Hospital Santo António dos Capuchos

BACKGROUND: Hydrocortisone is widely used in patients with septic shock even though a survival benefit has been reported only in patients who remained hypotensive after fluid and vasopressor resuscitation and whose plasma cortisol levels did not rise appropriately after the administration of corticotropin. METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, we assigned 251 patients to receive 50 mg of intravenous hydrocortisone and 248 patients to receive placebo every 6 hours for 5 days; the dose was then tapered during a 6-day period. At 28 days, the primary outcome was death among patients who did not have a response to a corticotropin test. RESULTS: Of the 499 patients in the study, 233 (46.7%) did not have a response to corticotropin (125 in the hydrocortisone group and 108 in the placebo group). At 28 days, there was no significant difference in mortality between patients in the two study groups who did not have a response to corticotropin (39.2% in the hydrocortisone group and 36.1% in the placebo group, P=0.69) or between those who had a response to corticotropin (28.8% in the hydrocortisone group and 28.7% in the placebo group, P=1.00). At 28 days, 86 of 251 patients in the hydrocortisone group (34.3%) and 78 of 248 patients in the placebo group (31.5%) had died (P=0.51). In the hydrocortisone group, shock was reversed more quickly than in the placebo group. However, there were more episodes of superinfection, including new sepsis and septic shock. CONCLUSIONS: Hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not have a response to corticotropin, although hydrocortisone hastened reversal of shock in patients in whom shock was reversed. (ClinicalTrials.gov number, NCT00147004.)

Thirty-five patients, exclusively girls, from three countries had a uniform and striking progressive encephalopathy. After normal general and psychomotor development up to the age of 7 to 18 months, developmental stagnation occurred, followed by rapid deterioration of higher brain functions. Within one-and-a-half years this deterioration led to severe dementia, autism, loss of purposeful use of the hands, jerky truncal ataxia, and acquired microcephaly. The destructive stage was followed by apparent stability lasting through decades. Additional insidious neurological abnormalities supervened, mainly spastic parapareses, vasomotor disturbances of the lower limbs, and epilepsy. Prior extensive laboratory investigations have not revealed the cause. The condition is similar to a virtually overlooked syndrome described by Rett in the German literature. The exclusive involvement of females, correlated with findings in family data analyses, suggests a dominant mutation on one X chromosome that results in affected girls and nonviable male hemizygous conceptuses.

OBJECTIVE: Behçet's disease (BD) is a chronic, relapsing, inflammatory vascular disease with no pathognomonic test. Low sensitivity of the currently applied International Study Group (ISG) clinical diagnostic criteria led to their reassessment. METHODS: An International Team for the Revision of the International Criteria for BD (from 27 countries) submitted data from 2556 clinically diagnosed BD patients and 1163 controls with BD-mimicking diseases or presenting at least one major BD sign. These were randomly divided into training and validation sets. Logistic regression, 'leave-one-country-out' cross-validation and clinical judgement were employed to develop new International Criteria for BD (ICBD) with the training data. Existing and new criteria were tested for their performance in the validation set. RESULTS: For the ICBD, ocular lesions, oral aphthosis and genital aphthosis are each assigned 2 points, while skin lesions, central nervous system involvement and vascular manifestations 1 point each. The pathergy test, when used, was assigned 1 point. A patient scoring ≥4 points is classified as having BD. In the training set, 93.9% sensitivity and 92.1% specificity were assessed compared with 81.2% sensitivity and 95.9% specificity for the ISG criteria. In the validation set, ICBD demonstrated an unbiased estimate of sensitivity of 94.8% (95% CI: 93.4-95.9%), considerably higher than that of the ISG criteria (85.0%). Specificity (90.5%, 95% CI: 87.9-92.8%) was lower than that of the ISG-criteria (96.0%), yet still reasonably high. For countries with at least 90%-of-cases and controls having a pathergy test, adding 1 point for pathergy test increased the estimate of sensitivity from 95.5% to 98.5%, while barely reducing specificity from 92.1% to 91.6%. CONCLUSION: The new proposed criteria derived from multinational data exhibits much improved sensitivity over the ISG criteria while maintaining reasonable specificity. It is proposed that the ICBD criteria to be adopted both as a guide for diagnosis and classification of BD.

OBJECTIVE: To develop a model to assess severity of illness and predict vital status at hospital discharge based on ICU admission data. DESIGN: Prospective multicentre, multinational cohort study. PATIENTS AND SETTING: A total of 16,784 patients consecutively admitted to 303 intensive care units from 14 October to 15 December 2002. MEASUREMENTS AND RESULTS: ICU admission data (recorded within +/-1 h) were used, describing: prior chronic conditions and diseases; circumstances related to and physiologic derangement at ICU admission. Selection of variables for inclusion into the model used different complementary strategies. For cross-validation, the model-building procedure was run five times, using randomly selected four fifths of the sample as a development- and the remaining fifth as validation-set. Logistic regression methods were then used to reduce complexity of the model. Final estimates of regression coefficients were determined by use of multilevel logistic regression. Variables selection and weighting were further checked by bootstraping (at patient level and at ICU level). Twenty variables were selected for the final model, which exhibited good discrimination (aROC curve 0.848), without major differences across patient typologies. Calibration was also satisfactory (Hosmer-Lemeshow goodness-of-fit test H=10.56, p=0.39, C=14.29, p=0.16). Customized equations for major areas of the world were computed and demonstrate a good overall goodness-of-fit. CONCLUSIONS: The SAPS 3 admission score is able to predict vital status at hospital discharge with use of data recorded at ICU admission. Furthermore, SAPS 3 conceptually dissociates evaluation of the individual patient from evaluation of the ICU and thus allows them to be assessed at their respective reference levels.

RATIONALE: Recent literature in mechanical ventilation includes strong evidence from randomized trials. Little information is available regarding the influence of these trials on usual clinical practice. OBJECTIVES: To describe current mechanical ventilation practices and to assess the influence of interval randomized trials when compared with findings from a 1998 cohort. METHODS: A prospective international observational cohort study, with a nested comparative study performed in 349 intensive care units in 23 countries. We enrolled 4,968 consecutive patients receiving mechanical ventilation over a 1-month period. We recorded demographics and daily data related to mechanical ventilation for the duration of ventilation. We systematically reviewed the literature and developed 11 practice-change hypotheses for the comparative cohort study before seeing these results. In assessing practice changes, we only compared data from the 107 intensive care units (1,675 patients) that also participated in the 1998 cohort (1,383 patients). MEASUREMENTS AND MAIN RESULTS: In 2004 compared with 1998, the use of noninvasive ventilation increased (11.1 vs. 4.4%, P < 0.001). Among patients with acute respiratory distress syndrome, tidal volumes decreased (7.4 vs. 9.1 ml/kg, P < 0.001) and positive end-expiratory pressure levels increased slightly (8.7 vs. 7.7 cm H(2)O, P = 0.02). More patients were successfully extubated after their first attempt of spontaneous breathing (77 vs. 62%, P < 0.001). Use of synchronized intermittent mandatory ventilation fell dramatically (1.6 vs. 11%, P < 0.001). Observations confirmed 10 of our 11 practice-change hypotheses. CONCLUSIONS: The strong concordance of predicted and observed practice changes suggests that randomized trial results have advanced mechanical ventilation practices internationally.

OBJECTIVE: Risk adjustment systems now in use were developed more than a decade ago and lack prognostic performance. Objective of the SAPS 3 study was to collect data about risk factors and outcomes in a heterogeneous cohort of intensive care unit (ICU) patients, in order to develop a new, improved model for risk adjustment. DESIGN: Prospective multicentre, multinational cohort study. PATIENTS AND SETTING: A total of 19,577 patients consecutively admitted to 307 ICUs from 14 October to 15 December 2002. MEASUREMENTS AND RESULTS: Data were collected at ICU admission, on days 1, 2 and 3, and the last day of the ICU stay. Data included sociodemographics, chronic conditions, diagnostic information, physiological derangement at ICU admission, number and severity of organ dysfunctions, length of ICU and hospital stay, and vital status at ICU and hospital discharge. Data reliability was tested with use of kappa statistics and intraclass-correlation coefficients, which were >0.85 for the majority of variables. Completeness of the data was also satisfactory, with 1 [0-3] SAPS II parameter missing per patient. Prognostic performance of the SAPS II was poor, with significant differences between observed and expected mortality rates for the overall cohort and four (of seven) defined regions, and poor calibration for most tested subgroups. CONCLUSIONS: The SAPS 3 study was able to provide a high-quality multinational database, reflecting heterogeneity of current ICU case-mix and typology. The poor performance of SAPS II in this cohort underscores the need for development of a new risk adjustment system for critically ill patients.

General illness severity scores are widely used in the ICU to predict outcome, characterize disease severity and degree of organ dysfunction, and assess resource use. In this article we review the most commonly used scoring systems in each of these three groups. We examine the history of the development of the initial major systems in each group, discuss the construction of subsequent versions, and, when available, provide recent comparative data regarding their performance. Importantly, the different types of scores should be seen as complementary, rather than competitive and mutually exclusive. It is possible that their combined use could provide a more accurate indication of disease severity and prognosis. All these scoring systems will need to be updated with time as ICU populations change and new diagnostic, therapeutic and prognostic techniques become available.

Factors influencing the morbidity and mortality associated with viremic hepatitis C virus (HCV) infection change over time and place, making it difficult to compare reported estimates. Models were developed for 17 countries (Bahrain, Bulgaria, Cameroon, Colombia, Croatia, Dominican Republic, Ethiopia, Ghana, Hong Kong, Jordan, Kazakhstan, Malaysia, Morocco, Nigeria, Qatar and Taiwan) to quantify and characterize the viremic population as well as forecast the changes in the infected population and the corresponding disease burden from 2015 to 2030. Model inputs were agreed upon through expert consensus, and a standardized methodology was followed to allow for comparison across countries. The viremic prevalence is expected to remain constant or decline in all but four countries (Ethiopia, Ghana, Jordan and Oman); however, HCV-related morbidity and mortality will increase in all countries except Qatar and Taiwan. In Qatar, the high-treatment rate will contribute to a reduction in total cases and HCV-related morbidity by 2030. In the remaining countries, however, the current treatment paradigm will be insufficient to achieve large reductions in HCV-related morbidity and mortality.

INTRODUCTION: Increasing numbers of cancer patients are being admitted to the intensive care unit (ICU), either for cancer-related complications or treatment-associated side effects, yet there are relatively few data concerning the epidemiology and prognosis of cancer patients admitted to general ICUs. The aim of this study was to assess the characteristics of critically ill cancer patients, and to evaluate their prognosis. METHODS: This was a substudy of the Sepsis Occurrence in Acutely Ill Patients (SOAP) study, a cohort, multicentre, observational study that included data from all adult patients admitted to one of 198 participating ICUs from 24 European countries during the study period. Patients were followed up until death, hospital discharge or for 60 days. RESULTS: Of the 3147 patients enrolled in the SOAP study, 473 (15%) had a malignancy, 404 (85%) had solid tumours and 69 (15%) had haematological cancer. Patients with solid cancers had the same severity of illness as the non-cancer population, but were older, more likely to be a surgical admission and had a higher frequency of sepsis. Patients with haematological cancer were more severely ill and more commonly had sepsis, acute lung injury/acute respiratory distress syndrome, and renal failure than patients with other malignancies; these patients also had the highest hospital mortality rate (58%). The outcome of all cancer patients was comparable with that in the non-cancer population, with a 27% hospital mortality rate. However, in the subset of patients with more than three failing organs, more than 75% of patients with cancer died compared with about 50% of patients without cancer (p = 0.01). CONCLUSIONS: In this large European study, patients with cancer were more often admitted to the ICU for sepsis and respiratory complications than other ICU patients. Overall, the outcome of patients with solid cancer was similar to that of ICU patients without cancer, whereas patients with haematological cancer had a worse outcome.

OBJECTIVE: Acute pancreatitis represents a spectrum of disease ranging from a mild, self-limited course requiring only brief hospitalization to a rapidly progressive, fulminant illness resulting in the multiple organ dysfunction syndrome (MODS), with or without accompanying sepsis. The goal of this consensus statement is to provide recommendations regarding the management of the critically ill patient with severe acute pancreatitis (SAP). DATA SOURCES AND METHODS: An international consensus conference was held in April 2004 to develop recommendations for the management of the critically ill patient with SAP. Evidence-based recommendations were developed by a jury of ten persons representing surgery, internal medicine, and critical care after conferring with experts and reviewing the pertinent literature to address specific questions concerning the management of patients with severe acute pancreatitis. DATA SYNTHESIS: There were a total of 23 recommendations developed to provide guidance to critical care clinicians caring for the patient with SAP. Topics addressed were as follows. 1) When should the patient admitted with acute pancreatitis be monitored in an ICU or stepdown unit? 2) Should patients with severe acute pancreatitis receive prophylactic antibiotics? 3) What is the optimal mode and timing of nutritional support for the patient with SAP? 4) What are the indications for surgery in acute pancreatitis, what is the optimal timing for intervention, and what are the roles for less invasive approaches including percutaneous drainage and laparoscopy? 5) Under what circumstances should patients with gallstone pancreatitis undergo interventions for clearance of the bile duct? 6) Is there a role for therapy targeting the inflammatory response in the patient with SAP? Some of the recommendations included a recommendation against the routine use of prophylactic systemic antibacterial or antifungal agents in patients with necrotizing pancreatitis. The jury also recommended against pancreatic debridement or drainage for sterile necrosis, limiting debridement or drainage to those with infected pancreatic necrosis and/or abscess confirmed by radiologic evidence of gas or results or fine needle aspirate. Furthermore, the jury recommended that whenever possible, operative necrosectomy and/or drainage be delayed at least 2-3 wk to allow for demarcation of the necrotic pancreas. CONCLUSIONS: This consensus statement provides 23 different recommendations concerning the management of patients with SAP. These recommendations differ in several ways from previous recommendations because of the release of recent data concerning the management of these patients and also because of the focus on the critically ill patient. There are a number of important questions that could not be answered using an evidence-based approach, and areas in need of further research were identified.

OBJECTIVE: To assess on a multinational level the frequency, characteristics, contributing factors, and preventive measures of administration errors in parenteral medication in intensive care units. DESIGN: Observational, prospective, 24 hour cross sectional study with self reporting by staff. SETTING: 113 intensive care units in 27 countries. PARTICIPANTS: 1328 adults in intensive care. MAIN OUTCOME MEASURES: Number of errors; impact of errors; distribution of error characteristics; distribution of contributing and preventive factors. RESULTS: 861 errors affecting 441 patients were reported: 74.5 (95% confidence interval 69.5 to 79.4) events per 100 patient days. Three quarters of the errors were classified as errors of omission. Twelve patients (0.9% of the study population) experienced permanent harm or died because of medication errors at the administration stage. In a multiple logistic regression with patients as the unit of analysis, odds ratios for the occurrence of at least one parenteral medication error were raised for number of organ failures (odds ratio per increase of one organ failure: 1.19, 95% confidence interval 1.05 to 1.34); use of any intravenous medication (yes v no: 2.73, 1.39 to 5.36); number of parenteral administrations (per increase of one parenteral administration: 1.06, 1.04 to 1.08); typical interventions in patients in intensive care (yes v no: 1.50, 1.14 to 1.96); larger intensive care unit (per increase of one bed: 1.01, 1.00 to 1.02); number of patients per nurse (per increase of one patient: 1.30, 1.03 to 1.64); and occupancy rate (per 10% increase: 1.03, 1.00 to 1.05). Odds ratios for the occurrence of parenteral medication errors were decreased for presence of basic monitoring (yes v no: 0.19, 0.07 to 0.49); an existing critical incident reporting system (yes v no: 0.69, 0.53 to 0.90); an established routine of checks at nurses' shift change (yes v no: 0.68, 0.52 to 0.90); and an increased ratio of patient turnover to the size of the unit (per increase of one patient: 0.73, 0.57 to 0.93). CONCLUSIONS: Parenteral medication errors at the administration stage are common and a serious safety problem in intensive care units. With the increasing complexity of care in critically ill patients, organisational factors such as error reporting systems and routine checks can reduce the risk for such errors.

Height, mass and skeletal maturity (Fels method) were assessed in 135 elite youth soccer players aged 10.7-16.5 years (only two boys were < 11.0 years). Sample sizes, years of training and current weekly training volume by two-year age groups were: 11-12 years (n = 63), 2.6 +/- 1.0 years and 4.1 +/- 1.7 h; 13-14 years (n = 29), 3.1 +/- 1.6 years and 4.5 +/- 1.7 h; 15-16 years (n = 43), 4.7 +/- 2.4 years and 6.1 +/- 2.0 h. The oldest age group included members of the national youth team. Heights and masses were compared to US reference values, and skeletal age and chronological age were contrasted. The players were also classified as late, average ('on time') and early maturers on the basis of differences between skeletal and chronological age, with the average category including boys with skeletal ages within +/- 1 year of chronological age. The mean heights and masses of 11- to 12-year-old soccer players equalled the US reference values, while those of players aged 13-14 and 15-16 years were slightly above the reference values. The mean skeletal age approximated mean chronological age in players aged 11-12 years (12.4 +/- 1.3 and 12.3 +/- 0.5 years, respectively), while mean skeletal age was in advance of mean chronological age in the two older groups (14.3 +/- 1.2 and 13.6 +/- 0.7 years, respectively, in 13- to 14-year-olds; 16.7 +/- 1.0 and 15.8 +/- 0.4 years, respectively, in 15- to 16-year-olds). Seven boys in the oldest age group were already skeletally mature and were not included when calculating differences between skeletal and chronological age. The proportion of late maturing boys in this sample of elite soccer players decreased with increasing chronological age. Among 11- to 12-year-old players, the percentages of late and early maturing boys were equal at 21% (n = 13). Among 13- to 14-year-old players, the percentages of late and early maturing boys were 7% (n = 2) and 38% (n = 11) respectively, while among players aged 15-16 years the percentages of late and early maturing boys were 2% (n = 1) and 65% (n = 28) respectively. The results of this comparative analysis suggest that the sport of soccer systematically excludes late maturing boys and favours average and early maturing boys as chronological age and sport specialization increase. It is also possible that late maturing boys selectively drop-out of soccer as age and sport specialization increase.

BACKGROUND: This intercontinental study aimed to study gram-negative rod (GNR) resistance in hematopoietic stem cell transplantation (HSCT). METHODS: GNR bacteremias occurring during 6 months post-HSCT (February 2014-May 2015) were prospectively collected, and analyzed for rates and risk factors for resistance to fluoroquinolones, noncarbapenem anti-Pseudomonas β-lactams (noncarbapenems), carbapenems, and multidrug resistance. RESULTS: Sixty-five HSCT centers from 25 countries in Europe, Australia, and Asia reported data on 655 GNR episodes and 704 pathogens in 591 patients (Enterobacteriaceae, 73%; nonfermentative rods, 24%; and 3% others). Half of GNRs were fluoroquinolone and noncarbapenem resistant; 18.5% carbapenem resistant; 35.2% multidrug resistant. The total resistance rates were higher in allogeneic HSCT (allo-HSCT) vs autologous HSCT (auto-HSCT) patients (P < .001) but similar in community-acquired infections. Noncarbapenem resistance and multidrug resistance were higher in auto-HSCT patients in centers providing vs not providing fluoroquinolone prophylaxis (P < .01). Resistance rates were higher in southeast vs northwest Europe and similar in children and adults, excluding higher fluoroquinolone- and β-lactam/β-lactamase inhibitor resistance rates in allo-HSCT adults. Non-Klebsiella Enterobacteriaceae were rarely carbapenem resistant. Multivariable analysis revealed resistance risk factors in allo-HSCT patients: fluoroquinolone resistance: adult, prolonged neutropenia, breakthrough on fluoroquinolones; noncarbapenem resistance: hospital-acquired infection, breakthrough on noncarbapenems or other antibiotics (excluding fluoroquinolones, noncarbapenems, carbapenems), donor type; carbapenem resistance: breakthrough on carbapenem, longer hospitalization, intensive care unit, previous other antibiotic therapy; multidrug resistance: longer hospitalization, breakthrough on β-lactam/β-lactamase inhibitors, and carbapenems. Inappropriate empiric therapy and mortality were significantly more common in infections caused by resistant bacteria. CONCLUSIONS: Our data question the recommendation for fluoroquinolone prophylaxis and call for reassessment of local empiric antibiotic protocols. Knowledge of pathogen-specific resistance enables early appropriate empiric therapy. Monitoring of resistance is crucial. CLINICAL TRIALS REGISTRATION: NCT02257931.

Chronic infection with hepatitis C virus (HCV) is a leading indicator for liver disease. New treatment options are becoming available, and there is a need to characterize the epidemiology and disease burden of HCV. Data for prevalence, viremia, genotype, diagnosis and treatment were obtained through literature searches and expert consensus for 16 countries. For some countries, data from centralized registries were used to estimate diagnosis and treatment rates. Data for the number of liver transplants and the proportion attributable to HCV were obtained from centralized databases. Viremic prevalence estimates varied widely between countries, ranging from 0.3% in Austria, England and Germany to 8.5% in Egypt. The largest viremic populations were in Egypt, with 6,358,000 cases in 2008 and Brazil with 2,106,000 cases in 2007. The age distribution of cases differed between countries. In most countries, prevalence rates were higher among males, reflecting higher rates of injection drug use. Diagnosis, treatment and transplant levels also differed considerably between countries. Reliable estimates characterizing HCV-infected populations are critical for addressing HCV-related morbidity and mortality. There is a need to quantify the burden of chronic HCV infection at the national level.

BACKGROUND: Zidovudine, lamivudine, and efavirenz comprise a highly effective and well-tolerated triple regimen for antiretroviral-naive patients. Evaluating other unique nucleoside reverse-transcriptase inhibitor (NRTI) combinations for long-term viral suppression is desirable. METHODS: This multicenter, randomized, double-blind noninferiority clinical trial compared the efficacy and safety of abacavir with that of zidovudine plus lamivudine and efavirenz in 649 antiretroviral-naive HIV-infected patients. The primary objective was a comparison of proportions of patients achieving plasma HIV-1 RNA levels <or=50 copies/mL through week 48 of the study. RESULTS: At study week 48, 70% of patients in the abacavir group, compared with 69% in the zidovudine group, maintained confirmed plasma HIV-1 RNA levels of <or=50 copies/mL (in the intent-to-treat exposed population). Virologic failure was infrequent (6% in the abacavir group and 4% in the zidovudine group). There was a significant CD4(+) cell response (209 cells/mm(3) in the abacavir group and 155 cells/mm(3) in the zidovudine group). Safety profiles were as expected. CONCLUSION: Abacavir provided an effective and durable antiretroviral response that was noninferior to zidovudine, when combined with lamivudine and efavirenz.

The number of hepatitis C virus (HCV) infections is projected to decline while those with advanced liver disease will increase. A modeling approach was used to forecast two treatment scenarios: (i) the impact of increased treatment efficacy while keeping the number of treated patients constant and (ii) increasing efficacy and treatment rate. This analysis suggests that successful diagnosis and treatment of a small proportion of patients can contribute significantly to the reduction of disease burden in the countries studied. The largest reduction in HCV-related morbidity and mortality occurs when increased treatment is combined with higher efficacy therapies, generally in combination with increased diagnosis. With a treatment rate of approximately 10%, this analysis suggests it is possible to achieve elimination of HCV (defined as a >90% decline in total infections by 2030). However, for most countries presented, this will require a 3-5 fold increase in diagnosis and/or treatment. Thus, building the public health and clinical provider capacity for improved diagnosis and treatment will be critical.

Systemic and superficial fungal infections are a major problem among immunocompromised patients with hematological malignancy. A double-blind, double-placebo, randomized, multicenter trial was performed to compare the efficacy and safety of itraconazole oral solution (2.5 mg/kg of body weight twice a day) with amphotericin B capsules (500 mg orally four times a day) for prophylaxis of systemic and superficial fungal infection. Prophylactic treatment was initiated on the first day of chemotherapy and was continued until the end of the neutropenic period (>0.5 x 10(9) neutrophils/liter) or up to a maximum of 3 days following the end of neutropenia, unless a systemic fungal infection was documented or suspected. The maximum treatment duration was 56 days. In the intent-to-treat population, invasive aspergillosis was noted in 5 (1.8%) of the 281 patients assigned to itraconazole oral solution and in 9 (3.3%) of the 276 patients assigned to oral amphotericin B; of these, 1 and 4 patients died, respectively. Proven systemic fungal infection (including invasive aspergillosis) occurred in 8 patients (2.8%) who received itraconazole, compared with 13 (4.7%) who received oral amphotericin B. Itraconazole significantly reduced the incidence of superficial fungal infections as compared to oral amphotericin B (2 [1%] versus 13 [5%]; P = 0.004). Although the incidences of suspected fungal infection (including fever of unknown origin) were not different between the groups, fewer patients were administered intravenous systemic antifungals (mainly intravenous amphotericin B) in the group receiving itraconazole than in the group receiving oral amphotericin B (114 [41%] versus 132 [48%]; P = 0.066). Adequate plasma itraconazole levels were achieved in about 80% of the patients from 1 week after the start of treatment. In both groups, the trial medication was safe and well tolerated. Prophylactic administration of itraconazole oral solution significantly reduces superficial fungal infection in patients with hematological malignancies and neutropenia. The incidence of proven systemic fungal infections, the number of deaths due to deep fungal infections, and the use of systemic antifungals tended to be lower in the itraconazole-treated group than in the amphotericin B-treated group, without statistical significance. Itraconazole oral solution is a broad-spectrum systemic antifungal agent with prophylactic activity in neutropenic patients, especially for those at high risk of prolonged neutropenia.

// Lourdes Mart&iacute;n-Mart&iacute;n 1 , Antonio L&oacute;pez 1 , Bel&eacute;n Vidriales 2 , Mar&iacute;a Dolores Caballero 2 , Ant&oacute;nio Silva Rodrigues 3 , Silvia In&ecirc;s Ferreira 4 , Margarida Lima 5 , S&eacute;rgio Almeida 6 , Berta Valverde 7 , Pilar Mart&iacute;nez 8 , Ana Ferrer 9 , Jorge Candeias 10 , Francisco Ru&iacute;z-Cabello 11 , Josefa Marco Buadesa 12 , Amparo Sempere 13 , Neus Villamor 14 , Alberto Orfao 1, * , Julia Almeida 1, * 1 Cancer Research Centre (IBMCC, USAL-CSIC), Institute for Biomedical Research of Salamanca (IBSAL) and Department of Medicine and Cytometry Service, University of Salamanca (USAL), Salamanca, Spain 2 Hematology Department and IBSAL, University Hospital of Salamanca, Salamanca, Spain 3 Hematology Department, Hospital de Santo Ant&oacute;nio dos Capuchos, Lisboa, Portugal 4 Santa Luzia Medical Laboratory, Florian&oacute;polis, SC, Brazil 5 Clinical Hematology Department, Hospital de Santo Ant&oacute;nio, Porto, Portugal 6 Hematology Department, Hospital Universidade de Coimbra, Coimbra, Portugal 7 Hematology Department, Hospital Nacional de Ni&ntilde;os Dr. Carlos S&aacute;enz Herrera, San Jos&eacute;, Costa Rica 8 Hematology Department, Hospital 12 de Octubre, Madrid, Spain 9 Pathology Department, Hospital del Mar, Barcelona. IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain 10 Immunology Department, Hospital S&atilde;o Jo&atilde;o, Porto, Portugal 11 Clinical Analysis and Immunology Department, Hospital Virgen de las Nieves, Granada, Spain 12 Hematology Department, Hospital General de Castell&oacute;n, Castell&oacute;n, Spain 13 Hematology Department, University Hospital La F&eacute;, Valencia, Spain 14 Hospital Clinic, Barcelona, Spain * These authors have contributed equally to this work Correspondence to: Alberto Orfao, e-mail: orfao@usal.es Keywords: blastic plasmacytoid dendritic cell neoplasm, flow cytometry, maturation profile, acute leukemia, lymphoma Received: April 15, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: May 11, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: May 25, 2015 ABSTRACT Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare subtype of leukemia/lymphoma, whose diagnosis can be difficult to achieve due to its clinical and biological heterogeneity, as well as its overlapping features with other hematologic malignancies. In this study we investigated whether the association between the maturational stage of tumor cells and the clinico-biological and prognostic features of the disease, based on the analysis of 46 BPDCN cases classified into three maturation-associated subgroups on immunophenotypic grounds. Our results show that blasts from cases with an immature plasmacytoid dendritic cell (pDC) phenotype exhibit an uncommon CD56 &minus; phenotype, coexisting with CD34 + non-pDC tumor cells, typically in the absence of extramedullary (e.g. skin) disease at presentation. Conversely, patients with a more mature blast cell phenotype more frequently displayed skin/extramedullary involvement and spread into secondary lymphoid tissues. Despite the dismal outcome, acute lymphoblastic leukemia-type therapy (with central nervous system prophylaxis) and/or allogeneic stem cell transplantation appeared to be the only effective therapies. Overall, our findings indicate that the maturational profile of pDC blasts in BPDCN is highly heterogeneous and translates into a wide clinical spectrum -from acute leukemia to mature lymphoma-like behavior-, which may also lead to variable diagnosis and treatment.

OBJECTIVE: To evaluate the performance of the New Simplified Acute Physiology Score (SAPS II) and the admission Mortality Probability Model (MPM0) in a large independent database, using formal statistical assessment. DESIGN: Analysis of the database of a multicenter, multinational, prospective cohort study, EURICUS-I. SETTING: Eighty nine intensive care units (ICUs) from 13 European areas. PATIENTS: Data of 16,060 patients consecutively admitted to the participating ICUs were collected during a period of 4 months. Following the original SAPS II and MPM0 criteria, the analysis excluded: patients <18 ys of age; readmissions; patients admitted with acute myocardial infarction; burns; and patients in the postoperative period after coronary artery bypass surgery. All patients with a length of stay <8 hrs were excluded from the study to keep comparability between both systems. A total of 10,027 patients were analyzed. INTERVENTIONS: Collection of the first 24 hrs' admission data necessary for the calculation of SAPS II and MPM0 and basic demographic statistics. Vital status at discharge from the hospital was registered. MEASUREMENTS AND MAIN RESULTS: Despite having a good discriminative capability, as measured by the area under the receiver operating characteristic (ROC) curves (SAPS II: ROC = 0.822 +/- 0.005 SEM; MPM0: ROC = 0.785 +/- 0.006 SEM), both models presented poor calibration, with significant differences between observed and predicted mortality (Hosmer-Lemeshow goodness-of-fit tests H and C, p < .0001). Both SAPS II (predicted risk >40%) and MPM0 (predicted risk >30%) overestimated the risk of death. The evaluation of the uniformity of fit of SAPS II and MPM0 demonstrated large variations across the various subgroups of patients. CONCLUSIONS: The original SAPS II and MPM0 models did not accurately predict mortality on an independent large international multicenter ICU patient database. Results of studies utilizing general outcome prediction models without previous validation in the target population should be interpreted with prudence.

The Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire is an instrument to assess QOL in diabetic polyneuropathy. The objective of this observational, cross-sectional study in 61 patients with V30M transthyretin familial amyloid polyneuropathy (TTR-FAP) and 16 healthy volunteers was to validate the Norfolk QOL-DN for assessment of QOL in TTR-FAP. Comparisons were conducted to identify the best items to discriminate disease stages and assess which individual Norfolk domains (symptoms, large fiber, small fiber, autonomic, and activities of daily living) would be most affected by disease stage. Analysis of individual items revealed a significant pattern of discrimination among disease stages (p < 0.001). Total QOL scores increased (indicating worsening) with duration of symptoms, with a steeper increase observed earlier in the course of disease. Significant correlations were observed between each Norfolk domain and other measures of neurological function. Limitations include cross-sectional study design, low patient numbers in this rare disease, and the ordinal-based character of the metric used; future areas to explore include item response theory approaches such as Rasch analysis. These results suggest the Norfolk QOL-DN is a reliable indicator of the impact of disease severity on QOL in patients with TTR-FAP.