Prognostic factors for chronic post-surgical pain after lung and pleural surgery: a systematic review with meta-analysis, meta-regression and trial sequential analysis.

Chronic post-surgical pain is known to be a common complication of thoracic surgery and has been associated with a lower quality of life, increased healthcare utilisation, substantial direct and indirect costs, and increased long-term use of opioids. This systematic review with meta-analysis aimed to identify and summarise the evidence of all prognostic factors for chronic post-surgical pain after lung and pleural surgery. Electronic databases were searched for retrospective and prospective observational studies as well as randomised controlled trials that included patients undergoing lung or pleural surgery and reported on prognostic factors for chronic post-surgical pain. We included 56 studies resulting in 45 identified prognostic factors, of which 16 were pooled with a meta-analysis. Prognostic factors that increased chronic post-surgical pain risk were as follows: higher postoperative pain intensity (day 1, 0-10 score), mean difference (95%CI) 1.29 (0.62-1.95), p < 0.001; pre-operative pain, odds ratio (95%CI) 2.86 (1.94-4.21), p < 0.001; and longer surgery duration (in minutes), mean difference (95%CI) 12.07 (4.99-19.16), p < 0.001. Prognostic factors that decreased chronic post-surgical pain risk were as follows: intercostal nerve block, odds ratio (95%CI) 0.76 (0.61-0.95) p = 0.018 and video-assisted thoracic surgery, 0.54 (0.43-0.66) p < 0.001. Trial sequential analysis was used to adjust for type 1 and type 2 errors of statistical analysis and confirmed adequate power for these prognostic factors. In contrast to other studies, we found that age had no significant effect on chronic post-surgical pain and there was not enough evidence to conclude on sex. Meta-regression did not reveal significant effects of any of the study covariates on the prognostic factors with a significant effect on chronic post-surgical pain. Expressed as grading of recommendations, assessment, development and evaluations criteria, the certainty of evidence was high for pre-operative pain and video-assisted thoracic surgery, moderate for intercostal nerve block and surgery duration and low for postoperative pain intensity. We thus identified actionable factors which can be addressed to attempt to reduce the risk of chronic post-surgical pain after lung surgery.

Salivary Biomarkers for Diagnosis and Therapy Monitoring in Patients with Heart Failure. A Systematic Review.

The aim of this study was to perform a systematic review on the potential value of saliva biomarkers in the diagnosis, management and prognosis of heart failure (HF). The correlation between saliva and plasma values of these biomarkers was also studied. PubMed was searched to collect relevant literature, i.e., case-control, cross-sectional studies that either compared the values of salivary biomarkers among healthy subjects and HF patients, or investigated their role in risk stratification and prognosis in HF patients. No randomized control trials were included. The search ended on 31st of December 2020. A total of 15 studies met the inclusion criteria. 18 salivary biomarkers were analyzed and the levels of all biomarkers studied were found to be higher in HF patients compared to controls, except for amylase, sodium, and chloride that had smaller saliva concentrations in HF patients. Natriuretic peptides are the most commonly used plasma biomarkers in the management of HF. Their saliva levels show promising results, although the correlation of saliva to plasma values is weakened in higher plasma values. In most of the publications, differences in biomarker levels between HF patients and controls were found to be statistically significant. Due to the small number of patients included, larger studies need to be conducted in order to facilitate the use of saliva biomarkers in clinical practice.

Determination of volatile organic compounds in exhaled breath of heart failure patients by needle trap micro-extraction coupled with gas chromatography-tandem mass spectrometry.

The analytical performances of needle trap micro-extraction (NTME) coupled with gas chromatography-tandem mass spectrometry were evaluated by analyzing a mixture of twenty-two representative breath volatile organic compounds (VOCs) belonging to different chemical classes (i.e. hydrocarbons, ketones, aldehydes, aromatics and sulfurs). NTME is an emerging technique that guarantees detection limits in the pptv range by pre-concentrating low volumes of sample, and it is particularly suitable for breath analysis. For most VOCs, detection limits between 20 and 500 pptv were obtained by pre-concentrating 25 ml of a humidified standard gas mixture at a flow rate of 15 ml min-1. For all compounds, inter- and intra-day precisions were always below 15%, confirming the reliability of the method. The procedure was successfully applied to the analysis of exhaled breath samples collected from forty heart failure (HF) patients during their stay in the University Hospital of Pisa. The majority of patients (about 80%) showed a significant decrease of breath acetone levels (a factor of 3 or higher) at discharge compared to admission (acute phase) in correspondence to the improved clinical conditions during hospitalization, thus making this compound eligible as a biomarker of HF exacerbation.

Comparison of sampling bags for the analysis of volatile organic compounds in breath.

Nalophan, Tedlar and Cali-5-Bond polymeric bags were compared to determine the most suitable type for breath sampling and storage when volatile organic compounds are to be determined. Analyses were performed by thermal desorption gas chromatography mass spectrometry. For each bag, the release of contaminants and the chemical stability of a gaseous standard mixture containing eighteen organic compounds, as well as the CO2 partial pressure were assessed. The selected compounds were representative of breath constituents and belonged to different chemical classes (i.e. hydrocarbons, ketones, aldehydes, aromatics, sulfurs and esters). In the case of Nalophan, the influence of the surface-to-volume ratio, related to the bag's filling degree, on the chemical stability was also evaluated. Nalophan bags were found to be the most suitable in terms of contaminants released during storage (only 2-methyl-1,3-dioxalane), good sample stability (up to 24 h for both dry and humid samples), and very limited costs (about 1 € for a 20 liter bag). The (film) surface-to-(sample) volume ratio was found to be an important factor affecting the stability of selected compounds, and therefore we recommended to fill the bag completely.

A cardiovascular simulator tailored for training and clinical uses.

OBJECTIVE: In the present work a cardiovascular simulator designed both for clinical and training use is presented. METHOD: The core of the simulator is a lumped parameter model of the cardiovascular system provided with several modules for the representation of baroreflex control, blood transfusion, ventricular assist device (VAD) therapy and drug infusion. For the training use, a Pre-Set Disease module permits to select one or more cardiovascular diseases with a different level of severity. For the clinical use a Self-Tuning module was implemented. In this case, the user can insert patient's specific data and the simulator will automatically tune its parameters to the desired hemodynamic condition. The simulator can be also interfaced with external systems such as the Specialist Decision Support System (SDSS) devoted to address the choice of the appropriate level of VAD support based on the clinical characteristics of each patient. RESULTS: The Pre-Set Disease module permits to reproduce a wide range of pre-set cardiovascular diseases involving heart, systemic and pulmonary circulation. In addition, the user can test different therapies as drug infusion, VAD therapy and volume transfusion. The Self-Tuning module was tested on six different hemodynamic conditions, including a VAD patient condition. In all cases the simulator permitted to reproduce the desired hemodynamic condition with an error<10%. CONCLUSIONS: The cardiovascular simulator could be of value in clinical arena. Clinicians and students can utilize the Pre-Set Diseases module for training and to get an overall knowledge of the pathophysiology of common cardiovascular diseases. The Self-Tuning module is prospected as a useful tool to visualize patient's status, test different therapies and get more information about specific hemodynamic conditions. In this sense, the simulator, in conjunction with SDSS, constitutes a support to clinical decision - making.

Modulation of lipid homeostasis in response to continuous or intermittent high-fat diet in pigs.

A high-fat diet is known to induce atherosclerosis in animal models. Dietary factors and timing of atherogenic food delivery may affect plasma lipoprotein content composition and its potential atherogenic effect. Increasingly often, humans spend periods/days eating in a completely unregulated way, ingesting excessive amounts of food rich in oils and fats, alternating with periods/days when food intake is more or less correct. We investigate the effect on lipid homeostasis of a high-fat diet administered either continuously or intermittently. We investigated control pigs receiving standard diet (C, n=7), pigs receiving a high-fat diet every day for 10 weeks (CHF, n=5), and pigs receiving a high-fat diet every other week for 10 weeks (IHF, n=7). IHF animals were shown to have a different lipid profile compared with CHF animals, with a significant increase in high-density lipoproteins (HDL) levels with respect to C and CHF groups. CHF also showed significantly higher values of TC/HDL cholesterol compared with C and IHF. Hepatic expression analysis of genes involved in lipid homeostasis showed an increasing trend of nuclear receptor LXRα along with its target genes in the CHF group and in the IHF group, whereas SREBP2 and LDLr were significantly inhibited. A significant correlation was found between ABCA1 expression and circulating levels of HDL-C. Periodic withdrawals of a high-fat atherogenic diet compared with a regular administration results in a different adaptive response of lipoprotein metabolism, which leads to a significantly higher plasma level of HDL-C and lower TC/HDL-C.

A dynamic control algorithm based on physiological parameters and wearable interfaces for adaptive ventricular assist devices.

In this work we present an innovative algorithm for the dynamic control of ventricular assist devices (VADs), based on the acquisition of continuous physiological and functional parameters such as heart rate, blood oxygenation, temperature, and patient movements. Such parameters are acquired by wearable devices (MagIC & Winpack) and sensors implanted close to the VAD. The aim of the proposed algorithm is to dynamically control the hydraulic power of the VAD as a function of the detected parameters, patient's activity and emotional status. In this way, the cardiac dynamics regulated by the proposed autoregulation control algorithm for sensorized VADs, thus providing new therapy approaches for heart failure.

A decision support system for the treatment of patients with ventricular assist device support.

BACKGROUND: Heart failure (HF) is affecting millions of people every year and it is characterized by impaired ventricular performance, exercise intolerance and shortened life expectancy. Despite significant advancements in drug therapy, mortality of the disease remains excessively high, as heart transplant remains the gold standard treatment for end-stage HF when no contraindications subsist. Traditionally, implanted Ventricular Assist Devices (VADs) have been employed in order to provide circulatory support to patients who cannot survive the waiting time to transplantation, reducing the workload imposed on the heart. In many cases that process could recover its contractility performance. OBJECTIVES: The SensorART platform focuses on the management and remote treatment of patients suffering from HF. It provides an interoperable, extendable and VAD-independent solution, which incorporates various hardware and software components in a holistic approach, in order to improve the quality of the patients' treatment and the workflow of the specialists. This paper focuses on the description and analysis of Specialist's Decision Support System (SDSS), an innovative component of the SensorART platform. METHODS: The SDSS is a Web-based tool that assists specialists on designing the therapy plan for their patients before and after VAD implantation, analyzing patients' data, extracting new knowledge, and making informative decisions. RESULTS: SDSS offers support to medical and VAD experts through the different phases of VAD therapy, incorporating several tools covering all related fields; Statistics, Association Rules, Monitoring, Treatment, Weaning, Speed and Suction Detection. CONCLUSIONS: SDSS and its modules have been tested in a number of patients and the results are encouraging.

An autoregulation unit for enabling adaptive control of sensorized left ventricular assist device.

This paper describes an integrated system for facing heart failures (HF) in an innovative way. Existing left ventricular assist devices (LVAD or VAD) are usually devoted to blood pumping without the possibility to adapt the speed to patient conditions during everyday activities. This is essentially due to the lack of sensorization, bulkiness, and the need of relying on device-specific controllers with reduced computing ability for the existing ventricular assist systems. In this work, an innovative integrated and portable device, the ARU, is presented for enhancing VADs applicability as a long-term solution to HF. The ARU is an universal device able to fulfill with the needs of sensorized VADs in terms of data storing, continuous monitoring, autoregulation and adaptation to patient condition changes during daily activities. The ARU is able to wirelessly interface wearable devices for offering additional monitoring features from remote. The ARU functionalities on bench have been tested by the interfacing with a sensorized VAD platform in order to prove the feasibility of the approach. Experiments of local and remote VAD speed changes and autoregulation algorithms have been successfully tested showing response time of 1 s.

Experimental integration of Autoregulation Unit for left ventricular assist devices in a cardiovascular hybrid simulator.

In this paper, an Autoregulation Unit (ARU) for left ventricular sensorized assist devices (LVAD) has been used with a cardiovascular hybrid simulator mimicking physiological and pathological patient conditions. The functionalities of the ARU have been demonstrating for the successful receiving and visualization of system parameters, sending of commands for LVAD speed changes, and enabling of the autonomous flow control algorithm. Experiments of speed changes and autoregulation are reported, showing the feasibility of the approach for both local and remote control of a LVAD.

Post-operative elimination of sevoflurane anesthetic and hexafluoroisopropanol metabolite in exhaled breath: pharmacokinetic models for assessing liver function.

Sevoflurane (SEV), a commonly used anesthetic agent for invasive surgery, is directly eliminated via exhaled breath and indirectly by metabolic conversion to inorganic fluoride and hexafluoroisopropanol (HFIP), which is also eliminated in the breath. We studied the post-operative elimination of SEV and HFIP of six patients that had undergone a variety of surgeries lasting between 2.5 to 8.5 h using exhaled breath analysis. A classical three compartments pharmacokinetic model developed for the study of environmental contaminants was fitted to the breath data. We found that SEV kinetic behavior following surgery (for up to six days) is consistent across all subjects whereas the production and elimination of HFIP varies to some extent. We developed subject specific parameters for HFIP metabolism and interpreted the differences in the context of timing and dose of anesthesia, type of surgery, and specific host factors. We propose methods for assessing individual patient liver function using SEV as a probe molecule for assessing efficiency of liver metabolism to HFIP. This work is valuable not only for the clinical study of metabolism recovery, but potentially also for the study of the interaction of other manufactured and environmental compounds with human systems biology in controlled exposure and observational studies.

Monitoring breath during oral glucose tolerance tests.

The evolution of breath composition during oral glucose tolerance tests (OGTTs) was analysed by thermal desorption/gas chromatography/mass spectrometry in 16 subjects and correlated to blood glucose levels. The glucose tolerance tests classified five of the subjects as diabetics, eight as affected by impaired glucose tolerance and three as normoglycaemic. Acetone levels were generally higher in diabetics (average concentration values: diabetics, 300 ± 40 ppbv; impaired glucose tolerance, 350 ± 30 ppbv; normoglycaemic, 230 ± 20 ppbv) but the large inter-individual variability did not allow us to identify the three groups by this parameter alone. The exhalation of 3-hydroxy-butan-2-one and butane-2,3-dione, likely due to the metabolization of glucose by bacteria in the mouth, was also observed. Future work will involve the extension of the analyses to other volatile compounds by attempting to improve the level of discrimination between the various classes of subjects.

The practical role of anti-Müllerian hormone in assisted reproduction.

The objective of this study was to offer a brief critical summary of the literature on the role of AMH in the subfertility work up and during ART, while exploring its role in predicting ART success.

IL-33/ST2 pathway and classical cytokines in end-stage heart failure patients submitted to left ventricular assist device support: a paradoxic role for inflammatory mediators?

BACKGROUND: Inflammation is a critical process contributing to heart failure (HF). We hypothesized that IL-33/ST2 pathway, a new mechanism regulated during cardiac stress, may be involved in the functional worsening of end-stage HF patients, candidates for left ventricular assist device (LVAD) implantation, and potentially responsible for their outcome. METHODS: IL-33, ST2, and conventional cytokines (IL-6, IL-8, and TNF-α) were determined in cardiac biopsies and plasma of 22 patients submitted to LVAD implantation (pre-LVAD) and compared with (1) control stable chronic HF patients on medical therapy at the moment of heart transplantation without prior circulatory support (HT); (2) patients supported by LVAD at the moment of LVAD weaning (post-LVAD). RESULTS: Cardiac expression of ST2/IL-33 and cytokines was lower in the pre-LVAD than in the HT group. LVAD determined an increase of inflammatory mediators comparable to levels of the HT group. Only ST2 correlated with outcome indices after LVAD implantation. CONCLUSIONS: IL-33/ST2 and traditional cytokines were involved in decline of cardiac function of ESHF patients as well as in hemodynamic recovery induced by LVAD. IL-33/ST2 pathway was also associated to severity of clinical course. Thus, a better understanding of inflammation is the key to achieving more favorable outcome by new specific therapies.

Reoperation rates after breast conserving surgery for breast cancer among women in England: retrospective study of hospital episode statistics.

OBJECTIVES: To examine whether rate of reoperation after breast conserving surgery is associated with patients' characteristics and investigate whether reoperation rates vary among English NHS trusts. DESIGN: Cohort study using patient level data from hospital episode statistics. SETTING: English NHS trusts. PARTICIPANTS: Adult women who had breast conserving surgery between 1 April 2005 and 31 March 2008. MAIN OUTCOME MEASURE: Reoperation rates after primary breast conserving surgery within 3 months, adjusted using logistic regression for tumour type, age, comorbidity, and socioeconomic deprivation. Tumours were grouped by whether a carcinoma in situ component was coded at the time of the primary breast conserving surgery. RESULTS: 55,297 women had primary breast conserving surgery in 156 NHS trusts during the three year period. 11,032 (20.0%, 95% confidence interval 19.6% to 20.3%) women had at least one reoperation. 10,212 (18.5%, 18.2% to 18.8%) had one reoperation only; of these, 5943 (10.7%, 10.5% to 11.0%) had another breast conserving procedure and 4269 (7.7%, 7.5% to 7.9%) had a mastectomy. Of the 45,793 women with isolated invasive disease, 8229 (18.0%) had at least one reoperation. In comparison, 2803 (29.5%) of the 9504 women with carcinoma in situ had at least one reoperation (adjusted odds ratio 1.9, 95% confidence interval 1.8 to 2.0). Substantial differences were found in the adjusted reoperation rates among the NHS trusts (10th and 90th centiles 12.2% and 30.2%). CONCLUSION: One in five women who had breast conserving surgery in England had a reoperation. Reoperation was nearly twice as likely when the tumour had a carcinoma in situ component coded. Women should be informed of this reoperation risk when deciding on the type of surgical treatment of their breast cancer.

Regional variation in use of immediate breast reconstruction after mastectomy for breast cancer in England.

AIMS: English national guidelines recommend that breast reconstruction is made available to women with breast cancer undergoing mastectomy. We examined the use of immediate reconstruction (IR) across English Cancer Networks, who are responsible for the regional organisation of cancer services and ensuring equitable access to treatment. METHODS: We analysed Hospital Episodes Statistics data for all women with breast cancer who underwent mastectomy in the English NHS between April 2006 and February 2009. IR rates were calculated for the 30 Networks. Multivariable logistic regression was used to adjust the rates for patient age, comorbidity, ethnicity and socioeconomic deprivation. RESULTS: Of 44 837 mastectomy patients, 7375 (16.5%) underwent IR. The IR rate was highest in women under 50 years (32.7%) and lowest in women aged 70 years or over (1.5%), and was lower in women with more comorbidities. Unadjusted IR rates varied from 8.4% to 31.9% among the 30 Networks (p<0.001). Adjusting for their patient characteristics did not appreciably reduce Network-level variation, with adjusted IR rates still ranging from 8.0% to 29.4% (p<0.001). The risk-model also suggested that non-white women and those from more deprived areas were less likely to undergo immediate reconstruction. CONCLUSIONS: There is substantial regional variation in immediate reconstruction use in England that is not explained by the characteristics of the local patient population. English Cancer Networks should act to reduce this variation. They should also examine why rates of reconstruction differ between particular patient groups.

Computer simulation of coronary flow waveforms during caval occlusion.

OBJECTIVES: Mathematical modeling of the cardiovascular system is a powerful tool to extract physiologically relevant information from multi-parametric experiments. The purpose of the present work was to reproduce by means of a computer simulator, systemic and coronary measurements obtained by in vivo experiments in the pig. METHODS: We monitored in anesthetized open-chest pig the phasic blood flow of the left descending coronary artery, aortic pressure, left ventricular pressure and volume. Data were acquired before, during, and after caval occlusion. Inside the software simulator (CARDIOSIM) of the cardiovascular system, coronary circulation was modeled in three parallel branching sections. Both systemic and pulmonary circulations were simulated using a lumped parameter mathematical model. Variable elastance model reproduced Starling's law of the heart. RESULTS: Different left ventricular pressure-volume loops during experimental caval occlusion and simulated cardiac loops are presented. The sequence of coronary flow-aortic pressure loops obtained in vivo during caval occlusion together with the simulated loops reproduced by the software simulator are reported. Finally experimental and simulated instantaneous coronary blood flow waveforms are shown. CONCLUSIONS: The lumped parameter model of the coronary circulation, together with the cardiovascular system model, is capable of reproducing the changes during caval occlusion, with the profound shape deformation of the flow signal observed during the in vivo experiment. In perspectives, the results of the present model could offer new tool for studying the role of the different determinants of myocardial perfusion, by using the coronary loop shape as a "sensor" of ventricular mechanics in various physiological and pathophysiological conditions.

Experimental study of a new vascular anastomotic technique in a swine model: short and mid-term results.

This study reports the development of a new open external vascular stent: the lock stent device (LSD). It enables a novel end-to-end sleeve anastomotic technique, named locked anastomosis (LA). The LA technique consists of inserting a graft sleeve within an artery, secured in place by an internal stent and an external LSD. The internal stent, graft, vessel wall, and LSD are fastened together with single sutures. The LSD placement does not require a complete transection of the vessel wall as it can be enlarged and then relaxed to clasp the vessel neck. The tensile strength of the LA technique was accurately measured ex vivo and its stability successfully tested in vivo by acute pressure peak tests and mid-term survival studies. Ex vivo, the ratio between the tensile strength of the LA technique with two, three, and six stitches and that of hand-sewn anastomoses was 0.41 +/- 0.02, 0.59 +/- 0.17, and 1.03 +/- 0.04. In vivo, LA anastomoses tolerated marked increases in blood pressure (peak systolic pressure 195-230 mm Hg) for periods of 15-25 min without leakage. Five pigs survived 10 weeks with abdominal aorto-aortic bypass performed according to the LA technique with three stitches. Aortograms showed no narrowing or thromboses, and histological findings confirm uniform flattening of the aortic wall at the anastomosis, with proliferating neointima and uniformly hypotrophic media. Minimal changes were observed in the adventitia.

Risk factors for cataract subtypes waterclefts and retrodots: two case-control studies.

UNLABELLED: Waterclefts and retrodots are independently associated with visual impairment, yet a review identified no data on risk factors. PURPOSE: To investigate risk factors for these two human lens cataract subtypes. METHOD: Two nested case-control studies: The host study comprised 1078 subjects (55 years) attending the Somerset and Avon Eye Study (SAES). In total, 197 watercleft cases (Oxford grade 0.2 in either eye) and 199 retrodot cases (Oxford grade 1.0 in either eye) were individually age/gender matched to controls. Detailed ophthalmic and potential risk factor data were collected, including body mass index (BMI), smoking, alcohol, diabetes, hypertension, analgesics, vitamin supplementation, nutrition, sunlight exposure, dehydration, hormonal (women), blood lipids, glucose, urea, creatinine, uric acid, and vitamin levels. RESULTS: For waterclefts, univariable analysis identified BMI, alcohol intake, vitamin status, sunlight, urea, creatinine, and uric acid as possible risk factors. Multivariable analysis identified two independent associations. Total number of 'any' analgesics in the previous year: adjusted P<0.01 (U-shaped risk profile, unadjusted high vs medium use (=reference) OR 2.39, 95% CI 1.35-4.26 with medium use vs none (=reference) OR 0.43, 95% CI 0.26-0.72); total sunlight: adjusted P=0.03 (unadjusted highest exposure vs lowest (=reference) OR 3.25, 95% CI 1.11-9.50). For retrodots, univariable analysis identified alcohol, HRT, and lipids. Multivariable analysis identified two independent associations. Mean number of alcohol units consumed per month, adjusted P=0.02 and HDL cholesterol levels, adjusted P=0.02 (unadjusted ORs NS both). CONCLUSION: This is the first available published information on risk factors for the human cataractous lens features waterclefts and retrodots.

Cardiopulmonary bypass in ewe's fetus: advances and setbacks in our learning curve.

Fetal cardiac surgery represents a surgical challenge and several centers are attempting to establish a suitable methodology in animals. We present our experience with extra-corporeal bypass procedures in preterm and term sheep fetuses. Twenty-two fetuses (103-139 days gestation, mean 115 days gestation) underwent a 1-hour period of right heart-to-pulmonary artery extracorporeal circulation followed by 1 hour of observation. Animals were divided into group 1 and group 2, according to gestational age (above and below 0.85). Three pumps were used: centrifugal without (group 1) reservoir, centrifugal with (group 2) reservoir, and roller with reservoir (group 2). Experiments were completed in 75% of fetuses in group 1 and in 37% of fetuses in group 2. Bleeding was the main cause of failure, especially for group 2. A slow deterioration of blood gas status was noted in group 1, while this trend could be partially reversed in group 2 with corrective measures. Complete heart bypass could not be achieved in either group, and residual fluctuations in arterial pressure were observed. During bypass, body temperature decreased more in group 2 than in group 1. We conclude that cardiac bypass is feasible over a short period in near-term fetuses. A successful outcome may also be obtained in younger fetuses, but better measures need to be implemented for the prevention of surgical bleeding.