Output factor measurement in high dose-per-pulse IORT electron beams.

PURPOSE: To assess the capability of different types of detectors to measure relative output factors (OF) at high dose per pulse by comparison with alanine dosimeters, which are independent of dose rate. METHODS: Measurements were made in 9 MeV and 7 MeV electron beams produced by a Novac7 accelerator for intraoperative radiotherapy. Applicators with diameter of 10-7-6-5 and 4 cm were used. The dose per pulse varied from about 30 mGy, for the 10 cm reference applicator, to about 70 mGy, for the 4 cm applicator. Five types of plane-parallel ionization chambers (PTW Advanced Markus, Markus and Roos, IBA PPC40 and PPC05), two types of silicon diodes (PTW 60017 and IBA EFD3G) and a PTW 60019 microDiamond were considered. For the ionization chambers, correction factors for ion recombination effects were determined for each applicator using a modified two-voltage-analysis method that includes the free-electron component. RESULTS: Reference OF values were determined by alanine dosimeters with a standard combined uncertainty of 0.8%. Deviations from the reference OFs were generally within 1.5% for all the detectors, hence within the 95% confidence interval of alanine measurements. Larger deviations of up to about 2% obtained in a few cases are consistent with a 0.7% long-term reproducibility of OF measurements. CONCLUSIONS: Comparison with alanine measurements demonstrated that all the detectors considered in this work can be used to measure OFs in high dose-per-pulse electron beams with an accuracy better than 2%, provided that appropriate corrections for ion recombination effects are applied when using ionization chambers.

A new method to evaluate the influence of the glenosphere positioning on stability and range of motion of a reverse shoulder prosthesis.

PURPOSE: Shoulder instability and reduced range of motion are two common complications of a total reverse shoulder arthroplasty. In this work, a new approach is proposed to estimate how the glenoid component positioning can influence the stability and the range of motion of a reverse shoulder prosthesis. MATERIALS AND METHODS: A standard reverse shoulder prosthesis has been analysed. To perform virtual simulation of the shoulder-prosthesis assembly, all the components of the prosthesis have been acquired via a 3D laser scanner and the solid models of the shoulder bones have been reconstructed through CT images. Loads on the shoulder joint have been estimated using anatomical models database. A new virtual/numerical procedure has been implemented using a 3D parametric modelling software to find the optimal position of the glenosphere. RESULTS: Several analyses have been performed using different configurations obtained by changing the glenoid component tilt and the lateral position of the glenosphere, modified through the insertion of a cylindrical spacer. For the analysed case study, it was found that the interposition of a spacer (between the baseplate and the glenoid) and 15° inferior tilt of the glenosphere allow improving the range of motion and the stability of the shoulder. CONCLUSIONS: Some common complications of the reverse shoulder arthroplasty could be effectively reduced by a suitable positioning of the prosthesis components. In this work, using a new method based on virtual simulations, the influence of the glenosphere positioning has been investigated. An optimal configuration for the analysed case study has been found. The proposed approach could be used to find, with no in vivo experiments, the optimal position of a reverse shoulder prosthesis depending on the different dimensions and shape of the bones of each patient.

Graphite particles induce ROS formation in cell free systems and human cells.

It is commonly accepted that the toxicity of carbonaceous particulate matter (PM) is due to the production of reactive oxygen species (ROS) which induce biological damage in the exposed cells. It is also known that PM produced during the combustion processes consists of a carbonaceous core "dressed" with other organic and/or inorganic materials. In spite of this knowledge, the role of these materials in the production of ROS has not yet been clear. This work aims at understanding whether "naked" carbonaceous particles are capable of forming ROS either in cell-free or in-cell systems. The problem has been treated based on the data collected from pure graphite samples of different sizes obtained by ball-milling pure graphite for various lengths of time. The experimental approach considered Raman, ESR (spin trapping), cell viability and fluorescence spectroscopy measurements. These techniques allowed us to carry out measurements both in cell and cell-free systems and the results consistently indicate that also pure naked carbonaceous particles can catalyze the electron transfer that produces superoxide ions. The process depends on the particle size and enlightens the role of the edges of the graphitic platelets. Evidence has been collected that even "naked" graphitic nanoparticles are capable of producing ROS and decreasing the cell viability thus representing a potential danger to human health.

Photon correlation spectroscopy applied to tear analysis.

This study aims to deepen the knowledge on tear film properties by the development of a protocol for analyses of Photon Correlation Spectroscopy (PCS) on human tears and by the comparison between PCS results obtained on tears of contact lens wearers and non-wearers. Tears (5µL) were collected by a glass capillary. The analyses provide the hydrodynamic diameter of tear components by analyzing intensity fluctuations in time of scattered light. PCS appears a promising technique for studying tear features and for shedding light on specific eye conditions, such as on the clinical effects of CL wear. In fact, statistical difference (p<0.001) was found between the measured mean hydrodynamic diameter of tear components of wearers and non-wearers, the resulting value significantly higher for CL wearers. The scenario does not substantially change after (25±5)min from the CL removal. The difference is attributed to changes in the interactions between tear constituents due to CL wear. In order to get deeper insights on the influence of CL wear on aggregation and structure of tear components, a preliminary Electron Spin Resonance (ESR) investigation was performed, monitoring Fe3+ species. ESR spectra on tears of both CL wearers and non-wearers showed the presence of intense signals, probably associated to iron (III) centers in proteins such as lactoferrin, and a weaker resonance attributable to Fe3+ species interacting with S-S bridges of lysozyme. Differences in ESR spectra between CL wearers and non-wearers were detected and tentatively ascribed to changes in coordination or in local environment of Fe3+ centers connected to aggregation phenomena induced by CL wear, which promote their interaction with other neighboring iron species.

Quantitative 177Lu SPECT imaging using advanced correction algorithms in non-reference geometry.

Peptide receptor therapy with 177Lu-labelled somatostatin analogues is a promising tool in the management of patients with inoperable or metastasized neuroendocrine tumours. The aim of this work was to perform accurate activity quantification of 177Lu in complex anthropomorphic geometry using advanced correction algorithms. Acquisitions were performed on the higher 177Lu photopeak (208keV) using a Philips IRIX gamma camera provided with medium-energy collimators. System calibration was performed using a 16mL Jaszczak sphere surrounded by non-radioactive water. Attenuation correction was performed using µ-maps derived from CT data, while scatter and septal penetration corrections were performed using the transmission-dependent convolution-subtraction method. SPECT acquisitions were finally corrected for dead time and partial volume effects. Image analysis was performed using the commercial QSPECT software. The quantitative SPECT approach was validated on an anthropomorphic phantom provided with a home-made insert simulating a hepatic lesion. Quantitative accuracy was studied using three tumour-to-background activity concentration ratios (6:1, 9:1, 14:1). For all acquisitions, the recovered total activity was within 12% of the calibrated activity both in the background region and in the tumour. Using a 6:1 tumour-to-background ratio the recovered total activity was within 2% in the tumour and within 5% in the background. Partial volume effects, if not properly accounted for, can lead to significant activity underestimations in clinical conditions. In conclusion, accurate activity quantification of 177Lu can be obtained if activity measurements are performed with equipment traceable to primary standards, advanced correction algorithms are used and acquisitions are performed at the 208keV photopeak using medium-energy collimators.

Gamma camera calibration and validation for quantitative SPECT imaging with (177)Lu.

Over the last years (177)Lu has received considerable attention from the clinical nuclear medicine community thanks to its wide range of applications in molecular radiotherapy, especially in peptide-receptor radionuclide therapy (PRRT). In addition to short-range beta particles, (177)Lu emits low energy gamma radiation of 113keV and 208keV that allows gamma camera quantitative imaging. Despite quantitative cancer imaging in molecular radiotherapy having been proven to be a key instrument for the assessment of therapeutic response, at present no general clinically accepted quantitative imaging protocol exists and absolute quantification studies are usually based on individual initiatives. The aim of this work was to develop and evaluate an approach to gamma camera calibration for absolute quantification in tomographic imaging with (177)Lu. We assessed the gamma camera calibration factors for a Philips IRIX and Philips AXIS gamma camera system using various reference geometries, both in air and in water. Images were corrected for the major effects that contribute to image degradation, i.e. attenuation, scatter and dead- time. We validated our method in non-reference geometry using an anthropomorphic torso phantom provided with the liver cavity uniformly filled with (177)LuCl3. Our results showed that calibration factors depend on the particular reference condition. In general, acquisitions performed with the IRIX gamma camera provided good results at 208keV, with agreement within 5% for all geometries. The use of a Jaszczak 16mL hollow sphere in water provided calibration factors capable of recovering the activity in anthropomorphic geometry within 1% for the 208keV peak, for both gamma cameras. The point source provided the poorest results, most likely because scatter and attenuation correction are not incorporated in the calibration factor. However, for both gamma cameras all geometries provided calibration factors capable of recovering the activity in anthropomorphic geometry within about 10% (range -11.6% to +7.3%) for acquisitions at the 208keV photopeak. As a general rule, scatter and attenuation play a much larger role at 113keV compared to 208keV and are likely to hinder an accurate absolute quantification. Acquisitions of only the (177)Lu main photopeak (208keV) are therefore recommended in clinical practice. Preliminary results suggest that the gamma camera calibration factor can be assessed with a standard uncertainty below (or of the order of) 3% if activity is determined with equipment traceable to primary standards, accurate volume measurements are made, and an appropriate chemical carrier is used to allow a homogeneous and stable solution to be used during the measurements.

A graphite calorimeter for absolute measurements of absorbed dose to water: application in medium-energy x-ray filtered beams.

The Italian National Institute of Ionizing Radiation Metrology (ENEA-INMRI) has designed and built a graphite calorimeter that, in a water phantom, has allowed the determination of the absorbed dose to water in medium-energy x-rays with generating voltages from 180 to 250 kV. The new standard is a miniaturized three-bodies calorimeter, with a disc-shaped core of 21 mm diameter and 2 mm thickness weighing 1.134 g, sealed in a PMMA waterproof envelope with air-evacuated gaps. The measured absorbed dose to graphite is converted into absorbed dose to water by means of an energy-dependent conversion factor obtained from Monte Carlo simulations. Heat-transfer correction factors were determined by FEM calculations. At a source-to-detector distance of 100 cm, a depth in water of 2 g cm(-2), and at a dose rate of about 0.15 Gy min(-1), results of calorimetric measurements of absorbed dose to water, D(w), were compared to experimental determinations, D wK, obtained via an ionization chamber calibrated in terms of air kerma, according to established dosimetry protocols. The combined standard uncertainty of D(w) and D(wK) were estimated as 1.9% and 1.7%, respectively. The two absorbed dose to water determinations were in agreement within 1%, well below the stated measurement uncertainties. Advancements are in progress to extend the measurement capability of the new in-water-phantom graphite calorimeter to other filtered medium-energy x-ray qualities and to reduce the D(w) uncertainty to around 1%. The new calorimeter represents the first implementation of in-water-phantom graphite calorimetry in the kilovoltage range and, allowing independent determinations of D(w), it will contribute to establish a robust system of absorbed dose to water primary standards for medium-energy x-ray beams.

Results of closed subtalar dislocations.

BACKGROUND: The subtalar dislocation (SD) of the foot is an uncommon injury characterized by a simultaneous dislocation of talocalcaneal and talonavicular joints without involvement of the tibiotalar and calcaneocuboid joints. PURPOSES: The purpose of this study was to evaluate the clinical and radiological outcome in a consecutive series of close SD. METHODS: We retrospectively evaluated a case series of patients who presented a close SD. Thirteen patients were selected for this study. There were 9 patients with a medial SD, 3 patients with a lateral dislocation and 1 patient with a posterior subtalar dislocation. RESULTS: The most frequent symptoms observed in our study included transient mild pain, swelling and decreased ankle ROM, which did not restrict patients' daily activities. However, lower AOFAS scores were observed on patients with associate peritalar osseous injuries. CONCLUSION: The results of the present study suggest that detecting and treating any associate peritalar fractures are the keys to a successful long-term outcome.

Comments to the paper "do we really need new medical information about the Turin Shroud?".

Following the interesting arguments raised in a recent letter to the editor, about a paper recently published in this journal, the authors are happy to take a cue from them to clarify some facts that have not been sufficiently treated for space. After a description of the methods used, arguments regarding a blunt trauma on the right shoulder with consequent dislocation, the position of the hands on the pubis with brachial plexus injury, and the wrist nailing that caused retracted thumbs are discussed in detail.

The filler-rubber interface in styrene butadiene nanocomposites with anisotropic silica particles: morphology and dynamic properties.

Silica-styrene butadiene rubber (SBR) nanocomposites were prepared by using shape-controlled spherical and rod-like silica nanoparticles (NPs) with different aspect ratios (AR = 1-5), obtained by a sol-gel route assisted by a structure directing agent. The nanocomposites were used as models to study the influence of the particle shape on the formation of nanoscale immobilized rubber at the silica-rubber interface and its effect on the dynamic-mechanical behavior. TEM and AFM tapping mode analyses of nanocomposites demonstrated that the silica particles are surrounded by a rubber layer immobilized at the particle surface. The spherical filler showed small contact zones between neighboring particles in contact with thin rubber layers, while anisotropic particles (AR > 2) formed domains of rods preferentially aligned along the main axis. A detailed analysis of the polymer chain mobility by different time domain nuclear magnetic resonance (TD-NMR) techniques evidenced a population of rigid rubber chains surrounding particles, whose amount increases with the particle anisotropy, even in the absence of significant differences in terms of chemical crosslinking. Dynamic measurements demonstrate that rod-like particles induce stronger reinforcement of rubber, increasing with the AR. This was related to the self-alignment of the anisotropic silica particles in domains able to immobilize rubber.

Patient-specific instrumentation for total knee arthroplasty: a literature review.

During the past decade, total knee arthroplasty (TKA) has been markedly increased. Recently, patient-specific custom cutting guides have been commercially introduced in order to achieve an accurate component alignment during TKA. In fact, these cutting blocks are specific to a patient's knee anatomy and should help the surgeons to perform bone cuts, reducing the complexity of conventional alignment and sizing tools. Nevertheless, there are critical arguments against patient-specific cutting guides for routine use, such as poor evidence and higher costs. Additionally, there are still no mild and long-term results available that describe the clinical outcomes following patient-specific instrumentation of TKR, cost-effectiveness and lower revision rates. Aim of the current manuscript was to describe the recent improvements of the surgical technique and instrumentation of TKA, reviewing the recent literature concerning the PSI technology.

Indications and limitations of the fixator TGF "Gex-Fix" in proximal end humeral fractures.

The incidence of fractures of the humerus has increased exponentially in recent years. The most used classifications for humerus fracture are morphological (Neer), biological (AO/ASIF) and descriptive (Hertel). The types of surgical treatment for humerus fracture include prosthetic replacement and synthesis using different devices, including the Tension Guide Fixator (TGF), Gex-Fix. External fixation for displaced proximal humeral fractures avoids dissection and soft tissue stripping and has been reported by some authors to be associated with higher union rates, a lower incidence of avascular necrosis, less scarring of the scapulohumeral interface, and faster rehabilitation compared with open reduction and internal fixation. Other authors have reported that external fixation does not ensure acceptable reduction and fracture stability, particularly in patients with osteoporosis. The external fixation technique involves the introduction of Steinmann's pin to keep manual reduction, the introduction of two K-wires in the humeral head, the removal of the Steinmann's pin, and the introduction of two fiches on the humeral shaft. Hub connectors are mounted on the wires and on the chips to connect the outer bar and tensioning system. A total of 84 patients aged 42-84 years with proximal end humeral fractures (66% had two-part fractures) were treated with Fixator TGF in this study from December 2007 to June 2012. The postoperative recovery was earlier and the active-assisted motion was less painful than has been reported with other surgical techniques. The TGF was removed without anaesthesia at the outpatient clinic at a mean of 7 weeks (range 5-8 weeks) after surgery, and there was no loss of reduction or secondary displacement after removal. These results, after five years of experience, confirm that the best indication for this fixator is two- or three-part fractures because the device enables early active mobilisation. The limitations of this fixator are evident in fractures in which closed reduction is not possible and in three-part fractures with varus displacement because the TGF has less stability than other systems, such as the plate or cage. The short learning curve, reduced surgical time and risk, and low cost encourage the use of this technique.

How was the Turin Shroud Man crucified?

As the literature is not exhaustive with reference to the way the Turin Shroud (TS) Man was crucified, and it is not easy to draw significant information from only a "photograph" of a man on a linen sheet, this study tries to add some detail on this issue based on both image processing of high resolution photos of the TS and on experimental tests on arms and legs of human cadavers. With regard to the TS Man hands, a first hypothesis states that the left hand of the TS Man was nailed twice at two different anatomical sites: the midcarpal joint medially to the pisiform between the lunate/pyramidal and capitate/uncinate bones (Destot's space) and the radiocarpal joint between the radio, lunate and scaphoid; also the right hand would have been nailed twice. A second hypothesis, preferred by the authors, states that the hands were nailed only once in the Destot's space with partial lesion of the ulnar nerve and flexion of the metacarpophalangeal joint of the thumbs. With regard to the TS Man feet, the imprint of the sole of the right foot leads to the conclusion that TS Man suffered a dislocation at the ankle just before the nailing. The entrance hole of the nail on the right foot is a few inches from the ankle, and excludes a double nailing. The nail has been driven between the tarsal bones. The TS Man suffered the following tortures during crucifixion: a very serious and widespread causalgia due to total paralysis of the upper right limb (paradoxical causalgia); a nailing of the left wrist with damage to the ulnar nerve; a similar nailing of the right wrist; and a nailing to both feet using one only nail that injured the plantaris medialis nerves. The respiratory limitation was probably not sufficient to cause death by asphyxiation. Also considering the hypovolemia produced by scourging and the many other tortures detectable on the TS, the principal cause of death can be attributed to a myocardial infarction.

Optimal positioning of the humeral component in the reverse shoulder prosthesis.

INTRODUCTION: Total reverse shoulder arthroplasty is becoming more and more the standard therapeutic practice for glenohumeral arthropathy with massive lesions of the rotator cuff. The biomechanical principle of this prosthesis is represented by the reversion of the normal anatomy of the shoulder joint. This non-anatomical prosthesis leads to a medialization of the rotation centre of the glenohumeral joint and also to a distalization of the humeral head. All that causes a deltoid tension increasing so allowing a larger abduction of the arm. Main complications of the reverse shoulder prosthesis are due to the joint instability, the scapular notching and the wear of the polyethylene insert. PURPOSE: The main goal of the present work is to study the effect of the positioning of the humeral component on the intrinsic stability of the reverse shoulder prosthesis. In particular, through finite element method simulations, the variation of the stability ratio of the shoulder joint has been calculated for both vertical and horizontal dislocating loads depending on the humeral stem version angle. Moreover, in order to estimate the wear of the polyethylene cup, some analyses have been developed to calculate the pressures on the polyethylene insert. RESULTS: The obtained results demonstrate the dislocation of a shoulder prosthesis and the wear of the polyethylene insert can be prevented or limited by conveniently varying the version angle of the humeral component.

Do we really need new medical information about the Turin Shroud?

Image processing of the Turin Shroud (TS) shows that the Man represented in it has undergone an under glenoidal dislocation of the humerus on the right side and lowering of the shoulder, and has a flattened hand and enophthalmos; conditions that have not been described before, despite several studies on the subject. These injuries indicate that the Man suffered a violent blunt trauma to the neck, chest and shoulder from behind, causing neuromuscular damage and lesions of the entire brachial plexus. The posture of the left claw-hand is indicative of an injury of the lower brachial plexus, as is the crossing of the hands on the pubis, not above the pubis as it would normally be, and are related to traction of the limbs as a result of the nailing to the patibulum. The disappearance of the thumbprints is because of entrainment of the flexor pollicis longus tendons while the nails were driven through the wrists. The blunt chest trauma, which resulted in the body falling forwards, was the direct cause of a lung contusion and haemothorax, confirmed by the post-mortem leakage of clots and serum from the chest caused by the stabbing with the spear, and was a likely cause of cardiac contusion. All the evidence is in favour of the hypothesis that the TS Man is Jesus of Nazareth.

Wound drainages in total hip arthroplasty: to use or not to use? Review of the literature on current practice.

Aim of this study is to analyze data reported in literature concerning the efficacy of using wound low-vacuum suction drainages in orthopedic surgery after total hip arthroplasty. We analyzed studies concerning the use of drainages in prosthetic hip replacement surgery, performing our research through Pubmed, Cochrane database and Google Scholar, and selecting the ones evaluating the following parameters: bleeding, the need for blood transfusions, number or reinforcement of post-operative medications, length of hospitalization, functional results, periprosthetic and surgical wound infection, post-operative hematoma. Our review did not show any demonstrated advantage from the use of wound drainages in total hip arthroplasty. Moreover, some studies enlighted a possible complication related to their employment, represented by the greater need for blood transfusions. Despite the absence of a statistically demonstrated positive influence on wound outcome using suction drains after total hip replacement, many orthopedic surgeons still recommend using drainages, just because there is no certified proof of a negative effect.

Multiple 3D inversion recovery imaging for volume T1 mapping of the heart.

In this article, a three-dimensional inversion recovery sequence was optimized with the aim of generating in vivo volume T(1) maps of the heart using a 1.5-T MR system. Acquisitions were performed before and after gadolinium diethylenetriamine penta-acetic acid (Gd-DTPA) administration in one patient with hypertrophic cardiomyopathy and in two healthy volunteers. Data were acquired with a multishot fast field echo readout using both ECG and respiratory triggers. A dedicated phantom, composed of four solutions with different T(1) values, was positioned on the subjects' thoracic region to perform patient-specific calibration. Pixel based T(1) maps were calculated with a custom Matlab(®) code. Phantom measurements showed a good accuracy of the technique and in vivo T(1) estimation of liver, skeletal muscle, myocardium, and blood resulted in good agreement with values reported in the literature. Multiple three-dimensional inversion recovery technique is a feasible and accurate method to perform T(1) volume mapping.

Quantitative evaluation on [9°Y] DOTATOC PET and SPECT imaging by phantom acquisitions and clinical applications in locoregional and systemic treatments.

AIM: The aim of this paper was to compare [9°Y]-PET and SPECT imaging quantification for dosimetric applications in targeted radionuclide therapy. METHODS: Imaging studies were carried out by SPECT-CT and PET equipment performing phantom tests first. [9°Y]-SPECT and PET scans were compared in terms of sensitivity, minimum detectable activity concentration, recovery coefficients (RCs) and system spatial resolution (FWHM). Quantitative evaluations by PET and SPECT acquisitions were then assessed in patients who received therapeutic activity of [9°Y]-DOTATOC directly injected into the surgical cavity by locoregional route in glioma treatment and by systemic route in neuroendocrine tumour patients who underwent intravenous infusion. Finally 3D-dose distributions by SPECT and PET images were obtained. RESULTS: Sensitivity was proven to be about fivefold higher for SPECT than for PET. To obtain a good-quality PET imaging, the minimum detectable activity concentration was determined to be equal to 1 MBq/mL compared with 0.05 MBq/mL that was sufficient to assess adequate SPECT imaging. RCs were 100% for volume ≥ 25.5 mL for PET and ≥ 110 mL for SPECT. FWHM was 7 mm for PET and 19 mm for SPECT scans. With regard to locoregional therapy, excellent imaging was obtained with both PET and SPECT. On the contrary, systemic administration did not permit us to obtain suitable PET imaging. PET and SPECT images were affected by considerable noise, whose influence is much more important in the quantitative evaluation of dose volume histograms rather than in the visual interpretation of images. CONCLUSION: [9°Y]-activity quantification is feasible by SPECT and PET imaging. For clinical applications, SPECT-CT is the best technique for visualizing the radiopharmaceuticals following systemic infusion, while both SPECT and PET scans are effective in analyzing locoregional distribution. Nevertheless PET study demonstrates the best spatial definition.

Cardiac risk stratification in elective non-cardiac surgery: role of NT-proBNP.

AIM: The aim of the study was to investigate the utility of NT-proBNP measurement for the stratification of presurgical cardiac risk. METHODS: Cardiac risk before elective non-cardiac surgery was evaluated in 82 consecutive patients. From each patient a venous blood sample was drawn to determinate NT-proBNP levels. Patients were followed up over three months in order to detect the occurrence of cardiac adverse events. RESULTS: NT-proBNP was positively correlated (P<0.0001) with age, days of hospitalization (P=0.001) and ASA class (P=0.001). High surgical risk (P<0.0001), diabetes (P=0.004), dyslipidemia (P=0.006) and elevated levels of NT-proBNP (P<0.0001) were significantly correlated with events. Using a logistic regression analysis we found an independent association between pre-operative elevated NT-proBNP and postoperative cardiac events (OR 1.2, 95% CI 1.0-1.4, P=0.01). CONCLUSION: Measuring NT-proBNP before non cardiac surgery in clinical practice could be useful to better stratify patients' risk.