Defining responses to therapy and study outcomes in clinical trials of invasive fungal diseases: Mycoses Study Group and European Organization for Research and Treatment of Cancer consensus criteria.

Invasive fungal diseases (IFDs) have become major causes of morbidity and mortality among highly immunocompromised patients. Authoritative consensus criteria to diagnose IFD have been useful in establishing eligibility criteria for antifungal trials. There is an important need for generation of consensus definitions of outcomes of IFD that will form a standard for evaluating treatment success and failure in clinical trials. Therefore, an expert international panel consisting of the Mycoses Study Group and the European Organization for Research and Treatment of Cancer was convened to propose guidelines for assessing treatment responses in clinical trials of IFDs and for defining study outcomes. Major fungal diseases that are discussed include invasive disease due to Candida species, Aspergillus species and other molds, Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. We also discuss potential pitfalls in assessing outcome, such as conflicting clinical, radiological, and/or mycological data and gaps in knowledge.

Small and long non-coding RNAs in cardiac homeostasis and regeneration

Cardiovascular diseases and in particular heart failure are major causes of morbidity and mortality in the Western world. Recently, the notion of promoting cardiac regeneration as a means to replace lost cardiomyocytes in the damaged heart has engendered considerable research interest. These studies envisage the utilization of both endogenous and exogenous cellular populations, which undergo highly specialized cell fate transitions to promote cardiomyocyte replenishment. Such transitions are under the control of regenerative gene regulatory networks, which are enacted by the integrated execution of specific transcriptional programs. In this context, it is emerging that the non-coding portion of the genome is dynamically transcribed generating thousands of regulatory small and long non-coding RNAs, which are central orchestrators of these networks. In this review, we discuss more particularly the biological roles of two classes of regulatory non-coding RNAs, i.e. microRNAs and long non-coding RNAs, with a particular emphasis on their known and putative roles in cardiac homeostasis and regeneration. Indeed, manipulating non-coding RNA-mediated regulatory networks could provide keys to unlock the dormant potential of the mammalian heart to regenerate. This should ultimately improve the effectiveness of current regenerative strategies and discover new avenues for repair. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction.

Delirium: guidelines for general hospitals.

OBJECTIVE: Delirium is highly prevalent in general hospitals but remains underrecognized and undertreated despite its association with increased morbidity, mortality, and health services utilization. To enhance its management, we developed guidelines covering all aspects, from risk factor identification to preventive, diagnostic, and therapeutic interventions in adult patients. METHODS: Guidelines, systematic reviews, randomized controlled trials (RCT), and cohort studies were systematically searched and evaluated. Based on a synthesis of retrieved high-quality documents, recommendation items were submitted to a multidisciplinary expert panel. Experts scored the appropriateness of recommendation items, using an evidence-based, explicit, multidisciplinary panel approach. Each recommendation was graded according to this process' results. RESULTS: Rated recommendations were mostly supported by a low level of evidence (1.3% RCT and systematic reviews, 14.3% nonrandomized trials vs. 84.4% observational studies or expert opinions). Nevertheless, 71.1% of recommendations were considered appropriate by the experts. Prevention of delirium and its nonpharmacological management should be fostered. Haloperidol remains the first-choice drug, whereas the role of atypical antipsychotics is still uncertain. CONCLUSIONS: While many topics addressed in these guidelines have not yet been adequately studied, an explicit panel and evidence-based approach allowed the proposal of comprehensive recommendations for the prevention and management of delirium in general hospitals.

Epidemiology of pulmonary hypertension: new data from the Swiss registry.

since 1999 data from pulmonary hypertension (PH) patients from all PH centres in Switzerland were prospectively collected. We analyse the epidemiological aspects of these data. PH was defined as a mean pulmonary artery pressure of >25 mm Hg at rest or >30 mm Hg during exercise. Patients with pulmonary arterial hypertension (PAH), PH associated with lung diseases, PH due to chronic thrombotic and/or embolic disease (CTEPH), or PH due to miscellaneous disorders were registered. Data from adult patients included between January 1999 and December 2004 were analysed. 250 patients were registered (age 58 +/- 16 years, 104 (41%) males). 152 patients (61%) had PAH, 73 (29%) had CTEPH and 18 (7%) had PH associated with lung disease. Patients <50 years (32%) were more likely to have PAH than patients >50 years (76% vs. 53%, p <0.005). Twenty-four patients (10%) were lost to followup, 58 patients (26%) died and 150 (66%) survived without transplantation or thrombendarterectomy. Survivors differed from patients who died in the baseline six-minute walking distance (400 m [300-459] vs. 273 m [174-415]), the functional impairment (NYHA class III/IV 86% vs. 98%), mixed venous saturation (63% [57-68] vs. 56% [50-61]) and right atrial pressure (7 mm Hg [4-11] vs. 11 mm Hg [4-18]). PH is a disease affecting adults of all ages. The management of these patients in specialised centres guarantees a high quality of care. Analysis of the registry data could be an instrument for quality control and might help identify weak points in assessment and treatment of these patients.

Immunonutrition in gastrointestinal surgery.

Background: Patients undergoing major gastrointestinal surgery are at increased risk of developing complications. The use of immunonutrition (IN) in such patients is not widespread because the available data are heterogeneous, and some show contradictory results with regard to complications, mortality and length of hospital stay. Methods: Randomized controlled trials (RCTs) published between January 1985 and September 2009 that assessed the clinical impact of perioperative enteral IN in major gastrointestinal elective surgery were included in a meta-analysis. Results: Twenty-one RCTs enrolling a total of 2730 patients were included in the meta-analysis. Twelve were considered as high-quality studies. The included studies showed significant heterogeneity with respect to patients, control groups, timing and duration of IN, which limited group analysis. IN significantly reduced overall complications when used before surgery (odds ratio (OR) 0.48, 95 per cent confidence interval (c.i.) 0.34 to 0.69), both before and after operation (OR 0.39, 0.28 to 0.54) or after surgery (OR 0.46, 0.25 to 0.84). For these three timings of IN administration, ORs of postoperative infection were 0.36 (0.24 to 0.56), 0.41 (0.28 to 0.58) and 0.53 (0.40 to 0.71) respectively. Use of IN led to a shorter hospital stay: mean difference -2.12 (95 per cent c.i. -2.97 to -1.26) days. Beneficial effects of IN were confirmed when low-quality trials were excluded. Perioperative IN had no influence on mortality (OR 0.90, 0.46 to 1.76). Conclusion: Perioperative enteral IN decreases morbidity and hospital stay but not mortality after major gastrointestinal surgery; its routine use can be recommended.

Health correlates of overweight and obesity in adults aged 50 years and over: results from the Survey of Health, Ageing and Retirement in Europe (SHARE)

QUESTIONS UNDER STUDY: To examine the association between overweight/obesity and several self-reported chronic diseases, symptoms and disability measures. METHODS: Data from eleven European countries participating in the Survey of Health, Ageing and Retirement in Europe were used. 18,584 non-institutionalised individuals aged 50 years and over with BMI > or = 18.5 (kg/m2) were included. BMI was categorized into normal weight (BMI 18.5-24.9), overweight (BMI 25.0-29.9) and obesity (BMI > or = 30). Dependent variables were 13 diagnosed chronic conditions, 11 health complaints, subjective health and physical disability measures. For both genders, multiple logistic regressions were performed adjusting for age, socioeconomic status and behaviour risks. RESULTS: The odds ratios for high blood pressure, high cholesterol, diabetes, arthritis, joint pain and swollen legs were significantly increased for overweight and obese adults. Compared to normal-weight individuals, the odds ratio (OR) for reporting > or = 2 chronic diseases was 2.4 (95% CI 1.9-2.9) for obese men and 2.7 (95% CI 2.2-3.1) for obese women. Overweight and obese women were more likely to report health symptoms. Obesity in men (OR 0.5, 95% CI 0.4-0.6), and overweight (OR 0.5, 95% CI 0.4-0.6) and obesity (OR 0.4, 95% CI 0.3-0.5) in women, were associated with poorer subjective health (i.e. a decreased risk of reporting excellent, very good or good subjective health). Disability outcomes were those showing the greatest differences in strength of association across BMI categories, and between genders. For example, the OR for any difficulty in walking 100 metres was non-significant at 0.8 for overweight men, at 1.9 (95% CI 1.3-2.7) for obese men, at 1.4 (95% CI 1.1-1.8) for overweight women, and at 3.5 (95% CI 2.6-4.7) for obese women. CONCLUSIONS: These results highlight the impact of increased BMI on morbidity and disability. Healthcare stakeholders of the participating countries should be aware of the substantial burden that obesity places on the general health and autonomy of adults aged over 50.

Modifiable and nonmodifiable risk factors for postoperative delirium after cardiac surgery with cardiopulmonary bypass.

Postoperative delirium after cardiac surgery is associated with increased morbidity and mortality as well as prolonged stay in both the intensive care unit and the hospital. The authors sought to identify modifiable risk factors associated with the development of postoperative delirium in elderly patients after elective cardiac surgery in order to be able to design follow-up studies aimed at the prevention of delirium by optimizing perioperative management. A post hoc analysis of data from patients enrolled in a randomized controlled trial was performed. A single university hospital. One hundred thirteen patients aged 65 or older undergoing elective cardiac surgery with cardiopulmonary bypass. None. MEASUREMENTS AND MAINS RESULTS: Screening for delirium was performed using the Confusion Assessment Method (CAM) on the first 6 postoperative days. A multivariable logistic regression model was developed to identify significant risk factors and to control for confounders. Delirium developed in 35 of 113 patients (30%). The multivariable model showed the maximum value of C-reactive protein measured postoperatively, the dose of fentanyl per kilogram of body weight administered intraoperatively, and the duration of mechanical ventilation to be independently associated with delirium. In this post hoc analysis, larger doses of fentanyl administered intraoperatively and longer duration of mechanical ventilation were associated with postoperative delirium in the elderly after cardiac surgery. Prospective randomized trials should be performed to test the hypotheses that a reduced dose of fentanyl administered intraoperatively, the use of a different opioid, or weaning protocols aimed at early extubation prevent delirium in these patients.

Alcohol consumption in late adolescence and early adulthood - where is the problem?

Risky single-occasion drinking (RSOD) is more common in late adolescence and early adulthood (approximately between the ages of 16 and 30) than in any other period in life. This is also the age when young people in Switzerland and many other European countries are legally allowed to buy and drink alcohol, but they usually do not yet have adult responsibilities. This paper reviews evidence from the international literature and provides examples of studies conducted in Switzerland demonstrating that (a) RSOD is by far most prevalent on Saturday evenings followed by Friday evenings, usually because young people go out and do not have any work or study responsibilities the next day; (b) RSOD results from drinking in private before going out ("predrinking") and accelerating the pace of drinking (i.e. increasing the number of drinks consumed per hour); (c) RSOD is often not accidental but purposeful,. to seek excitement, to have fun and to feel the effects of alcohol; (d) RSOD occurs predominantly outside the home, mostly in bars, pubs, discos or at special events and festivals; (e) RSOD often results in intended and unintended injuries and other acute consequences, which are leading risk factors for mortality and morbidity in this age group. Effective prevention strategies should include attempts to reduce opportunities to engage in heavy drinking as well as strategies to reduce its harmful consequences.

Toxoplasmosis during pregnancy and infancy. A new approach for Switzerland.

In recent years it has become evident that screening for and treatment of acute toxoplasmosis during pregnancy may have no measurable impact on vertical transmission and neonatal morbidity and mortality. A broad lack of evidence with regard to many aspects of congenital toxoplasmosis has been recognised in a common European initiative (EUROTOXO) which reviewed several thousand published papers on the subject of toxoplasmosis during pregnancy and childhood. It was therefore clear that the strategies currently implemented in our country would, on closer inspection, no longer withstand the claim for evidence-based procedures. The arguments and call for a change of paradigm in Switzerland which follow here are the result of a national consensus-finding process involving experts from various specialities, including gynaecology/obstetrics, paediatrics/neonatology, infectiology, ophthalmology and laboratory medicine, together with representatives of the public health authorities.

The health status of children without resident permit consulting the Children's Hospital of Lausanne.

OBJECTIVE: To assess social, economic and medical data concerning children without a resident permit taken into care by the Children's Hospital of Lausanne (HEL) in order to evaluate their specific needs. METHODS: Prospective exploratory study by a questionnaire including the socio-demographic, medical and education data of 103 children without a resident permit, who consulted the HEL for the first time between August 2003 and March 2006. These children were then recalled for a second check-up one year later in order to allow a regular monitoring. RESULTS: Eighty-seven percent of the children were native of Latin America, 36% being less than two years old. This population of children lived in precarious conditions with a family income lower than the poverty level (89% of the families with less than 3100 CHF/month). Forty-five percent of the children had a health insurance. The main reasons for consultation were infectious diseases, a check-up requested by the school or a check-up concerning newborn children. Most of them were in good health and the others were affected by illnesses similar to those found in other children of the same age. At least 13% of the children were obese and 27% were overweight. All children who were of educational age went to school during the year after the first check-up and 48% were affiliated to a health insurance. CONCLUSIONS: The majority of the children from Latin America lived in very precarious conditions. Their general health status was good and most of them could benefit from regular check-ups. Prevention, focused on a healthier life style, was particularly important among this population characterised by a high incidence of overweight and obesity.

Host genetics of invasive Aspergillus and Candida infections.

Invasive candidiasis and aspergillosis are major complications in surgical and onco-hematological patients, and still associated with an important morbidity and mortality. A large number of studies highlighted the potential role of host genetic polymorphisms that may influence susceptibility to fungal pathogens, but many were limited by insufficient statistical power, problematic design, and/or lack of replication. However, some relevant polymorphisms are now emerging from well-conducted studies whose associations have been replicated and/or are supported by strong biological evidence. Such polymorphisms together with other biomarkers may play a role in the prediction, diagnosis, and management of severe fungal infections in high-risk patients in the coming years.

Genome-wide profiling of blood pressure in adults and children.

Hypertension is an important determinant of cardiovascular morbidity and mortality and has a substantial heritability, which is likely of polygenic origin. The aim of this study was to assess to what extent multiple common genetic variants contribute to blood pressure regulation in both adults and children and to assess overlap in variants between different age groups, using genome-wide profiling. Single nucleotide polymorphism sets were defined based on a meta-analysis of genome-wide association studies on systolic blood pressure and diastolic blood pressure performed by the Cohort for Heart and Aging Research in Genome Epidemiology (n=29 136), using different P value thresholds for selecting single nucleotide polymorphisms. Subsequently, genetic risk scores for systolic blood pressure and diastolic blood pressure were calculated in an independent adult population (n=2072) and a child population (n=1034). The explained variance of the genetic risk scores was evaluated using linear regression models, including sex, age, and body mass index. Genetic risk scores, including also many nongenome-wide significant single nucleotide polymorphisms, explained more of the variance than scores based only on very significant single nucleotide polymorphisms in adults and children. Genetic risk scores significantly explained ≤1.2% (P=9.6*10(-8)) of the variance in adult systolic blood pressure and 0.8% (P=0.004) in children. For diastolic blood pressure, the variance explained was similar in adults and children (1.7% [P=8.9*10(-10)] and 1.4% [P=3.3*10(-5)], respectively). These findings suggest the presence of many genetic loci with small effects on blood pressure regulation both in adults and children, indicating also a (partly) common polygenic regulation of blood pressure throughout different periods of life.

Ebstein's anomaly: one and a half ventricular repair.

Patients with Ebstein's anomaly can present after childhood or adolescence with cyanosis, arrhythmias, severe right ventricular dysfunction and frequently with left ventricular dysfunction secondary to the prolonged cyanosis and to the right ventricular interference. At this point conventional repair is accompanied by elevated mortality and morbidity and poor functional results. We report our experience with three patients (8, 16 and 35 years of age) with Ebstein's anomaly, very dilated right atrium, severe tricuspid valve regurgitation (4/4), bi-directional shunt through an atrial septal defect and reduced left ventricular function (mean ejection fraction = 58%, mean shortening fraction = 25%). All underwent one and a half ventricular repair consisting of closure of the atrial septal defect, tricuspid repair with reduction of the atrialised portion of the right ventricle and end-to-side anastomosis of the superior vena cava to the right pulmonary artery. All patients survived, with a mean follow-up of 33 months. In all there was complete regression of the cyanosis and of the signs of heart failure. Postoperative echocardiography showed reduced degree of tricuspid regurgitation (2/4) and improvement of the left ventricular function (mean ejection fraction = 77%, mean shortening fraction = 40%). In patients with Ebstein's anomaly referred late for surgery with severely compromised right ventricular function or even with reduced biventricular function, the presence of a relatively hypoplastic and/or malfunctioning right ventricular chamber inadequate to sustain the entire systemic venous return but capable of managing part of the systemic venous return, permits a one and a half ventricular repair with good functional results.

Heart transplantation: current practice and outlook to the future.

QUESTIONS UNDER STUDY: The field of heart transplantation has seen substantial progress in the last 40 years. The breakthroughs in long-term survival were followed by a period of stagnation in the last decade. This review summarises current recommendations for the identification of candidates for heart transplantation and their immunological and non-immunological postoperative follow-up. RESULTS: The progress made in the treatment of patients with advanced heart failure has considerably changed the profile of candidates for heart transplantation. Patients are older, and the load of co-morbidities is more important requiring careful evaluation for candidacy. Long-standing research in the field of immunosuppression made available various drugs, which decrease the risk of acute allograft rejection and prolong survival after heart transplantation. Powerful new molecules are entering early phase clinical studies, suggesting further improvement in the near future. As a consequence, treatment of non-immunological co-morbidity after heart transplantation will gain in importance, however, the base of evidence guiding current recommendations is poor. CONCLUSIONS: The substantial progress in heart failure treatment and immunosuppression after heart transplantation has changed the profile of heart transplant recipients. The arrival of new molecules will provide additional alternatives for immunosuppressive treatment while studies have to address non-immunological treatment in order to improve long-term survival after heart transplantation.

Comparing potentially avoidable hospitalization rates related to ambulatory care sensitive conditions in Switzerland: the need to refine the definition of health conditions and to adjust for population health status.

BACKGROUND: Regional rates of hospitalization for ambulatory care sensitive conditions (ACSC) are used to compare the availability and quality of ambulatory care but the risk adjustment for population health status is often minimal. The objectives of the study was to examine the impact of more extensive risk adjustment on regional comparisons and to investigate the relationship between various area-level factors and the properly adjusted rates. METHODS: Our study is an observational study based on routine data of 2 million anonymous insured in 26 Swiss cantons followed over one or two years. A binomial negative regression was modeled with increasingly detailed information on health status (age and gender only, inpatient diagnoses, outpatient conditions inferred from dispensed drugs and frequency of physician visits). Hospitalizations for ACSC were identified from principal diagnoses detecting 19 conditions, with an updated list of ICD-10 diagnostic codes. Co-morbidities and surgical procedures were used as exclusion criteria to improve the specificity of the detection of potentially avoidable hospitalizations. The impact of the adjustment approaches was measured by changes in the standardized ratios calculated with and without other data besides age and gender. RESULTS: 25% of cases identified by inpatient main diagnoses were removed by applying exclusion criteria. Cantonal ACSC hospitalizations rates varied from to 1.4 to 8.9 per 1,000 insured, per year. Morbidity inferred from diagnoses and drugs dramatically increased the predictive performance, the greatest effect found for conditions linked to an ACSC. More visits were associated with fewer PAH although very high users were at greater risk and subjects who had not consulted at negligible risk. By maximizing health status adjustment, two thirds of the cantons changed their adjusted ratio by more than 10 percent. Cantonal variations remained substantial but unexplained by supply or demand. CONCLUSION: Additional adjustment for health status is required when using ACSC to monitor ambulatory care. Drug-inferred morbidities are a promising approach.