), alanine aminotransferase (ALT), total protein, albumin and BUN were evaluated. Oxidative stress was determined by malondialdehyde (MDA) assay, catalase (CAT), superoxide dismutase (SOD), myeloperoxidase (MPO) and butyrylcholinesterase (BuChe) at baseline, 36 and 48 h after the last administration of meloxicam. Serotonin (5-HT) concentration was also evaluated at baseline, 36 and 48 h after the last administration of meloxicam. Responses to surgical stimulus were evaluated. Physiological and hematological parameters they fell within the normal ranges for anesthetized dogs. Glycemia increased, albumin levels decreased after surgery. No rescue analgesia was required. MDA and 5-HT concentrations significantly increased from the baseline at 36 and 48 h after surgery (p < .001). 5-HT levels could be used as an indicator for oxidative stress induced by surgery and it might be employed for objectively quantifying the well-being of the surgical patient.

Occurrence and health risk assessment of mineral composition and aflatoxin M1 in cow milk samples from different areas of Sicily, Italy.

This study aimed to determine 16 mineral elements (Cd, Pb, As, Na, Mg, Al, Ca, K, Cr, Mn, Fe, Ni, Cu, Zn and Se) using inductively coupled plasma mass spectrometry (ICP-MS) and a direct mercury analyzer (DMA-80) for Hg evaluation. Aflatoxin M1 was determined by high-performance liquid chromatography with fluorescence detection (HPLC-FLD) in cow milk samples. This research considered 180 milk samples, 20 by province (Palermo, Catania, Messina), collected for a period of three years (2020-2022) to assess the potential risks for consumer, the safety status and nutritional quality related to mineral intake by consuming of milk. All samples showed a Pb concentration below the limit reported by European Regulation 915/2023. Cadmium and Hg concentrations were below the Limit Of Quantification (LOQ) in all samples analyzed. The milk samples analyzed proved to be a good source of Ca (up to 44.5 % of the dietary reference values), with well percentages also for Na (up to 7.6 %), K (up to 23.1 %) and Mg (up to 11.1 %). Regarding trace elements, the results reported that chromium requires attention; its value was always higher than 168.8 % in all samples analyzed. Levels of arsenic and lead were up to 20.2 % and up 7.1 % respectively. Aflatoxin M1 concentrations were below the limit of detection (< 0,009 mcg/kg) in all milk analyzed. Therefore, further studies are needed to safeguard consumer health, the quality of the product and to assess the state of animal health.

Exploring the Impact of Genetics in a Large Cohort of Moebius Patients by Trio Whole Exome Sequencing.

Moebius syndrome (MBS) is a rare congenital disorder characterized by non-progressive facial palsy and ocular abduction paralysis. Most cases are sporadic, but also rare familial cases with autosomal dominant transmission and incomplete penetrance/variable expressivity have been described. The genetic etiology of MBS is still unclear: de novo pathogenic variants in REV3L and PLXND1 are reported in only a minority of cases, suggesting the involvement of additional causative genes. With the aim to uncover the molecular causative defect and identify a potential genetic basis of this condition, we performed trio-WES on a cohort of 37 MBS and MBS-like patients. No de novo variants emerged in REV3L and PLXND1. We then proceeded with a cohort analysis to identify possible common causative genes among all patients and a trio-based analysis using an in silico panel of candidate genes. However, identified variants emerging from both approaches were considered unlikely to be causative of MBS, mainly due to the lack of clinical overlap. In conclusion, despite this large cohort, WES failed to identify mutations possibly associated with MBS, further supporting the heterogeneity of this syndrome, and suggesting the need for integrated omics approaches to identify the molecular causes underlying MBS development.

Tramadol vs. Lidocaine Administered Intraperitoneally and in Incisional Lines for the Intraoperative and Postoperative Pain Management of Romifidine-Telazol-Anesthetized Swine Undergoing Umbilical Hernia Repair.

The aim of the study was to compare the analgesic efficacy of tramadol and lidocaine for local anesthesia during umbilical hernia repair in swine. The study was performed on 66 large white crossbred swine. The swine received a mixture of tiletamine/zolazepam at 5 mg/kg and romifidine at 80 µg/kg, administered intramuscularly. Then, they were divided into three groups (n = 22) that received different treatments with lidocaine at 4 mg/kg and tramadol at 4 mg/kg. The LL group received lidocaine both by infiltration of the surgical planes and intraperitoneally. The LT group received lidocaine by infiltration of the surgical planes and tramadol intraperitoneally. The TT group received tramadol both by infiltration of the surgical planes and intraperitoneally. In all groups, the infiltration of the surgical planes into the umbilical region involved both the skin and muscle planes. Heart rate, noninvasive arterial blood pressure, and respiratory frequency were recorded during surgery. The response to the surgical stimulus was evaluated using a cumulative pain scale (the cut-off point for rescue analgesia was set to 10). Postoperative pain was assessed using the UNESP-Botucatu pig composite acute pain scale (the cut-off point was set to 4). The trend of physiological variables was adequate for patients under anesthesia. No subject required intraoperative and postoperative rescue analgesia. Tramadol could therefore be used for pain management in livestock.

[A review of nursing and multidisciplinary journals for nurses in Italy]. / Le riviste degli infermieri e le riviste multidisciplinari di interesse infermieristico in Italia: una rassegna.

General nursing journals are only three and 6 specialistic nursing journals (for intensive care, neurology, neurosurgery and psychiatric nurses, paediatric nurses, diabetes cardiology and perioperative nurses) are published in Italy. Several Italian journals include in their mission a special focus to nurses and nursing care. The main journals are presented and described and some reflections are offered on the future challenges for Italian nursing journals.

[Research studies published in Assistenza infermieristica e ricerca from 1991 to 2011]. / Le ricerche pubblicate sulla rivista 'Assistenza infermieristica e ricerca' dal 1991 al 2011.

OBJECTIVE: The research studies published on Assistenza Infermieristica e Ricerca along the last 21 years were analysed to identify main trends. METHOD: Research articles were extracted and each was classified according to the main area, authors, place of origin, design. RESULTS: The number of research papers is progressively increasing and represents 50% of the papers published in 2006-2001. Most papers are focused on clinical practice and deal with issues relevant for the practice such as symptom control, organization or problems of elderly and frail populations. The number of experimental-quasi-experimental studies is limited (12%) but the variety of research designs increased in the last 5 years, with qualitative and validation studies. CONCLUSIONS: Although the number good quality research papers is increasing, most studies are monocentric and research needs to be incremented and promoted.

[Health projects managed by Nursing Coordinators: an analysis of contents and degree of success]. / I progetti gestiti dai Coordinatori: analisi del loro profilo e successo.

AIM: To describe the evolution and results of health projects run in hospitals and managed by Nursing Coordinators. METHODS: A convenience sample of 13 north Italian hospital, and a sample of 56 Nursing Coordinators with a permanent position from at least 1 year, was contacted. The following information was collected with a structured interview: projects run in 2009, topic, if bottom up or top down, number of staff involved and state (ended, still running, stopped). RESULTS: In 2009 Nursing Coordinators started 114 projects (mean 1.8±1.2 each): 94 (82.5%) were improvement projects, 17 (14.9%) accreditation, and 3 (2.6%) research. The projects involved 2.732 staff members (73.7%; average commitment 84 hours); 55 (48.2%) projects were still running, 52 (45.6%) completed, for 5 (4.4%) there was no assessment and 2 (1.8%) had been stopped. CONCLUSIONS: Nurses are regularly involved in several projects. A systematic monitoring of the results obtained and stabilization strategies are scarce. Due to the large number of resources invested, a correct management and the choice of areas relevant for patients' problems and needs are pivotal.

Development of a new scoring method in the neurofunctional assessment of preterm infants.

Infants born preterm are at high risk of presenting neurodevelopmental delay. The Neurofunctional Assessment (NFA) describes infants' neurodevelopment through the evaluation of six different domains. This study aimed to evaluate how, in a cohort of preterm infants, each NFA domain assessed at 3 months of corrected age (CA) was associated with neurodevelopment at 2 years of CA using the Griffiths Mental Developmental Scales Extended Revised (GMDS-ER). In addition, by introducing the NFA complexity score (CS), the study aimed to define a threshold that can help clinicians discriminate infants at higher risk of later neurodevelopmental delay. We conducted an observational, longitudinal study including 211 preterm infants. At 3 months of CA, infants who had normal scores in each domain showed a significantly higher GMDS-ER global quotient (GQ) at 2 years of CA. In addition, linear model results showed a significant negative relationship between the NFA CS and 2-year GMDS-ER GQ (estimate: - 0.27; 95% CI - 0.35, - 0.20; p value < 0.001). Each 10-point increase in the NFA CS was associated with an average 2.7-point decrease in the GMDS GQ. These results highlight how the NFA domains and NFA CS are compelling instruments for the early identification of children at risk for long-term adverse outcomes.

Snail Mucus Filtrate Reduces Inflammation in Canine Progenitor Epidermal Keratinocytes (CPEK).

Atopic dermatitis (AD) is an inflammatory and allergic disease, whose multifactorial etiopathogenesis is the consequence of the link between the genetic, immunological and environmental components. The complexity and difficulty in understanding the causes that trigger or exacerbate this pathology makes it difficult, once diagnosed, to proceed with a targeted and effective therapeutic process. Today, the new frontiers of research look to natural and innovative treatments to counteract the different manifestations of dermatitis. From this point of view, the mucus secreted by Helix aspersa Muller has proven, since ancient times, to be able to neutralize skin diseases. To study canine atopic dermatitis (cAD), we used cell lines of canine epidermal keratinocytes (CPEK) that are optimal to understand the biological reactivity of keratinocytes in vitro. The data obtained from our study demonstrate the anti-inflammatory capacity of snail secretion filtrate (SSF) in counteracting the production of proinflammatory cytokines produced during cAD, highlighting the opportunities for further studies to be able to identify new, natural and safe treatments for cAD and to open new frontiers for veterinarians and owners.

Small bowel obstruction and intestinal ischemia: emphasizing the role of MDCT in the management decision process.

The objective of this article is to assess the computed tomography (CT) findings of small bowel obstruction (SBO) complicated by ischemia. SBO is a frequent clinical entity characterized by high morbidity and mortality. The radiologic aim is not just to diagnose the obstruction itself but to rule out the presence of complications related to SBO. This is crucial for differentiating which patients can be safely treated non-operatively from the ones who may need an urgent surgical approach. The main complication of SBO is intestinal ischemia. In the emergency setting, CT imaging is the modality of choice for SBO because of its ability to assess the bowel wall, the supporting mesentery and peritoneal cavity all in one. On the other hand, the radiologist who documents an intestinal ischemia should think about SBO as possible cause. In this case, the main finding which helps the radiologist in the identification of SBO is the presence of multiple and packed valvulae conniventes in the dilated bowel wall and the "transition zone" that indicates the passage between compressed and decompressed small bowel, otherwise the localization of the obstruction cause. Once the site of obstruction has been recognized, the other issue is to assess the cause of obstruction, considering that the most common cause of SBO remains "unidentified" and related to intra-abdominal adhesions. After that, the following most important point is to rule out the presence of an ischemic bowel and mesenteric changes associated to SBO. CT signs of bowel ischemia include reduced or increased bowel wall enhancement, mesenteric edema or engorgement, fluid or free air in the peritoneal cavity. This condition usually leads to an urgent laparotomy and, in some cases, to a surgical resection.

A Multimodal Ensemble Driven by Multiobjective Optimisation to Predict Overall Survival in Non-Small-Cell Lung Cancer.

Lung cancer accounts for more deaths worldwide than any other cancer disease. In order to provide patients with the most effective treatment for these aggressive tumours, multimodal learning is emerging as a new and promising field of research that aims to extract complementary information from the data of different modalities for prognostic and predictive purposes. This knowledge could be used to optimise current treatments and maximise their effectiveness. To predict overall survival, in this work, we investigate the use of multimodal learning on the CLARO dataset, which includes CT images and clinical data collected from a cohort of non-small-cell lung cancer patients. Our method allows the identification of the optimal set of classifiers to be included in the ensemble in a late fusion approach. Specifically, after training unimodal models on each modality, it selects the best ensemble by solving a multiobjective optimisation problem that maximises both the recognition performance and the diversity of the predictions. In the ensemble, the labels of each sample are assigned using the majority voting rule. As further validation, we show that the proposed ensemble outperforms the models learning a single modality, obtaining state-of-the-art results on the task at hand.

Impact of adjuvant imatinib on bone and muscle density in patients with resected gastrointestinal stromal tumors.

Adjuvant treatment with Imatinib is the standard of care for high-risk resected GISTs. Imatinib is known to have an impact on bone mineral density in patients affected by chronic myeloid leukemia, however this effect has never been investigated in GISTs. We retrospectively evaluated, on CT scans, the effect of adjuvant Imatinib (400 mg/die) on bone mineral density and muscle composition in 14 patients with surgically resected GISTs and in a control group of 8 patients who did not received any treatment. The effect of bone and muscle composition on Imatinib-tolerance was assessed as well. Overall patients receiving Imatinib experienced an increase in bone mineral density during treatment (p = 0.021); with higher increase in patients with basal values < 120 mg/cm3 (p = 0.002). No changes were observed in the control group (p = 0.918). Skeletal muscle index and lean body mass did not change over time during Imatinib therapy; however, patients with lower lean body mass and lower body mass index experienced more grade 3 treatment related toxicities (p = 0.024 and p = 0.014 respectively). We also found a non-significant trend between basal BMD and grade 3 toxicities (p = 0.060).

Augmented reality 3D navigation system for percutaneous CT-guided pulmonary ground-glass opacity biopsies: a comparison with the standard CT-guided technique.

Background: Augmented reality navigation system for percutaneous computed tomography (CT)-guided pulmonary biopsies has recently been introduced. There are no studies in literature about its use for ground glass lesions biopsies. The aim of this study is to evaluate the effectiveness of an augmented reality infrared navigation system performance on CT-guided percutaneous lung ground glass opacity (GGO) biopsy compared to a standard CT-guided technique. Methods: A total of 80 patients with lung GGO who underwent to a percutaneous CT-guided lung biopsy with an augmented reality infrared navigation system were retrospectively enrolled in the study. Comparison was performed with a group of 80 patients who underwent to lung biopsy with the standard CT-guided technique. Evaluation of maximum lesion diameter (MLD), distance between lesion and pleural surface (DPS), distance travelled by the needle (DTP), procedural time, validity of histological sample, procedural complications and the radiation dose to the patient's chest were recorded for each patient of both groups. In addition, each group was divided into two subgroups based on lesion size, according to a cut-off of 1.5 cm (<1.5 cm; ≥1.5 cm). Results: Augmented reality navigation system showed a significant reduction in procedural time, radiation dose administrated to patients and complications rate compared to a standard CT-guided technique. Technical success was achieved in the 100% of cases in both groups, but the diagnostical success was higher in the group where patients underwent to lung biopsies with the use of navigation system. We also found that using an augmented reality navigation system increases the diagnostical success rate for lesion <1.5 cm. MLD, DPS and DTP did not differ significantly between the two groups of patients. Conclusions: The use of an augmented reality navigation system for percutaneous CT-guided pulmonary GGO biopsies has demonstrated a lower incidence of post-procedural complications, a significantly reduction of the radiation dose administered to patients and a higher diagnostical success rate.

A patient with multiple brown tumors due to secondary hyperparathyroidism: A case report.

Brown tumor is an uncommon non-neoplastic radiolucent bone lesion due to a rapid bone loss replaced by haemorrhage and reparative granulation tissue. It is a manifestation of hyperparathyroidism related to the high level of parathyroid hormone and represents a problem linked to the adherence to therapy. We present a case of a 44 years-old Caucasian female with hemodialysis-dependent chronic kidney disease in poor sanitary condition with CT evidence of innumerable and widespread bone tumors. At first, we considered these bone lesions strongly suspicious for metastasis, so we recommended an oncological consultation and laboratory studies, that showed a secondary hyperparathyroidism with elevated serum parathormone level of 923 pg/mL (normal range: 10-70 pg/mL). According to our experience, in case of radiological evidence of multiple bone lesions, a correct medical history is mandatory. When the patient has a history of chronic kidney disease and dialysis and high blood levels of parathyroid hormone are present, secondary hyperparathyroidism should always be considered in the differential diagnosis.

Physicochemical, Nutritional, Microbiological, and Sensory Qualities of Chicken Burgers Reformulated with Mediterranean Plant Ingredients and Health-Promoting Compounds.

The quality of chicken burgers reformulated by the partial replacement of meat by Mediterranean plant ingredients and enriched with peculiar amounts of n-3 PUFAs, Mg, Fe, Se, and folic acid, was evaluated in comparison to conventional chicken burgers. Specifically, two types of burger were developed, namely the "Sicilian burger"-based on cherry tomato and rosemary-and the "Mediterranean burger"-with basil leaves and thyme essential oil-every recipe being differentially functionalized according to the nutritional requirements of consumers, such as children, pregnant women and elderly. Mediterranean ingredients were responsible for different pH, color, and cooking loss between conventional and functional burgers. Except for n-3 PUFAs resulting poorly fortified, the functionalization with Mg, Fe, Se, and vitamin B9 was successful in all products. Considering the target consumer categories, the daily consumption of the functional burger may assure an intake of Mg, Fe, and Se equal, respectively, to 37.31-59.90%, 17.76-46.81%, and 27.20-50.05%, and a cover of vitamin B9 of 31.98-48.31% of the relative population reference intakes. Fortified products kept a good microbiological quality during 5 days of refrigerated storage, and, according to the sensorial descriptive analysis and the hedonic test, they showed a higher acceptability than conventional burgers.

Increased T1 Signal Intensity of the Anterior Pituitary Gland on Unenhanced Magnetic Resonance Images After Chronic Exposure to Gadodiamide.

OBJECTIVE: The aim of this study was to assess the signal intensity of the anterior pituitary (AP) gland on unenhanced T1-weighted images in patients with history of serial intravenous injections of gadodiamide and normal renal function. MATERIALS AND METHODS: We included 53 patients who had undergone at least 5 injections of gadodiamide and a control group of 15 subjects who underwent at least 5 brain magnetic resonance imaging without gadolinium-based contrast agents. Using unenhanced sagittal T1-weighted images, values of mean signal intensity of the AP and of the central pons were obtained. Anterior pituitary-to-pons signal intensity ratios were calculated dividing the values of the AP by those of the pons. Then, the ratios were compared between the first and the last magnetic resonance imaging scans for all the subjects. To assess the difference between the first and the last ratios, nonparametric Wilcoxon signed-rank test with Monte Carlo resampling was applied. A P value less than 0.05 was considered as statistically significant. RESULTS: The comparison between the first and the last scan revealed a statistically significant increase of AP-to-pons ratio in the last scan for the gadolinium-exposed group (P < 0.001), whereas nonsignificant results were found for the control group (P = nonsignificant). CONCLUSIONS: We found an increased signal intensity of the AP on unenhanced T1-weighted images in patients with history of serial intravenous injections of gadodiamide and normal renal function, suggesting gadolinium deposition or long-term retention within the AP gland. Our findings need to be confirmed by further histochemical analysis of AP gland tissue samples.

Anterior pituitary gland T1 signal intensity is influenced by time delay after injection of gadodiamide.

To test the hypothesis of washout from the anterior pituitary (AP) gland after serial injections of gadodiamide. We included 59 patients with history of at least 5 injections of gadodiamide. Values of mean signal intensity of the AP and of the central pons were measured on unenhanced sagittal T1-weighted images. AP-to-pons signal intensity ratios were calculated dividing the values of the AP by those of the pons. The measurements were performed using MR images acquired at four different time points including baseline (prior to any gadodiamide injection), minimum post-injection time delay, maximum post-injection time delay, and last available MR scans. Normalized ratios (i.e. ratios divided total volume of injected gadodiamide) were also calculated. To assess the difference between ratios, non-parametric Wilcoxon signed-rank test was applied. The correlations were tested with non-parametric Spearman correlation coefficient. A p-value < 0.05 was considered as statistically significant. A statistically significant increase of AP signal intensity was found by comparing the baseline scans with both the minimum time delay (p = 0.003) and maximum time delay scans (p = 0.005). We found significant higher normalized ratios for minimum post-injection time delay with respect to maximum post-injection time delay (p < 0.001). The normalized ratios demonstrated a statistically significant negative correlation with the post-injection time delay (r = - 0.31; p = 0.006). The findings of this study suggest that washout phenomena of retained/deposited gadolinium from the AP are influenced by the total injected volume and post-injection time delay.