Risk of malignancy in small pancreatic cysts decreases over time.

BACKGROUND: Pancreatic cysts <15 mm without worrisome features have practically no risk of malignancy at the time of diagnosis but this can change over time. Optimal duration of follow-up is a matter of debate. We evaluated predictors of malignancy and attempted to identify a time to safely discontinue surveillance. METHODS: Bi-centric study utilizing prospectively collected databases of patients with pancreatic cysts measuring <15 mm and without worrisome features who underwent surveillance at the Massachusetts General Hospital (1988-2017) and at the University of Verona Hospital Trust (2000-2016). The risk of malignant transformation was assessed using the Kaplan-Meier method and parametric survival models, and predictors of malignancy were evaluated using Cox regression. RESULTS: 806 patients were identified. Median follow-up was 58 months (6-347). Over time, 58 (7.2%) cysts were resected and of those, 11 had high grade dysplasia (HGD) or invasive cancer. Three additional patients had unresectable cancer for a total rate of malignancy of 1.7%. Predictors of development of malignancy included an increase in size ≥2.5 mm/year (HR = 29.54, 95% CI: 9.39-92.91, P < 0.001) and the development of worrisome features (HR = 9.17, 95% CI: 2.99-28.10, P = 0.001). Comparison of parametric survival models suggested that the risk of malignancy decreased after three years of surveillance and was lower than 0.2% after five years. CONCLUSIONS: Pancreatic cysts <15  mm at the time of diagnosis have a very low risk of malignant transformation. Our findings indicate the risk decreases over time. Size increase of ≥2.5 mm/year is the strongest predictor of malignancy.

An elevated CA 19-9 is associated with invasive cancer and worse survival in IPMN.

BACKGROUND: Current guidelines for IPMN include an elevated serum carbohydrate antigen (CA) 19-9 among the worrisome features. However, the correlation of CA 19-9 with histological malignant features and survival is unclear. Serum CEA is also currently used for preoperative management of IPMN, although its measurement is not evidence-based. Accordingly, we aimed to assess the role of these tumor markers as predictors of malignancy in IPMN. METHODS: IPMN resected between 1998 and 2018 at Massachusetts General Hospital were analyzed. Clinical, pathological and survival data were collected and compared to preoperative levels of CA 19-9 and CEA. Receiver operating characteristic (ROC) and Cox regression analyses were performed considering cut-offs of 37 U/ml (CA 19-9) and 5 µg/l (CEA). RESULTS: Analysis of 594 patients showed that preoperative CA 19-9 levels > 37 U/ml (n = 128) were associated with an increased likelihood of invasive carcinoma when compared to normal levels (45.3% vs. 18.0%, P < 0.001), while there was no difference with respect to high-grade dysplasia (32.9% vs 31.9%, P = 0.88). The proportion of concurrent pancreatic cancer was higher in patients with CA 19-9 > 37 U/ml (17.2% vs 4.9%, P < 0.001). An elevated CA 19-9 was also associated with worse overall and disease-free survival (HR = 1.943, P = 0.007 and HR = 2.484, P < 0.001 respectively). CEA levels did not correlate with malignancy. CONCLUSION: In patients with IPMN, serum CA19-9 > 37 U/ml is associated with invasive IPMN and concurrent pancreatic cancer as well as worse survival, but not with high-grade dysplasia. Serum CEA appears to have minimal utility in the management of these patients.

A protocol for a randomised double-blind placebo-controlled feasibility study to determine whether the daily consumption of flavonoid-rich pure cocoa has the potential to reduce fatigue in people with relapsing and remitting multiple sclerosis (RRMS).

BACKGROUND: Dietary interventions including consumption of flavonoids, plant compounds found in certain foods, may have the ability to improve fatigue. However, to date, no well-designed intervention studies assessing the role of flavonoid consumption for fatigue management in people with MS (pwMS) have been performed. The hypothesis is that the consumption of a flavonoid-rich pure cocoa beverage will reduce fatigue in pwMS. The aim of this study is to determine the feasibility and potential outcome of running a trial to evaluate this hypothesis. METHODS: Using a randomised (1:1) double-blind placebo-controlled feasibility study, 40 men and women (20 in each trial arm) with a recent diagnosis (< 10 years) of relapsing and remitting MS (RRMS) and who are over 18 years of age will be recruited from neurology clinics and throughout the Thames Valley community. During a 6-week nutrition intervention period, participants will consume the cocoa beverage, high flavonoid or low flavonoid content, at breakfast daily. At baseline, demographic factors and disease-related factors will be assessed. Fatigue, activity and quality of life, in addition to other measures, will be taken at three visits (baseline, week 3 and week 6) in a university setting by a researcher blinded to group membership. Feasibility and fidelity will be assessed through recruitment and retention, adherence and a quantitative process evaluation at the end of the trial.We will describe demographic factors (age, gender, level of education) as well as disease-related factors (disease burden scores, length of time diagnosed with MS) and cognitive assessment, depression and quality of life and general physical activity in order to characterise participants and determine possible mediators to identify the processes by which the intervention may bring about change. Feasibility (recruitment, safety, feasibility of implementation of the intervention and evaluation, protocol adherence and data completion) and potential for benefit (estimates of effect size and variability) will be determined to inform future planned studies. Results will be presented using point estimates, 95% confidence intervals and p values. Primary statistical analysis will be on an intention-to-treat basis and will use the complete case data set. DISCUSSION: We propose that a flavonoid-enriched cocoa beverage for the management of fatigue will be well received by participants. Further, if it is implemented early in the disease course of people diagnosed with RRMS, it will improve mobility and functioning by modifying fatigue. TRIAL REGISTRATION: Registered with ISRCTN Registry. Trial registration No: ISRCTN69897291; Date April 2016.

Flavonoid rich dark cocoa may improve fatigue in people with multiple sclerosis, yet has no effect on glycaemic response: An exploratory trial.

CONTEXT: Current research suggests that dark cocoa may reduce fatigue; however, the effect on fatigue in people with MS (pwMS) has never been established. The objective of this feasibility study was to explore the acute effect of high flavonoid cocoa on measures of fatigue and glycaemic response. METHODS: This was a randomised crossover participant blind exploratory study in 12 participants (2 male and 10 female) with MS-related fatigue (>4 on the Fatigue Severity Scale; FSS). After fasting overnight, participants consumed the high flavonoid cocoa drink (350 mg gallic acid equivalents {GAE}/g) or a low flavonoid cocoa control (120 mg GAE/g), consuming the alternative drink on the next visit. Fatigue was self-reported on a 100 mm visual analogue scale at 30-min time intervals for 2 h post cocoa consumption and every 2 h for the rest of the day. Fatigability was monitored using a 6 min walk test (6MWT) at the end of the visit (2 h), and activity monitors worn for 24 h commencing at 12 noon on the day of testing. The feasibility of performing the trial including outcome measures was documented. RESULTS: A moderate effect was found in self-reported fatigue throughout the day in favour of the high flavonoid group (Cohen's d 0.32, 95% non-central t CI -0.57 to 1.20). Fatigability measures did not change. Participants consumed and enjoyed the cocoa, all participants completed the study and outcome measures were accepted. CONCLUSION: The results of this study support further trials to investigate the feasibility and efficacy of pure cocoa as a dietary supplement for fatigue in pwMS.

[A histopathologic and imaging study of verrucous hemangioma]. / Hemangioma verrugoso. Estudio histopatológico y radiológico.

The terms verrucous hemangioma and angiokeratoma circumscriptum have been used interchangeably in the literature to define clinically similar lesions. From a histologic perspective, however, angiokeratoma circumscriptum is limited to the papillary dermis whereas verrucous hemangioma extends as far as the hypodermis. We describe the case of a 38-year-old woman who consulted for a lesion on the right thigh that was initially diagnosed as angiokeratoma; magnetic resonance imaging, however, led to a final diagnosis of verrucous hemangioma.

Comparison of the efficacy and tolerability of topically administered azelastine, sodium cromoglycate and placebo in the treatment of seasonal allergic conjunctivitis and rhino-conjunctivitis.

OBJECTIVE AND SETTING: Azelastine (AZE) in a novel, eye drop, formulation, was compared with topically applied sodium cromoglycate (SCG) and placebo (PLA) in the treatment of seasonal allergic conjunctivitis or rhino-conjunctivitis in a multicentre, parallel group study. RESEARCH DESIGN: 144 subjects ranging in age from 16 to 65 years participated. All had at least a 2-year history of seasonal allergic conjunctivitis and were symptomatic at the time of inclusion. Medications were administered topically either twice daily (AZE/PLA) or four times daily (SCG) over a 2-week treatment period. Method and outcome measures: Azelastine and placebo were compared double-blind; the comparison versus SCG was carried out in an open manner. Itching, redness, flow of tears, eyelid swelling, foreign-body sensation, photophobia, soreness and discharge were scored on a 4-point severity scale. RESULTS: Results for the decrease of main conjunctivitis symptoms (itching, tearing and conjunctival redness) showed a marked effect for both active treatments on day 3 with a sustained improvement on days 7 and 14. A clear response to treatment (an improvement of sum scores for day 3 of >/=3 points compared to baseline) occurred in 85.4% of azelastine-treated patients, 83.0% of sodium cromoglycate patients and 56.3% of placebo patients. Response rates for both active treatments were statistically superior to those for placebo (azelastine p = 0.005; sodium cromoglycate p = 0.007). Global assessment of efficacy was at least 'satisfactory' for 90.0% of azelastine patients, 81.3% of sodium cromoglycate patients and 66.3% of placebo-treated patients. The most frequent adverse effects were transient application site reactions which tended to disappear with increasing duration of treatment, and, less frequently, taste perversion. CONCLUSION: The results of this study indicate that the therapeutic use of azelastine eye drops in patients with seasonal allergic conjunctivitis or rhino-conjunctivitis can be recommended.

Effects of propofol and nitrous oxide on middle cerebral artery flow velocity and cerebral autoregulation.

We studied the effects of adding 50% nitrous oxide to propofol anaesthesia administered by target-controlled infusion on middle cerebral artery flow velocity and autoregulatory indices derived from transient hyperaemic response tests. Nine healthy (ASA 1) adult patients scheduled to undergo elective surgery were recruited. A standardised anaesthetic comprising alfentanil 10 microg x kg(-1), propofol via a target-controlled infusion pump and vecuronium 0.1 mg x kg(-1) was used. Transcranial Doppler ultrasonography was used to measure middle cerebral artery (MCA) blood flow velocity and the transient hyperaemic response test was used to assess cerebral autoregulation. These measurements were performed while awake and then at an induction target concentration of propofol (the target at which consciousness was lost, mean 6.2 (SD 1.1) microg x ml(-1)). The measurements were repeated after the addition of 50% nitrous oxide to the breathing gas mixture. Propofol caused a significant decrease in MCA flow velocity and a significant increase in the strength of autoregulation. The addition of nitrous oxide had no significant effect on MCA flow velocity or cerebral autoregulation. These results suggest that addition of 50% nitrous oxide does not influence propofol-induced changes in cerebral haemodynamics.

The influence of age and gender on the immune system: a longitudinal study in Labrador Retriever dogs.

While aging studies employing a cross-sectional design have been informative in documenting many age-related alterations in immune function between different age cohorts within a population, longitudinal studies are invaluable for verifying changes at the level of the individual and for defining the precise periods of life during which particular changes occur. In the present study, a battery of immunological parameters were evaluated in a group of Labrador Retrievers as part of a comprehensive longitudinal aging study. Twenty-three dogs (14 females, 9 males; from 4 to 11 years of age) were evaluated annually for total WBC counts, lymphocyte subset distributions, natural killer cell activity and neutrophil phagocytic activity, and biannually for lymphoproliferative activity. An age-related decline in absolute numbers of lymphocytes, T-cells, CD4-cells and CD8-cells was observed in both genders. The distribution of lymphocyte subsets shifted with age, most dramatically in the females; percentages of B-cells declined while those of T-cells increased. Changes in percentages of CD4- and CD8-cells over the 8-year period were not dramatic; in females, percentages of CD8-cells increased significantly in early- to mid-life and then stabilized. Lymphoproliferative responses to mitogens declined over time in both genders. Males demonstrated higher levels of NK cytolytic activity than females; a marginal decline in activity with age was observed. No significant age-related changes in the phagocytic capacity of PMN were observed. These longitudinal findings help to discriminate between those immune parameters which change most dramatically in early-life versus those which either change more dramatically later in life or change gradually over the entire span of life. In addition they identify significant gender differences in several parameters and corroborate our previously published cross-sectional aging data in the same species.

Studies of binaural detection in the rabbit (Oryctolagus cuniculus) with Pavlovian conditioning.

A Pavlovian conditioned eyeblink response in rabbits (Oryctolagus cuniculus) was used to study psychoacoustical phenomena previously demonstrated in human listeners and other animals. This article contains the results of a tone-in-noise detection study to examine 2 psychoacoustical phenomena in rabbit and in human listeners: (a) the binaural masking level difference (BMLD) and (b) differential performance across reproducible noise masker waveforms. The rabbits demonstrated a BMLD comparable in size to other species. Significant differences in performance across reproducible noise masker waveforms were seen in the rabbits. This performance was compared with the performance of human listeners using the same set of waveforms.

Oxidative stress indices in IDDM subjects with and without long-term diabetic complications.

BACKGROUND: Numerous animal and population studies of diabetes have identified markers of oxidative stress. However, for most markers that have been measured the results are not consistent. In addition, it is less clear whether oxidative stress is related to the development of diabetic complications. The objective of this study was to evaluate a series of plasma markers and leukocyte markers to test the hypothesis that type 1 Insulin Dependent Diabetes Mellitus (IDDM) subjects experience oxidative stress. A related question was whether markers of oxidative stress are higher in IDDM subjects who have developed long-term complications. METHODS: The study population consisted of 22 IDDM subjects with diabetic complications and 22 IDDM subjects without complications, both groups matched by age and gender and with similar HbA1c levels, and 16 nondiabetic control subjects. Plasma levels of organoperoxides were determined by the ferrous oxidation/xylenol orange (FOX) assay, malondialdehyde by the thiobarbituric acid (TBARS) assay, and vitamin E by HPLC. Mononuclear cells and polymorphonuclear cells were analyzed for ascorbic acid by HPLC and for glutathione (GSH) by enzymatic recycling. In addition, GSH peroxidase, GSH transferase and glucose-6-phosphate dehydrogenase levels were determined in both cell fractions. RESULTS: Plasma organoperoxides were significantly elevated in the IDDM subjects compared to controls (p = 0.02) while TBARS and vitamin E levels were not significantly different. In the IDDM subjects, mononuclear cell levels of ascorbic acid were significantly lower (p < 0.02) and levels of GSH were lower, approaching significance (p = 0.07), compared to controls. Ascorbic acid and GSH levels in polymorphonuclear cells were not significantly different between IDDM subjects and controls, nor were enzyme levels different. In addition, the plasma and intracellular indices of oxidative status in IDDM subjects were not different when IDDM subjects with complications were compared to IDDM subjects without complications. CONCLUSION: Demonstration of oxidative stress in IDDM subjects depends upon which markers are measured. This is in agreement with previous studies of oxidative stress in various disease states including diabetes. Plasma levels of organoperoxides may be the most reliable indicators of oxidative stress. However, it is unclear whether elevated plasma organoperoxides indicate a generalized systemic stress or are produced in localized areas. By comparison, oxidative stress indices determined with isolated blood cells may provide a clearer picture. Depressed levels of ascorbic acid and GSH were observed only in mononuclear cells, which are mainly long-lived T lymphocytes. Mononuclear cells antioxidant status may reflect systemic oxidative stress. In this study, neither plasma markers nor intracellular markers of oxidative stress were different in IDDM subjects with long-term diabetic complications compared to subjects without complications.

Quantitative hepatobiliary scintigraphy in normal cats and in cats with experimental cholangiohepatitis.

Quantitative hepatobiliary scintigraphy using 99mTc-mebrofenin was performed on eight normal cats and on the same cats after induction of experimental cholangiohepatitis by infection with the liver fluke Platynosomum concinnum. Hepatobiliary scintigraphy was performed 3 times at 10 weeks, 4 months and 6 months after infection. In addition, routine biochemical tests, hepatic ultrasound and ultrasound guided hepatic biopsy samples were obtained at the same time points, and the results compared with hepatobiliary scintigraphy. The normal hepatic extraction fraction was determined to be 85%, and the normal hepatic excretion half time (T 1/2) was 14 minutes. There was no significant change in scintigraphic parameters compared to pre-infection values at any time following infection with the liver fluke. No correlation between scintigraphic parameters and histologic scores was found; however, significant correlation was identified between parasite burden and histologic scores 6 months following infection. Despite the presence of severe multifocal histologic abnormalities, minimal clinical, biochemical and scintigraphic derangements were identified using this model of cholangiohepatitis. Based on this study, hepatobiliary scintigraphy appears to be an insensitive test for structural hepatobiliary abnormalities. The role of hepatobiliary scintigraphy in functional hepatobiliary abnormalities of the feline liver has not been determined.

Extended photoreceptor viability by light stress in the RCS rats but not in the opsin P23H mutant rats.

PURPOSE: To determine the effect of light stress on retinal function and long-term photoreceptor viability in Royal College of Surgeons (RCS) rats and the applicability of the light treatment to the opsin P23H mutant rats. METHODS: RCS rats at postnatal day (P)23 were illuminated with 120 foot-candles (fc) white light for 10 hours. Photoreceptor survival and basic fibroblast growth factor (bFGF) expression were measured at P60 and P83. Retinal function was evaluated by electroretinography. Opsin P23H transgenic rats were treated with light at P28 and analyzed at P70 for photoreceptor viability, ultrastructure, and bFGF expression. RESULTS: Light-treated RCS rats at P60 had four to five rows of nuclei versus one to two rows in untreated littermates. The average amplitude of the ERG b-wave was 28 microV in treated rats, compared with 6 microV in untreated littermates. By P83 there was still significant preservation of the ONL in treated rats. Immunoblot analysis showed a high expression of bFGF in the treated retinas even 2 months after treatment. Illumination of P23H rats at P28 with 120 fc white light for 10 hours caused substantial photoreceptor cell death, although bFGF expression was upregulated. Lowered illumination dosages continued to cause photoreceptor damage until levels were reached that neither caused damage nor enhanced survival. CONCLUSIONS: Although light stress promotes photoreceptor survival and function in the RCS rat, it elicits death signals in the P23H rats that may not be overcome by survival-promoting factors. Therefore, use of light stress to promote photoreceptor survival should be considered with regard to sensitivity of the mutation to light damage.

Quantitative magnetic resonance imaging of the normal feline cranial abdomen.

Magnetic resonance images of the cranial abdomen were acquired from 15 clinically normal cats. All cats had T1-weighted images, 8 cats had T2-images made and 7 cats had T1-weighted post Gd-DTPA images acquired. Signal intensity measurements for T1, T2, and T1 post contrast sequences were calculated for liver, spleen, gallbladder, renal cortex, renal medulla, pancreas, epaxial muscles, and peritoneal fat. On T1-weighted images the epaxial muscle had the lowest signal intensity, followed by renal medulla, spleen, renal cortex, pancreas, liver and fat, respectively. On T2-weighted images, epaxial muscle had the lowest signal intensity followed by liver, spleen, fat, and gallbladder lumen. Calculations of specific organ percent enhancement following contrast medium administration were made and compared with that reported in humans. A brief review of the potential clinical uses of MR in cats is presented.

Molecular, morphometric and functional analyses demonstrate that the growth hormone deficient little mouse is not hypomyelinated.

To study the effects of naturally occurring growth hormone deficiency type I on CNS myelination, we compared the myelination of brains from little and wild-type littermate mice using molecular, histological, morphometric, and functional analyses. The little mouse produces only 6-8% of normal levels of growth hormone (GH) and approximately 20% of normal circulating levels of insulin-like growth factor 1 (IGF-1). Our data show that the expression of myelin basic protein (MBP) and proteolipid protein (PLP) of the little brain exhibit the same temporal pattern and amount as that of the wild-type brain. Furthermore, the density and size of myelinated axons and the myelin sheath thickness in the corpus callosum, anterior commissure and the optic nerve are comparable in the little and wild-type brains. These regions are reduced in size in the little mouse brain proportionate to the overall reduction in brain size implying a reduction in the total number of neurons. Therefore, it follows that the total myelin content is reduced, but when normalized to brain size, the myelin concentration is unchanged. Myelin staining patterns of whole brains were identical. Moreover, functional analysis of the visual pathway indicated no difference between the little and control mice. These results are inconsistent with previous reports of hypomyelination in the little mouse and suggest that this form of GH deficiency does not adversely affect the myelination process except possibly through neuronal proliferation. However, since axon size and density are maintained, the neuronal growth may conversely be inherently limited by other restricted brain growth.

The effects of sevoflurane and nitrous oxide on middle cerebral artery blood flow velocity and transient hyperemic response.

UNLABELLED: We studied the effects of sevoflurane, with and without nitrous oxide, on the indices of cerebral autoregulation (transient hyperemic response ratio and the strength of autoregulation) derived from the transient hyperemic response (THR) test. Twelve patients (ASA physical status I or II) aged 18-40 yr presenting for routine non-neurosurgical procedures were recruited. The middle cerebral artery blood flow velocity was continuously recorded using transcranial Doppler ultrasonography. Preinduction THR tests were performed before the patients were anesthetized with alfentanil, propofol, and vecuronium. End-tidal carbon dioxide concentration and mean arterial pressure (to within 10% with a phenylephrine infusion) were maintained at their preinduction values. THR tests were performed sequentially at the following end-tidal sevoflurane concentrations: 2.2% in oxygen, 3.4% in oxygen, 3.4% with 50% nitrous oxide in oxygen, and 2.2% with 50% nitrous oxide in oxygen. Neither 2.2% nor 3.4% sevoflurane significantly affected cerebral autoregulation. The addition of 50% nitrous oxide to the 2.2%, but not the 3.4%, concentration of sevoflurane increased middle cerebral artery blood flow velocity and decreased autoregulatory indices significantly. IMPLICATIONS: Transient hyperemic response is preserved during sevoflurane anesthesia but is significantly impaired when nitrous oxide is added to the lower concentration of sevoflurane (2.2%). These findings have implications for neurosurgical patients undergoing general anesthesia.

The interaction of sarin and soman with plasma proteins: the identification of a novel phosphonylation site.

Incubation of both sarin and soman with human plasma has shown that binding occurs to a tyrosine residue. Similar binding occurs when sarin and soman are incubated with human serum albumin. This binding may provide an important biological marker, which retains full structural information concerning the identity of the agent, in cases of allegations of chemical warfare use.

Scintigraphic, sonographic, and histologic evaluation of renal autotransplantation in cats.

OBJECTIVE: To determine scintigraphic, sonographic, and histologic changes associated with renal autotransplantation in cats. ANIMALS: 7 adult specific-pathogen-free cats: 5 males, 2 females, 1 to 9 years old. PROCEDURE: Renal autotransplantation was performed by moving a kidney (5 left, 2 right) to the left iliac fossa. Before and at multiple times after surgery, for a total of 28 days, cats were evaluated by B-mode and Doppler ultrasonography, scintigraphy, and renal biopsy. RESULTS: By 24 hours after surgery, a significant decrease (42%) in mean glomerular filtration rate (GFR) and an increase in mean renal size (81% increase in cross-sectional area) were evident in the transplanted kidney, compared with preoperative values. By postsurgery day 28, reduction in GFR was 23%. Significant changes in renal blood flow velocity were identified in both kidneys. Consistent changes in resistive index or pulsatility index for either kidney could not be identified. When all postoperative histologic data were combined, the histologic score, indicating degree and numbers of abnormalities detected, for the transplanted kidney was significantly higher than that for the control kidney. CONCLUSIONS: Significant changes in renal function, size, and histologic abnormalities develop secondary to acute tubular necrosis in cats after uncomplicated renal autotransplantation. CLINICAL RELEVANCE: Evaluation of renal size and function may be of benefit for clinical evaluation of feline renal transplant patients, whereas measurement of the resistive index may be of little clinical value.

A care package for managing female sexual assault in genitourinary medicine.

This paper describes the development of a designated in-house service for the management of adult female victims of sexual assault within the Department of Genitourinary Medicine (GUM) at St Mary's Hospital, London. This was set up in 1994 as a need was identified by medical, nursing, psychological and health advising staff for an appropriate streamlined service which would provide comprehensive sexual health screening, psychological support and therapy and adequate medico-legal documentation within the limitations of a busy GUM clinic. A structured package of care consisting of medical and psychological protocols with training for relevant staff and a specialist in-house referral clinic was introduced. Fifty-four patients were seen during the first 17 months of the service, the notes of 48 of these were examined and relevant epidemiological and audit data are presented here. By auditing the quality of documentation before and after the introduction of the protocols specifically looking at the appropriateness and comprehensiveness of the sexually transmitted diseases screen and the medico-legal documentation it was clear that the quality of care to these patients was improved. We present here the development of these protocols, a detailed description of the protocols themselves and the method of their implementation.