Maximizing agricultural reuse of recycled nutrients: A spatially explicit assessment of environmental consequences and costs.

Recovering nutrients from organic materials to reduce artificial fertilizer inputs requires the implementation of processing technologies and can involve considerable logistics and transportation costs. Reducing such costs by directly applying organic materials to agricultural land can contribute to pollution due to potential contaminants and unbalanced nutrient ratios. Assessing the cost of increased recycling requires a spatially explicit approach because availability of organic materials, nutrient demand and agro-ecosystem properties vary spatially. A multi-objective model was developed to estimate the trade-offs between costs of nutrient recovery and improvements in nutrient distribution for a case study area in The Netherlands. The evaluated recovery processes included solid-liquid separation followed by reverse osmosis to recover nutrients from pig manure which was compared to a conventional process via hygienisation and export. Results indicate that, even in a nutrient saturated area, replacement potential of artificial nitrogen (N) and phosphorus (P) fertilizers through locally reclaimed nutrients is limited to about 17% N and 55% P. A cost optimum was found when about 48% of the initial pig manure quantities were processed via nutrient recovery and directed to land. Increasing manure processing for nutrient recovery led to a redistribution of nutrients and trace metals (zinc (Zn) and copper (Cu)), resulting in more localized concentration. Zn and Cu were enriched by about 8% and 2%, respectively, when maximizing nutrient recovery. Our generic model offers a methodology to assess the trade-offs between increased recycling and associated spatial effects to facilitate sustainable recycling infrastructures for achieving more circular agriculture.

Evaluation of the immature platelet fraction contribute to the differential diagnosis of hereditary, immune and other acquired thrombocytopenias.

The differential diagnosis of immune (ITP) and hereditary macrothrombocytopenia (HM) is key to patient management. The immature platelet fraction (IPF) represents the subset of circulating platelets with higher RNA content, and has been shown to distinguish hypo- from hyperproliferative thrombocytopenias. Here we evaluated the diagnostic accuracy of IPF in the differential diagnosis between HM and other thrombocytopenias in a population of patients with post-chemotherapy thrombocytopenia (n = 56), bone marrow failure (n = 22), ITP (n = 105) and HM (n = 27). TPO levels were also measured in HM and ITP matched for platelet counts. Platelet counts were similar in all patient groups. Higher IPF values were observed in both ITP (12.3%; 2.4-65.6%) and HM (29.8%; 4.6-65.9%) compared to hypoproliferative thrombocytopenias. IPF values were also higher in HM compared to ITP, yielding a diagnostic accuracy of 0.80 (95%CI 0.70-0.90; P < 0.0001) to distinguish these two conditions. Intra- and inter-assays reproducibility of IPF in HM patients revealed that this is a stable parameter. In conclusion, IPF is increased in HM compared to both ITP and other thrombocytopenias and contributes to the differentiation between ITP and HM. Further studies are warranted to understand the biological rationale of these findings and to its incorporation in diagnostic algorithms of HM.

Tips and tricks for a safe and effective image-guided percutaneous renal tumour ablation.

Image-guide thermal ablations are nowadays increasingly used to provide a minimally invasive treatment to patients with renal tumours, with reported good clinical results and low complications rate. Different ablative techniques can be applied, each with some advantages and disadvantages according to the clinical situation. Moreover, percutaneous ablation of renal tumours might be complex in cases where there is limited access for image guidance or a close proximity to critical structures, which can be unintentionally injured during treatment. In the present paper we offer an overview of the most commonly used ablative techniques and of the most important manoeuvres that can be applied to enhance the safety and effectiveness of percutaneous image-guided renal ablation. Emphasis is given to the different technical aspects of cryoablation, radiofrequency ablation, and microwave ablation, on the ideal operating room setting, optimal image guidance, application of fusion imaging and virtual navigation, and contrast enhanced ultrasound in the guidance and monitoring of the procedure. Moreover, a series of protective manoeuvre that can be used to avoid damage to surrounding sensitive structures is presented. A selection of cases of image-guided thermal ablation of renal tumours in which the discussed technique were used is presented and illustrated. TEACHING POINTS: • Cryoablation, radiofrequency and microwave ablation have different advantages and disadvantages. • US, CT, fusion imaging, and CEUS increase an effective image-guidance. • Different patient positioning and external compression may increase procedure feasibility. • Hydrodissection and gas insufflation are useful to displace surrounding critical structures. • Cold pyeloperfusion can reduce the thermal damage to the collecting system.

Treatments for colorectal liver metastases: A new focus on a familiar concept.

A major challenge for the management of advanced-colorectal-cancer is the multidisciplinary approach required for the treatment of liver metastases. Reducing the burden of liver metastases with liver-directed therapy has an important impact on both survival and health-related quality of life. This paper debates the rationale and current liver-directed approaches for colorectal liver metastases based on the evidence of literature and new clinical trials. Surgery is the gold standard, when feasible, and it's the main treatment goal for patients with potentially-resectable disease as a means of prolonging progression-free survival. Better tumor response rates with modern systemic therapy mean that more unresectable patients are now down-staged for radical resection following conversion therapy but for other patients, additional procedures are needed. In multiple unilobar disease, when the projected remnant liver is <30% of the total liver, portal embolization or selective-internal-radiation-therapy (SIRT) can induce hypertrophy of the healthy liver, leading to resectability. In multiple bilobar disease, in situ destruction of non-resectable lesions by minimally invasive techniques may be associated with liver resection to achieve potential curative intent. Other palliative liver-directed approaches, such as SIRT or intra-hepatic chemotherapy (HAI), which are associated with higher response rates, may also have role in down-staging patients for resection. Until recently, such technologies have not been validated in prospective controlled trials. However in the light of new Phase 3 data for SIRT as well as for HAI combined with modern therapies or radiofrequency ablation in the first- and second-line setting, the clinical value of these treatments needs to be re-appraised.

Chemosaturation with percutaneous hepatic perfusions of melphalan for hepatic metastases: experience from two European centers.

PURPOSE: Chemosaturation with percutaneous hepatic perfusion (PHP; Hepatic CHEMOSAT(®) Delivery System; Delcath Systems Inc, USA) is a minimally invasive, repeatable regional therapy for unresectable hepatic metastases. It uses a system of catheters and filters to isolate hepatic venous blood from the systemic circulation, allowing delivery of high-dose chemotherapy to the hepatic artery. Effluent hepatic venous blood is filtered before being returned to the systemic circulation, thereby reducing exposure to chemotherapy. We describe our experiences with chemosaturation-PHP at 2 European centers. MATERIALS AND METHODS: 14 patients presented unresectable hepatic metastases from solid tumors; 13 received 1 - 3 sessions of chemosaturation-PHP. Melphalan 2.0 (n = 1) or 3.0 (n = 12) mg/kg was given as a 30-minute infusion into the hepatic artery. 12 patients were evaluable for tumor response. RESULTS: One complete (cholangiocarcinoma, n = 1) and 6 partial responses (ocular, n = 3 or cutaneous melanoma, n = 3) were observed, 5 patients had stable disease (ocular melanoma, n = 3; breast cancer, n = 1; gastric cancer, n = 1). Mild to moderate filter-related toxicity (i. e. thrombocytopenia, anemia) was observed immediately post-procedure. Grade 3/4 melphalan-related pancytopenia developed after 1 - 2 weeks. All hematological events were managed effectively with transfusions and/or other supportive measures. The new high-efficiency filter showed milder toxicity and faster recovery. In one case, chemosaturation-PHP was abandoned prematurely due to heparin-induced vaginal bleeding, and one patient died due to retroperitoneal hemorrhage from heparin anti-coagulation. CONCLUSION: Chemosaturation-PHP for non-resectable liver metastases is a feasible treatment option when performed by an experienced multi-disciplinary team. It may be a promising regional therapy for patients with no effective treatment options.

Interventional oncology in the elderly: complications and early response in liver and kidney malignancies.

OBJECTIVES: The complication rate, loco-regional responses and length of hospital stay were analyzed in patients with liver and kidney cancer older than 70years treated with interventional oncology procedures. The findings from the older population were compared with the younger patients (<70years) to detect any difference not related to chance. MATERIALS AND METHODS: Prospectively collected data on patients who underwent hepatic artery embolization (with or without radiofrequency ablation) and kidney radiofrequency ablation were retrospectively analyzed. Complication rates, loco-regional responses and length of hospital stay for patients older and younger than 70 were compared. RESULTS: 163 patients were treated, 66 (40.5%) older and 97 (59.5%) younger than 70years. The complication rate in patients older than 70 was 4.5% (3/66 pts) versus 3.1% (3/97 pts) (p=0.69) in the younger age-group. The complication rates for the liver embolization group, liver embolization plus radiofrequency and kidney radiofrequency group were 2/90 pts (2.2%), 2/42 pts (4.8%) and 2/31 pts (6.5%), respectively (p=0.46). Median hospital stay was three nights in both older and younger patients. Response rates were not significantly influenced by age. CONCLUSION: Liver embolization with or without radiofrequency and renal radiofrequency are safe and effective in older patients. Age alone should not be considered a contraindication to treatment in carefully selected patients.

Performance of a point-of-care device in determining prothrombin time in supra-therapeutic INRs.

INTRODUCTION: Point-of-care (POC) devices have been widely adopted for monitoring prothrombin time (PT) (INR) following the demonstration of their accuracy compared to standard INR determination. However, guidelines suggest confirmation of POC results when INRs increase above therapeutic range, due to concerns regarding possible inferior performance of POC devices in high INR levels. Unfortunately, patients with supra-therapeutic INRs are underrepresented in studies that validated these devices. METHODS: We performed a prospective evaluation of the performance of a POC device in monitoring oral anticoagulation in patients with INR values above 3.5 in a University outpatient anticoagulation clinic. During a 6-month period, 2322 INR determinations were performed with a POC device, and results above 3.5 were immediately repeated on an automated coagulometer. RESULTS: Dual INR determinations by two methods were obtained in 160 visits, with a mean INR from the POC device of 4.52 ± 0.96. Both classical statistics and clinical concordance analysis yielded satisfactory results when the two methods were compared. CONCLUSION: Our results demonstrate that POC devices present good correlation with standard laboratory methods for PT determination in supra-therapeutic INRs and that differences in clinical management do not support the need for systematic confirmation of these results in nonbleeding patients.

High-intensity focused ultrasound (HIFU) in patients with solid malignancies: evaluation of feasibility, local tumour response and clinical results.

PURPOSE: The purpose of this study was to evaluate the safety and efficacy of ultrasound-guided high-intensity focused ultrasound (USgHIFU) for ablation of solid tumours without damaging the surrounding structures. MATERIALS AND METHODS: A specific written informed consent was obtained from every patient before treatment. From September 2008 to April 2009, 22 patients with 29 lesions were treated: nine patients with liver and/or soft-tissue metastases from colorectal carcinoma (CRC), six with pancreatic solid lesions, three with liver and/or bone metastases from breast cancer, one with osteosarcoma, one with muscle metastasis from lung cancer, one with iliac metastasis from multiple myeloma and one with abdominal liposarcoma. The mean diameter of tumours was 4.2 cm. All patients were evaluated 1 day, 1 month and 3 months after HIFU treatment by multidetector computed tomography (MDCT), positron-emission tomography (PET)-CT and clinical evaluation. The treatment time and adverse events were recorded. RESULTS: All patients had one treatment. Average treatment and sonication times were, respectively, 162.7 and 37.4 min. PET-CT or/and MDCT showed complete response in 11/13 liver metastases; all bone, soft-tissue and pancreatic lesions were palliated in symptoms, with complete response to PET-CT, MDCT or magnetic resonance imaging (MRI); the liposarcoma was almost completely ablated at MRI. Local oedema was observed in three patients. No other side effects were observed. All patients were discharged 1-3 days after treatment. CONCLUSIONS: According to our preliminary experience in a small number of patients, we conclude that HIFU ablation is a safe and feasible technique for locoregional treatment and is effective in pain control.

Should liver metastases of breast cancer be biopsied to improve treatment choice?

BACKGROUND: Currently, the acquisition of tissue from metastatic deposits is not recommended as a routine practice. Our aim was to evaluate the discordance rate of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) receptor status between primary tumor and liver metastases and its potential impact on treatment choice. PATIENTS AND METHODS: We retrospectively analyzed a database including 1250 ultrasound-guided liver biopsies carried out at the European Institute of Oncology from August 1999 to March 2009. ER, PgR, and HER2 status were determined by immunohistochemistry and/or FISH. Differences between proportions were evaluated using Fisher's exact test. RESULTS: We identified 255 consecutive patients with matched primary and liver tissue samples. Changes in ER status were observed in 37 of 255 patients (14.5%). Changes in PgR status were observed in 124 of 255 patients (48.6%). Changes in HER2 status were observed in 24 of 172 assessable patients (13.9%). We observed a discordance in receptor status (ER, PgR, and HER2) between primary tumor and liver metastases, which led to change in therapy for 31 of 255 of patients (12.1%). CONCLUSIONS: Biopsy of metastases for reassessment of biological features should be considered in all patients, when safe and easy to carry out, since it is likely to impact treatment choice.

[The regions' contribution to assessment of work-related stress: an operative guide]. / Il contributo delle Regioni sulla valutazione del rischio stress lavoro-correlato: la guida operativa.

In order to formulate indications for work-related stress assessment established by Italian health and safety regulation (D.Lgs. 81/2008), the interregional technical committee has instituted a working group to define an operative guide. The guide indicates the elements that must be considered in the evaluation, criteria and methods for the assessment, the minimum requirements for the evaluation instruments, and the specific contents of the risk assessment document.The medical surveillance and the role of health and safety local authorities are also considered. The risk assessment must examine work organization indicators and the direct or indirect effects of work-related stress, like morbility, frequent accidents, changing job requests, legal actions, etc. Detecting subjective factors is a second step of the assessment, which must be carried out if the work organization indicators show considerable work-related stress problems, and only in the companies which employ more then ten workers.

Microparticles in deep venous thrombosis, antiphospholipid syndrome and Factor V Leiden.

Microparticles (MPs) are blebs released from cellular surfaces during activation/apoptosis. They are procoagulant, pro-inflammatory and could contribute to pathogenesis of deep venous thrombosis (DVT). This study compared the number, cellular origin and procoagulant activity of MPs on DVT patients in different clinical situations: at diagnosis (n = 9, 5F/4M; mean age = 41.11), 1-3 years after warfarin withdrawal (n = 10, 7F/3M; mean age = 32.90), associated to antiphospholipid syndrome (APS; n = 11, 9F/2M; mean age = 33.82), or asymptomatic carriers of Factor V Leiden (FVL; n = 7, 7F/0M; mean age = 34.00) vs healthy controls (CTR). The quantification and characterization were performed by flow cytometry using CD235, CD61, CD45, CD31, CD14, CD45, anti-TF and Annexin V. The plasmatic procoagulant activity was investigated by prothrombin fragment 1 + 2 (F1 + 2) determination. The MPs procoagulant activity was analyzed by D-dimer (DD2) and Thrombin Generation Test (TGT) on a healthy pool of plasmas adjusted or not by their number (10,000 MPs). The MPs percentages were not different between the groups, but absolute number was increased in patients 1-3 years after warfarin withdrawal vs CTR (P = 0.02). There was no difference of the MPs cellular origin comparing patients to controls. TGT using 10,000 MPs was lower on these patients (P = 0.01). APS patients showed a reduction of plasmatic procoagulant activity (P = 0.004), but they were under warfarin therapy. DD2 in the presence of MPs, independently of its number, was higher in patients with DVT at diagnosis (P < 0.0001). MPs of patients with spontaneous DVT at diagnosis can promote coagulation activation demonstrated by increased DD2. Even the increased MPs from patients 1-3 years after thrombotic episode generated lower amount of thrombin, they can have a protective effect by activation of Protein C anticoagulant pathway.

[Cancer genetics: estimation of the needs of the population in France for the next ten years]. / Oncogénétique : estimation des besoins de la population en France pour les dix ans à venir.

Organised since 1990 in France, cancer genetics has been strengthened since 2003 by the programme "Plan Cancer" which resulted in an improvement of the organisation of activities. The aim of this review is to present an update of the estimation of the needs of the population in this field for the next ten years, provided by a group of experts mandated by the French National Cancer Institute. Identification and management of major hereditary predispositions to cancer have a major impact on decrease in mortality and incidence. Sensitivity of criteria for the detection of BRCA1/2 mutations could be substantially improved by enlarging the indication for genetic testing to isolated cases of ovarian cancer occurring before 70 years and to familial cases occurring after this age limit. In the Lynch syndrome, the present criteria would have an excellent sensitivity for the detection of mutations in the mismatch repair (MMR) genes if the pre-screening of tumours on microsatellite instability (MSI) phenotype was effective, but these criteria are actually poorly applied. However, genetic testing should not be proposed to all the patients affected by tumours belonging to the spectrum of major predispositions and a fortiori to unaffected persons unless an affected relative has been identified as a carrier. The prescription of tests should continue to be strictly controlled and organised, in patients as well as in at-risk relatives. The enlargement of criteria and the improvement in the spreading of recommendations should result in an increase of genetic counselling activity and of the prescriptions of tests by a factor 2 to 4, and to a lesser extent in the clinical management of at risk persons. In a near future, it appears important to mandate experts on specific issues such as the determinants of the lack of effective application of tumour screening for MSI phenotype, the recommendations for the identification and the management of MYH-associated polyposis, or the predictive value of tumour characteristics for the identification of BRCA1/2 mutations. The expected increase in cancer genetics activity will need an optimal organisation to increase the throughput. Such measures will help in facing up to new predispositions that will probably be identified in common cancers.

The management of colorectal liver metastases: Expanding the role of hepatic resection in the age of multimodal therapy.

Colorectal cancer (CRC) caused nearly 204,000 deaths in Europe in 2004. Despite recent advances in the treatment of advanced disease, which include the incorporation of two new cytotoxic agents irinotecan and oxaliplatin into first-line regimens, the concept of planned sequential therapy involving three active agents during the course of a patient's treatment and the integrated use of targeted monoclonal antibodies, the 5-year survival rates for patients with advanced CRC remain unacceptably low. For patients with colorectal liver metastases, liver resection offers the only potential for cure. This review, based on the outcomes of a meeting of European experts (surgeons and medical oncologists), considers the current treatment strategies available to patients with CRC liver metastases, the criteria for the selection of those patients most likely to benefit and suggests where future progress may occur.

Best choice of central venous insertion site for the prevention of catheter-related complications in adult patients who need cancer therapy: a randomized trial.

BACKGROUND: Central venous access is extensively used in oncology, though practical information from randomized trials on the most convenient insertion modality and site is unavailable. METHODS: Four hundred and three patients eligible for receiving i.v. chemotherapy for solid tumors were randomly assigned to implantation of a single type of port (Bard Port, Bard Inc., Salt Lake City, UT), through a percutaneous landmark access to the internal jugular, a ultrasound (US)-guided access to the subclavian or a surgical cut-down access through the cephalic vein at the deltoid-pectoralis groove. Early and late complications were prospectively recorded until removal of the device, patient's death or ending of the study. RESULTS: Four hundred and one patients (99.9%) were assessable: 132 with the internal jugular, 136 with the subclavian and 133 with the cephalic vein access. The median follow-up was 356.5 days (range 0-1087). No differences were found for early complication rate in the three groups {internal jugular: 0% [95% confidence interval (CI) 0.0% to 2.7%], subclavian: 0% (95% CI 0.0% to 2.7%), cephalic: 1.5% (95% CI 0.1% to 5.3%)}. US-guided subclavian insertion site had significantly lower failures (e.g. failed attempts to place the catheter in agreement with the original arm of randomization, P = 0.001). Infections occurred in one, three and one patients (internal jugular, subclavian and cephalic access, respectively, P = 0.464), whereas venous thrombosis was observed in 15, 8 and 11 patients (P = 0.272). CONCLUSIONS: Central venous insertion modality and sites had no impact on either early or late complication rates, but US-guided subclavian insertion showed the lowest proportion of failures.

[Register of exposed to carcinogens]. / Registro di esposizione a cancerogeni.

Law Decree 626/94 already provided for the "register of exposed subjects" to be implemented by employer once the presence of cancerogenic agents falling into the definition of the norm itself have been assessed in working activities. The lack of an effective decree identifying the models and modalities of register keeping has led so far to an exposure under-evaluation. Of course the coming into force of Ministerial Decree 155/2007, almost at the same time as the new body of regulations made up by Law Decree 81/2008, stimulated the addressees to proceed with setting an exposure register to be forwarded to the National Institute for Occupational Safety and Prevention (ISPESL) and to the competent inspection authority. Starting for the regulations, the authors will go through the register forms and information flow management.

[The occupational and active research, diagnosis and reporting of occupational diseases]. / Il Medico Competente e la ricerca attiva, diagnosi e denuncia delle malattie professionali.

The Occupational Doctor plays a key role on the protection of workers safety and prevention of occupational and work-related disease. His training and his need of updating, due to the constant transformation of work, the evolution of technology and the medical progress, set him in the center of all activities carried out to protect health in workplaces. The Occupational Doctor should devote special attention to the working anamnesis as well as to the pathological anamnesis both close and remote. He should also pay attention to semeiotics. Another important element is the relationship between the Occupational Doctor and the Doctor of General Medicine (MMG); this synergy is of vital importance in protecting health and in investigating diseases whether occupational or not. D.Lgs. 81/08 emphasizes this synergy, in fact name and phone number of Doctor of General Medicine is compulsory in Case History. Major source of information for all form of prevention is the survey of occupational disease which is a tool for epidemiological control. The use of a systematic collection of data, of protocols, of guidelines and of scientific evidence is the basis for identifying occupational diseases, their diagnosis and subsequent denunciations. This is the line suggested in MAL PROF informative system, made for registration of work-related diseases, and which is important, with other instruments, in realizing an integrated informative system for prevention in workplace. The Covenant for the Protection of Health and Prevention in Workplaces (DPCM 17/12/2007) indicates the strategic objectives of the National Health System for the consolidation and development of the existing system and of the programs promoting health and safety. These include the growth of the culture of prevention and of the epidemiological control of occupational diseases. The Occupational Doctor has an important role because he can identify the early onset of diseases during the working age and start all forms of prevention and health promotion. In the case of diagnosis of a suspected professional disease the Occupational Doctor has three distinct obligations. The first is to report to the legal authority (C.P.P. art. 365). The second requirement is the declaration of the occupational disease (D.P.R. 1124/65 art. 139) and the third is to issue the first certificate of occupational disease for compensation insurance (D.P.R. 1124/65 artt. 53, 251).

Institutional guidelines and ongoing studies in management of liver tumours: the experience of the European Institute of Oncology.

BACKGROUND: An institutional task force on upper gastrointestinal tumours is active at the European Institute of Oncology (EIO). Members decided to collate the institutional guidelines on management of liver tumours (primary and metastatic) into a document. This article is aimed at presenting the current treatment guidelines as well as ongoing research protocols and trials in this field at the EIO. METHODS: A steering committee convened to assign tasks to individual members. Contributions from experts in each treatment area were collated in a single document, in order to produce a draft for subsequent review from the aforementioned committee. Six drafts have been discussed and the final version approved. RESULTS: Surgical, medical oncology, interventional radiology, nuclear medicine and radiation therapy approaches, their roles in management of liver tumours and ongoing research trials are presented and discussed in this article. CONCLUSIONS: At the EIO a multi-disciplinary integrated approach to liver tumours is standard and several ongoing research projects are currently active in this field.

Surgical 'damage control' treatment of a large retroperitoneal liposarcoma encasing a horseshoe kidney.

Damage control is a surgical strategy for severely compromised trauma patients based on speed control of life-threatening injuries that aims to rapidly resuscitate patients in an intensive care unit (ICU). We report on the use of such therapeutic strategy in a patient affected by a retroperitoneal sarcoma concomitant to a horseshoe kidney, a relatively rare anatomical malformation.

Occupational therapy and dementia: the experience of an Alzheimer special care unit.

This trial reports the outcomes of an occupational therapy (OT) program in a group of patients with moderately severe dementia, attending a day care center. Twenty-six patients were enrolled in this therapeutic program for a 12-month period. OT sessions were held for two hour a day, five days a week. The outcomes of the trial suggest that the introduction of OT and multidimensional assessment may improve management and mediate the psychophysical decline of persons with dementia. Indeed, the assessed performance indices remained relatively stable over time, as compared to the decline expected by the natural progression of disease. Moreover, behavioral disorders evaluated by the neuropsychiatric inventory (NPI) scores improved appreciably between treatment start and end. The day care center provides an opportunity for both the person with dementia and their family by optimizing therapy for the patient and providing medical assistance for morbid conditions that ensue during the course of disease and by lowering the burden of care and providing moral support for the family by a trained staff, with particular focus on behavioral disorders that are not amenable to pharmacological management.