Monitoring and risk assessment of hazardous chemicals in toy-slime and putty in the Netherlands.

In 2019, the Dutch Food and Consumer Product Safety Authority performed a market surveillance for toy-slime (23 samples) and putty (16 samples). For 35% of the toy-slimes and 13% of the putties, the migration of boron exceeded the European legal limit of 300 and 1200 mg/kg respectively. In 36% of the toy samples, methylisothiazolinone (MI) and chloromethylisothiazolinone (CMI) were detected in levels up to 25 and 38 mg/kg, respectively, much higher than the European legal limit for aqueous toys intended for children younger than three. 59% of the toys contained other preservatives such as 2-phenoxyethanol, p-hydroxybenzoic acid and parabens. In 2 toy-slimes and 2 putties N-nitrosodiethanolamine (NDELA) was found in amounts up to 2.3 mg/kg. A risk assessment was performed for boron and NDELA. The estimated exposure to boron did not exceed the health based guidance value. The estimated exposure to NDELA from 2 toy-slimes may pose a health risk. For 2 putties the estimated exposure to NDELA was somewhat lower, but health risks could not be excluded. The presence of isothiazolinones may lead to skin sensitisation. It is recommended to extend the legal limit for NDELA, MI and CMI in finger-paint and labelling requirements to other aqueous toys.

The effect of fluid resuscitation on the effective circulating volume in patients undergoing liver surgery: a post-hoc analysis of a randomized controlled trial.

To assess the significance of an analogue of the mean systemic filling pressure (Pmsa) and its derived variables, in providing a physiology based discrimination between responders and non-responders to fluid resuscitation during liver surgery. A post-hoc analysis of data from 30 patients undergoing major hepatic surgery was performed. Patients received 15 ml kg-1 fluid in 30 min. Fluid responsiveness (FR) was defined as an increase of 20% or greater in cardiac index, measured by FloTrac-Vigileo®. Dynamic preload variables (pulse pressure variation and stroke volume variation: PPV, SVV) were recorded additionally. Pvr, the driving pressure for venous return (=Pmsa-central venous pressure) and heart performance (EH; Pvr/Pmsa) were calculated according to standard formula. Pmsa increased following fluid administration in responders (n = 18; from 13 ± 3 to 17 ± 4 mmHg, p < 0.01) and in non-responders (n = 12; from 14 ± 4 to 17 ± 4 mmHg, p < 0.01). Pvr, which was lower in responders before fluid administration (6 ± 1 vs. 7 ± 1 mmHg; p = 0.02), increased after fluid administration only in responders (from 6 ± 1 to 8 ± 1 mmHg; p < 0.01). EH only decreased in non-responders (from 0.56 ± 0.17 to 0.45 ± 0.12; p < 0.05). The area under the receiver operating characteristics curve of Pvr, PPV and SVV for predicting FR was 0.75, 0.73 and 0.72, respectively. Changes in Pmsa, Pvr and EH reflect changes in effective circulating volume and heart performance following fluid resuscitation, providing a physiologic discrimination between responders and non-responders. Also, Pvr predicts FR equivalently compared to PPV and SVV, and might therefore aid in predicting FR in case dynamic preload variables cannot be used.

Small intestinal protein infusion in humans: evidence for a location-specific gradient in intestinal feedback on food intake and GI peptide release.

BACKGROUND: Protein infusion in the small intestine results in intestinal brake activation: a negative feedback mechanism that may be mediated by the release of gastrointestinal peptides resulting in a reduction in food intake. It has been proposed that duodenum, jejunum and ileum may respond differently to infused proteins. OBJECTIVE: To investigate differences in ad libitum food intake, feelings of hunger and satiety and the systemic levels of cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), peptide YY (PYY), glucose and insulin after intraduodenal, intrajejunal and intraileal protein infusion. METHODS: Fourteen subjects (four male, mean age: 23±2.1 years, mean body mass index: 21.6±1.8 kg m-2) were intubated with a naso-ileal catheter in this double-blind, randomized, placebo-controlled crossover study. Test days (four in total, executed on consecutive days) started with the ingestion of a standardized breakfast, followed by the infusion of 15 g of protein in the duodenum, jejunum or ileum over a period of 60 min. Food intake was measured by offering an ad libitum meal and Visual Analogue Scale (VAS) scores were used to assess feelings of hunger and satiety. Blood samples were drawn at regular intervals for CCK, GLP-1, PYY, glucose and insulin analyses. RESULTS: Intraileal protein infusion decreased ad libitum food intake compared with both intraduodenal and placebo infusion (ileum: 628.5±63 kcal vs duodenum: 733.6±50 kcal, P<0.01 and placebo: 712.2±53 kcal, P<0.05). GLP-1 concentrations were increased after ileal infusion compared with jejunal and placebo infusion, whereas CCK concentrations were only increased after intraileal protein infusion compared with placebo. None of the treatments affected VAS scores for hunger and satiety nor plasma concentrations of PYY and glucose. CONCLUSIONS: Protein infusion into the ileum decreases food intake during the next meal compared with intraduodenal infusion, whereas it increases systemic levels of GLP-1 compared with protein infusion into the jejunum and placebo respectively.

Introduction of a new paediatric asthma guideline: Effects on asthma control levels.

BACKGROUND: In 2008, a new national paediatric asthma management guideline based on the international Global Initiative for Asthma (GINA) guideline was launched in the Netherlands. We studied whether asthma control and treatment regimens improved after introduction of the guideline by comparing survey data before and after the guideline introduction. METHODS: Two comparable groups of children (6-16 years) with asthma were included before (2004) and after (2013) the introduction of the guideline. Children, parents and paediatricians completed questionnaires about asthma symptoms, medication and healthcare use. Spirometry was performed. RESULTS: Data of 209 patients were analysed. Level of asthma control did not improve between 2004 and 2013 with a proportion of (partly) controlled asthmatics of 51% in 2004 and 59% in 2013 (p = 0.28). In 2013, paediatricians characterized 76% of children as (partly) controlled, while 59% of children was (partly) controlled according to GINA criteria (p < 0.05). Step-down treatment in controlled patients was more applied by paediatricians in 2013 compared to 2004 (from 8 to 40%, p < 0.05). Step-up treatment in uncontrolled patients did not improve. CONCLUSIONS: Asthma control did not improve after the introduction of the new guideline. Compared to 2004, an improvement was observed in step-down treatment in patients with controlled disease.

Bidirectional associations between alcohol consumption and health-related quality of life amongst young and middle-aged women.

BACKGROUND: Evidence from cross-sectional studies has suggested a positive association between moderate alcohol consumption and health-related quality of life but prospective data remain scarce. OBJECTIVES: To examine the bidirectional relationships between alcohol consumption and health-related quality of life using a longitudinal study design. METHODS: A total of 92 448 participants of the Nurses' Health Study II reported their alcohol consumption (in 1991, 1995, 1999 and 2003) and health-related quality of life (in 1993, 1997 and 2001). Using generalized estimating equations, we modelled the physical and mental component summary (PCS and MCS) scores as a function of alcohol consumption 2 years earlier (n = 88 363) and vice versa (n = 84 621). RESULTS: Greater alcohol consumption was associated with better PCS scores 2 years later in a dose-response manner up to ~1 serving daily [mean difference (ß) = 0.67 ± 0.06 PCS units, for moderate versus infrequent drinkers]. After adjustment for previous PCS, a similar but attenuated pattern was observed (ß = 0.33 ± 0.07). Moderate alcohol consumption was not related to MCS, whereas moderate-to-heavy alcohol consumption was associated with lower MCS scores (ß = -0.34 ± 0.15). Higher PCS scores were associated with greater alcohol consumption 2 years later, also after adjustment for previous alcohol consumption (ß = 0.53 ± 0.05 g day(-1) ). MCS was not associated with alcohol consumption 2 years later. CONCLUSION: Amongst young and middle-aged women, moderate alcohol intake was associated with a small improvement in physical health-related quality of life 2 years later and vice versa. Moderate alcohol consumption was not associated with mental health-related quality of life in either direction.

Ileal brake activation: macronutrient-specific effects on eating behavior?

BACKGROUND: Activation of the ileal brake, by infusing lipid directly into the distal part of the small intestine, alters gastrointestinal (GI) motility and inhibits food intake. The ileal brake effect on eating behavior of the other macronutrients is currently unknown. OBJECTIVE: The objective of this study was to investigate the effects of ileal infusion of sucrose and casein on food intake, release of GI peptides, gastric emptying rate and small-bowel transit time with safflower oil as positive control. DESIGN: This randomized, single-blind, crossover study was performed in 13 healthy subjects (6 male; mean age 26.4±2.9 years; mean body mass index 22.8±0.4 kg m(-2)) who were intubated with a naso-ileal catheter. Thirty minutes after the intake of a standardized breakfast, participants received an ileal infusion, containing control ((C) saline), safflower oil ((HL) 51.7 kcal), low-dose casein ((LP) 17.2 kcal) or high-dose casein ((HP) 51.7 kcal), low-dose sucrose ((LC) 17.2 kcal) and high-dose sucrose ((HC) 51.7 kcal), over a period of 90 min. Food intake was determined during an ad libitum meal. Visual analogue score questionnaires for hunger and satiety and blood samples were collected at regular intervals. RESULTS: Ileal infusion of lipid, protein and carbohydrate resulted in a significant reduction in food intake compared with control (HL: 464.3±90.7 kcal, P<0.001; HP: 458.0±78.6 kcal, P<0.005; HC: 399.0±57.0 kcal, P<0.0001 vs control: 586.7±70.2 kcal, P<0.001, respectively). A reduction in energy intake was still apparent when the caloric amount of infused nutrients was added to the amount eaten during the ad libitum meal.Secretion of cholecystokinin and peptide YY but not of glucagon-like peptide-1 (7-36) was increased during ileal perfusion of fat, carbohydrates and protein. During ileal perfusion of all macronutrients, a delay in gastric emptying and intestinal transit was observed, but differences were not significant compared with control. CONCLUSION: Apart from lipids, also sucrose and casein reduce food intake on ileal infusion, thereby activating the ileal brake. In addition to food intake, also satiety and GI peptide secretion were affected.

Present and future breast cancer management--bench to bedside and back: a positioning paper of academia, regulatory authorities and pharmaceutical industry.

Insights into tumour biology of breast cancer have led the path towards the introduction of targeted treatment approaches; still, breast cancer-related mortality remains relatively high. Efforts in the field of basic research revealed new druggable targets which now await validation within the context of clinical trials. Therefore, questions concerning the optimal design of future studies are becoming even more pertinent. Aspects such as the ideal end point, availability of predictive markers to identify the optimal cohort for drug testing, or potential mechanisms of resistance need to be resolved. An expert panel representing the academic community, the pharmaceutical industry, as well as European Regulatory Authorities met in Vienna, Austria, in November 2012, in order to discuss breast cancer biology, identification of novel biological targets and optimal drug development with the aim of treatment individualization. This article summarizes statements and perspectives provided by the meeting participants.

Green light for liver function monitoring using indocyanine green? An overview of current clinical applications.

The dye indocyanine green is familiar to anaesthetists, and has been studied for more than half a century for cardiovascular and hepatic function monitoring. It is still, however, not yet in routine clinical use in anaesthesia and critical care, at least in Europe. This review is intended to provide a critical analysis of the available evidence concerning the indications for clinical measurement of indocyanine green elimination as a diagnostic and prognostic tool in two areas: its role in peri-operative liver function monitoring during major hepatic resection and liver transplantation; and its role in critically ill patients on the intensive care unit, where it is used for prediction of mortality, and for assessment of the severity of acute liver failure or that of intra-abdominal hypertension. Although numerous studies have demonstrated that indocyanine green elimination measurements in these patient populations can provide diagnostic or prognostic information to the clinician, 'hard' evidence - i.e. high-quality prospective randomised controlled trials - is lacking, and therefore it is not yet time to give a green light for use of indocyanine green in routine clinical practice.

Comparison of arterial pressure and plethysmographic waveform-based dynamic preload variables in assessing fluid responsiveness and dynamic arterial tone in patients undergoing major hepatic resection.

BACKGROUND: Dynamic preload variables to predict fluid responsiveness are based either on the arterial pressure waveform (APW) or on the plethysmographic waveform (PW). We compared the ability of APW-based variations in stroke volume (SVV) and pulse pressure (PPV) and of PW-based plethysmographic variability index (PVI) to predict fluid responsiveness and to track fluid changes in patients undergoing major hepatic resection. Furthermore, we assessed whether the PPV/SVV ratio, as a measure of dynamic arterial elastance (Eadyn), could predict a reduction in norepinephrine requirement after fluid administration. METHODS: Thirty patients received i.v. fluid (15 ml kg(-1) in 30 min) after hepatic resection and were considered responders when stroke volume index (SVI) increased ≥20% after fluid administration. SVV and SVI were measured by the FloTrac-Vigileo(®) device, and PVI was measured by the Masimo Radical 7 pulse co-oximeter(®). RESULTS: The areas under a receiver operating characteristic curve for SVV, PPV, and PVI were 0.81, 0.77, and 0.78, respectively. In responders, all dynamic variables, except PVI, decreased after fluid administration. Eadyn predicted a reduced norepinephrine requirement (AUC = 0.81). CONCLUSIONS: In patients undergoing major hepatic resection, both APW- and PW-based dynamic preload variables predict fluid responsiveness (preload) to a similar extent. Most variables (except PVI) also tracked fluid changes. Eadyn, as a measure of arterial elastance (afterload), might be helpful to distinguish the origin of hypotension. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01060683.

Responsiveness and interpretability of incontinence severity scores and FIQL in patients with fecal incontinence: a secondary analysis from a randomized controlled trial.

INTRODUCTION AND HYPOTHESIS: This study aims to assess the responsiveness and interpretability of the Vaizey score, Wexner score, and the Fecal Incontinence Quality of Life Scale (FIQL) for use in the evaluation of patients with fecal incontinence (FI). METHODS: Eighty patients with FI with a mean age of 59.3 (SD ± 11.9) were enrolled in a randomized controlled trial. The patient-reported outcomes were tested for internal and external responsiveness, longitudinal construct validity, and interpretability. RESULTS: All total scores proved to have both adequate to excellent responsiveness and longitudinal construct validity, and changes were in agreement with subjective improvement. Due to variability in minimally important change estimates (Vaizey score -5 to -3, Wexner score -3 to -2, FIQL 1.1 to 1.2), they should be used as indicators. All patient-reported outcomes showed psychometric or practical limitations. CONCLUSIONS: The instruments available to date to evaluate severity and quality of life in FI do not yet attain the highest levels of psychometric soundness. As the focus of patients may differ from that of physicians, it is recommended that several measures should be included for evaluation. So far, there are suggestions that the Wexner score is most suitable for severity assessment and the FIQL for evaluating quality of life.

Intraoperative ICG plasma disappearance rate helps to predict absence of early postoperative complications after orthotopic liver transplantation.

Early postoperative complications after orthotopic liver transplantation (OLT) are a common problem in intensive care medicine. Adequate assessment of initial graft function remains difficult, however, plasma disaperance rate of indocyanine green (PDRICG) may have an additional diagnostic and prognostic value in this setting. We retrospectively evaluated the ability of intraoperative PDRICG values to predict absence of early postoperative complications in 62 subjects. PDRICG was measured non-invasively by pulse dye densitometry during surgery and was correlated with initial graft function. At the end of surgery, PDRICG was higher in patients without complications: 24.9 % min(-1) (n = 40) versus 21.0 % min(-1), (n = 22; p = 0.034). An area under the ROC curve (AUROC) for PDRICG was 0.70, while the AUROC for pH, lactate and PT at ICU admission were 0.53, 0.50 and 0.46, respectively. The AUROC of serum bilirubin and PT at postoperative day 5 were 0.68 and 0.49, respectively. The optimal cut-off PDRICG value for predicting absence of development early postoperative complications was determined to be 23.5 % min(-1) with 72.4 % sensitivity and 71.0 % specificity. Intraoperative point-of-care PDRICG measurement during OLT already predicts absence of early postoperative complications, better and earlier than clinically used laboratory parameters.

When is supervised exercise therapy considered useful in peripheral arterial occlusive disease? A nationwide survey among vascular surgeons.

OBJECTIVES: Although international guidelines state that supervised exercise therapy (SET) should be offered to all patients with intermittent claudication (IC), SET appears to be underutilised in clinical practice. The aim of this study was to document current opinions of Dutch vascular surgeons on SET as treatment option for peripheral arterial occlusive disease (PAOD). MATERIALS AND METHODS: Vascular surgeons and fellows in vascular surgery were asked to complete a 24-question survey either at the 2011 Annual Meeting of the Dutch Society for Vascular Surgery or online. RESULTS: Ninety-one participants, including 83 vascular surgeons (51% of all Dutch vascular surgeons), completed the survey. The respondents would refer 75.4% of newly diagnosed patients with IC for SET. SET was considered less useful in patients with IC and major (cardiopulmonary) co-morbidity or a significant iliac artery stenosis. In critical limb ischaemia, the combination of SET and angioplasty was considered useful in 71.9%. Respondents regarded patient satisfaction (63.3%) and improvement in pain-free or maximal walking ability (26.6%) as clinically most relevant goals of SET. Most (84.4%) agreed that SET should also include lifestyle management. CONCLUSION: Although the vast majority of Dutch vascular surgeons consider SET as an important treatment option for PAOD, SET should receive more emphasis in clinical practice since arguments not to refer for SET are outdated. Furthermore, vascular surgeons agree that lifestyle management should be integrated in SET.

Accuracy of non-invasive measurement of haemoglobin concentration by pulse co-oximetry during steady-state and dynamic conditions in liver surgery.

BACKGROUND: The Masimo Radical 7 (Masimo Corp., Irvine, CA, USA) pulse co-oximeter(®) calculates haemoglobin concentration (SpHb) non-invasively using transcutaneous spectrophotometry. We compared SpHb with invasive satellite-lab haemoglobin monitoring (Hb(satlab)) during major hepatic resections both under steady-state conditions and in a dynamic phase with fluid administration of crystalloid and colloid solutions. METHODS: Thirty patients undergoing major hepatic resection were included and randomized to receive a fluid bolus of 15 ml kg(-1) colloid (n=15) or crystalloid (n=15) solution over 30 min. SpHb was continuously measured on the index finger, and venous blood samples were analysed in both the steady-state phase (from induction until completion of parenchymal transection) and the dynamic phase (during fluid bolus). RESULTS: Correlation was significant between SpHb and Hb(satlab) (R(2)=0.50, n=543). The modified Bland-Altman analysis for repeated measurements showed a bias (precision) of -0.27 (1.06) and -0.02 (1.07) g dl(-1) for the steady-state and dynamic phases, respectively. SpHb accuracy increased when Hb(satlab) was <10 g dl(-1), with a bias (precision) of 0.41 (0.47) vs -0.26 (1.12) g dl(-1) for values >10 g dl(-1), but accuracy decreased after colloid administration (R(2)=0.25). CONCLUSIONS: SpHb correlated moderately with Hb(satlab) with a slight underestimation in both phases in patients undergoing major hepatic resection. Accuracy increased for lower Hb(satlab) values but decreased in the presence of colloid solution. Further improvements are necessary to improve device accuracy under these conditions, so that SpHb might become a sensitive screening device for clinically significant anaemia.

Increased cytokines, chemokines and soluble adhesion molecules in exhaled breath condensate of asthmatic children.

BACKGROUND: Airway inflammation in asthma is characterized by the production of cytokines, chemokines and soluble adhesion molecules. The assessment of these inflammatory biomarkers in exhaled breath condensate (EBC) is hampered by low detection rates. However, the use of a glass condenser system combined with a sensitive analytical technique may increase the possibility to assess these biomarkers in EBC in a reliable way. OBJECTIVE: (1) To assess the detection rates of cytokines (IL-1alpha, -1beta, -2, -4, -5, -6, -10, -12p70, -13, -18, IFN-gamma, TNF-alpha), chemokines [MIP1alpha (CCL3), MIF, eotaxin (CCL11), RANTES (CCL5), IP10 (CXCL10), IL8 (CXCL8), MCP1] and soluble adhesion molecules [soluble intercellular adhesion molecule (sICAM), soluble vascular adhesion molecule (sVCAM)] in EBC of children with asthma and healthy control children; (2) To study the differences in the biomarker concentration between children with asthma and controls. METHODS: Sixty children were included: 31 asthmatics (71% atopic) and 29 controls. Exhaled breath condensate was collected using a glass condenser system. The inflammatory markers (IM) were analysed using multiplex immunoassay technology. RESULTS: Detection percentages of cytokines, chemokines and adhesion molecules ranged from 94% to 100%, except for eotaxin (CCL11) and RANTES (CCL5) (detection rates of 10% and 45% in healthy controls, respectively). The intra-subject variability of biomarkers in EBC in the group as a whole ranged from 5.2% to 35.0%. In asthmatics, the levels of cytokines (IL-2, -4, -5, -6, -13, IFN-gamma), chemokines (MIP1alpha [CCL3], MIF, RANTES [CCL5], IP10 [CXCL10], IL8 [CXCL8], MCP1) and adhesion molecules (sICAM, sVCAM) were significantly increased in comparison with controls (P<0.05). CONCLUSION: If collected with a glass condenser and analysed by multiplex immunoassay technology, cytokines, chemokines and soluble adhesion molecules can be reliably demonstrated in EBC of children. Most of these IM were elevated in EBC of asthmatics compared with controls.

Surveillance-embedded genomic outbreak resolution of methicillin-susceptible Staphylococcus aureus in a neonatal intensive care unit.

We observed an increase in methicillin-susceptible Staphylococcus aureus (MSSA) infections at a Dutch neonatal intensive care unit. Weekly neonatal MSSA carriage surveillance and cross-sectional screenings of health care workers (HCWs) were available for outbreak tracing. Traditional clustering of MSSA isolates by spa typing and Multiple-Locus Variable number tandem repeat Analysis (MLVA) suggested that nosocomial transmission had contributed to the infections. We investigated whether whole-genome sequencing (WGS) of MSSA surveillance would provide additional evidence for transmission. MSSA isolates from neonatal infections, carriage surveillance, and HCWs were subjected to WGS and bioinformatic analysis for identification and localization of high-quality single nucleotide polymorphisms, and in-depth analysis of subsets of isolates. By measuring the genetic diversity in background surveillance, we defined transmission-level relatedness and identified isolates that had been unjustly assigned to clusters based on MLVA, while spa typing was concordant but of insufficient resolution. Detailing particular subsets of isolates provided evidence that HCWs were involved in multiple outbreaks, yet it alleviated concerns about one particular HCW. The improved resolution and accuracy of genomic outbreak analyses substantially altered the view on outbreaks, along with apposite measures. Therefore, inclusion of the circulating background population has the potential to overcome current issues in genomic outbreak inference.

Development of a severe von Willebrand factor/ADAMTS13 dysbalance during orthotopic liver transplantation.

Patients with liver disease show profound changes in their hemostatic system, which may further change during liver transplantation. We previously demonstrated that highly elevated levels of the platelet adhesive protein von Willebrand factor (VWF) in patients with cirrhosis lead to an increased VWF-dependent platelet deposition under flow as compared to healthy controls. In this study we examined VWF parameters during the course of liver transplantation. We collected serial plasma samples from 20 patients undergoing liver transplantation in which we determined plasma levels of VWF and the VWF-cleaving protease ADAMTS13. Furthermore, we performed functional tests of VWF-dependent platelet adhesion. We found persistently elevated levels of VWF during and after liver transplantation. The capacity of VWF to interact with platelets normalized during the course of transplantation, and flow-mediated VWF-dependent platelet adhesion remained at levels far exceeding those observed in healthy individuals during and after transplantation. Plasma levels of ADAMTS13 dropped during transplantation, and in four patients levels below 10% of normal were observed after reperfusion. We observed the development of a hyperreactive primary hemostatic system, as evidenced by high levels of fully functional VWF and a temporary ADAMTS13 deficiency, during liver transplantation, and speculate that these changes contribute to postoperative thrombotic complications.

Innovation in oncology clinical trial design.

Progress in and better understanding of cancer biology causes a shift in cancer drug development: away from the evaluation of drugs in large tumour histology defined patient populations towards targeted agents in increasingly heterogeneous molecularly defined subpopulations. This requires novel approaches in clinical trial design by academia and industry, and development of new assessment tools by regulatory authorities. Pharmaceutical industry is developing new targeted agents generating many clinical studies, including target combinations. This requires improved operational efficiency by development of innovative trial designs, strategies for early-stage decision making and early selection of candidate drugs with a high likelihood of success. In addition, patient awareness and ethical considerations necessitate that agents will be rapidly available to patients. Regulatory Authorities such as the European Medicine Agency and national agencies recognise that these changes require a different attitude towards benefit-risk analysis for drug approval. The gold standard of randomised confirmatory Phase III trials is not always ethical or feasible when developing drugs for treatment of small cancer populations. Alternative strategies comprise accelerated approval via conditional marketing approval, which can be granted in the EU based on small non-randomised Phase II trials. The paper describes innovative trial designs with their pros and cons and efforts of pharmaceutical industry and regulatory authorities to deal with the paradigm shift. Furthermore, all stakeholders should continue to share their experiences and discuss problems in order to understand the position and concerns of the other stakeholders to learn from each other and to progress the field of novel oncology clinical trial design.

Effect of moderate alcohol consumption on adipokines and insulin sensitivity in lean and overweight men: a diet intervention study.

OBJECTIVE: Moderate alcohol consumption is associated with a decreased risk of type II diabetes. This study investigates the effect of moderate alcohol consumption on adipokines and insulin sensitivity. SUBJECTS: Twenty healthy, lean (body mass index (BMI) 18.5-25 kg/m(2); n=11) or overweight (BMI>27 kg/m(2); n=9) men (18-25 years). METHODS: Three cans of beer (40 g alcohol) or alcohol-free beer daily during 3 weeks. RESULTS: Adiponectin and ghrelin concentrations increased (P<0.01) by 11 and 8%, while acylation-stimulating protein (ASP) concentrations decreased by 12% (P=0.04) after moderate alcohol consumption. Concentrations of leptin and resistin remained unchanged. Insulin sensitivity by an oral glucose tolerance test (OGTT) was not affected by moderate alcohol consumption, but 2 h glucose concentrations were lower (P=0.01) after beer (4.5+/-0.1 mmol/l) than alcohol-free beer (4.9+/-0.1 mmol/l). Both free fatty acids and glucagon concentrations showed a stronger increase (P<0.01) after 90 min during OGTT after beer than alcohol-free beer. Changes of adiponectin were positively correlated (r=0.69, P<0.001), and changes of leptin (r=-0.53, P=0.016) and ASP (r=-0.43, P=0.067) were negatively correlated with changes of insulin sensitivity index. All these results did not differ between lean and overweight men. CONCLUSIONS: Moderate alcohol consumption increased adiponectin and ghrelin, while it decreased ASP concentrations both in lean and overweight men. These changes are in line with the hypothesized improvement of insulin sensitivity, but did not affect insulin sensitivity within 3 weeks of moderate alcohol consumption.

WITHDRAWN: Pelvic floor muscle training for urinary incontinence in women.

BACKGROUND: Pelvic floor muscle training is the most commonly recommended physical therapy treatment for women with stress leakage of urine. It is also used in the treatment of women with mixed incontinence, and less commonly for urge incontinence. Adjuncts, such as biofeedback or electrical stimulation, are also commonly used with pelvic floor muscle training. The content of pelvic floor muscle training programmes is highly variable. OBJECTIVES: To determine the effects of pelvic floor muscle training for women with symptoms or urodynamic diagnoses of stress, urge and mixed incontinence, in comparison to no treatment or other treatment options. SEARCH STRATEGY: Search strategy: We searched the Cochrane Incontinence Group trials register (May 2000), Medline (1980 to 1998), Embase (1980 to 1998), the database of the Dutch National Institute of Allied Health Professions (to 1998), the database of the Cochrane Rehabilitation and Related Therapies Field (to 1998), Physiotherapy Index (to 1998) and the reference lists of relevant articles. We handsearched the proceedings of the International Continence Society (1980 to 2000). We contacted investigators in the field to locate studies. Date of the most recent searches: May 2000. SELECTION CRITERIA: Randomised trials in women with symptoms or urodynamic diagnoses of stress, urge or mixed incontinence that included pelvic floor muscle training in at least one arm of the trial. DATA COLLECTION AND ANALYSIS: Two reviewers assessed all trials for inclusion/exclusion and methodological quality. Data were extracted by the lead reviewer onto a standard form and cross checked by another. Disagreements were resolved by discussion. Data were processed as described in the Cochrane Handbook. Sensitivity analysis on the basis of diagnosis was planned and undertaken where appropriate. MAIN RESULTS: Forty-three trials met the inclusion criteria. The primary or only reference for 15 of these was a conference abstract. The pelvic floor muscle training programs, and comparison interventions, varied markedly. Outcome measures differed between trials, and methods of data reporting varied, making the data difficult to combine. Many of the trials were small. Allocation concealment was adequate in five trials, and nine trials used assessors masked to group allocation. Thirteen trials reported that there were no losses to follow up, seven trials had dropout rates of less than 10%, but in the remaining trials the proportion of dropouts ranged from 12% to 41%. Pelvic floor muscle training was better than no treatment or placebo treatments for women with stress or mixed incontinence. 'Intensive' appeared to be better than 'standard' pelvic floor muscle training. PFMT may be more effective than some types of electrical stimulation but there were problems in combining the data from these trials. There is insufficient evidence to determine if pelvic floor muscle training is better or worse than other treatments. The effect of adding pelvic floor muscle training to other treatments (e.g. electrical stimulation, behavioural training) is not clear due to the limited amount of evidence available. Evidence of the effect of adding other adjunctive treatments to PFMT (e.g. vaginal cones, intravaginal resistance) is equally limited. The effectiveness of biofeedback assisted PFMT is not clear, but on the basis of the evidence available there did not appear to be any benefit over PFMT alone at post treatment assessment.Long-term outcomes of pelvic floor muscle training are unclear. Side effects of pelvic floor muscle training were uncommon and reversible. A number of the formal comparisons should be viewed with caution due to statistical heterogeneity, lack of statistical independence, and the possibility of spurious confidence intervals in some instances. AUTHORS' CONCLUSIONS: Pelvic floor muscle training appeared to be an effective treatment for adult women with stress or mixed incontinence. Pelvic floor muscle training was better than no treatment or placebo treatments. The limitations of the evidence available mean that is difficult to judge if pelvic floor muscle training was better or worse than other treatments. Most trials to date have studied the effect of treatment in younger, premenopausal women. The role of pelvic floor muscle training for women with urge incontinence alone remains unclear. Many of the trials were small with poor reporting of allocation concealment and masking of outcome assessors. In addition there was a lack of consistency in the choice and reporting of outcome measures that made data difficult to combine. Methodological problems limit the confidence that can be placed in the findings of the review. Further, large, high quality trials are necessary.

The development of a clinical practice stroke guideline for physiotherapists in The Netherlands: a systematic review of available evidence.

PURPOSE: To develop a clinical practice guideline for the physiotherapy management of patients with stroke as support for the clinical decision-making process, especially with respect to the selection of appropriate interventions, prognostic factors and outcome measures. INTRODUCTION: Physiotherapists have a high caseload of patients with stroke, so there is a need to identify effective evidence-based physiotherapy procedures. The availability of a guideline that includes information about prognostic factors, interventions, and outcome measures would facilitate clinical decision-making. METHOD: A systematic computerized literature search was performed to identify evidence concerning the use of: (i) prognostic factors related to functional recovery; (ii) physiotherapy interventions in patients with stroke; and (iii) outcome measures to assess patients' progress in functional health. Experts, physiotherapists working in the field of stroke rehabilitation, and a multidisciplinary group of health professionals reviewed the clinical applicability and feasibility of the recommendations for clinical practice and their comments were used to compose the definitive guideline. RESULTS: Of 9482 relevant articles, 322 were selected. These were screened for methodological quality. Seventy-two recommendations for clinical practice were retrieved from these articles and included in the guideline: Six recommendations concerned the prediction of functional recovery of activities of daily living (ADL), including walking ability and hand/arm use; 65 recommendations concerned the choice of physiotherapy interventions; and 1 recommendation concerned the choice of outcome instrument to use. A core set of seven reliable, responsive, and valid outcome measures was established, to determine impairments and activity limitations in patients with stroke. CONCLUSIONS: The guideline provides physiotherapists with an evidence-based instrument to assist them in their clinical decision making regarding patients with stroke. As most of the recommendations included in the guideline came from studies of patients in the post acute and chronic phase of stroke, and in general involved patients with less severe and uncomplicated stroke, more needs to be learned about the more complex cases.