Harry Pf Peters
email: harry.peters@unilever.com

PhD Peter Ravestein

MSc Harry Twm Van-Der-Hijden

PhD Hanny M Boers

MSc David J Mela

The effect of carbohydrate digestibility on appetite and its relationship to postprandial blood glucose and insulin levels

Keywords: appetite, glycemic index, "slow carbs", fibre, plasma glucose, blood insulin, carbohydrate digestibility

Background: 'Slowly digestible' carbohydrates have been claimed to reduce appetite via effects on postprandial glucose and insulin levels, but literature is inconsistent. The inconsistencies between studies might be explained by factors other than glycemic effects per se, e.g., nutritional or physical properties. We tested this possibility by examining postprandial glucose, insulin and appetite responses to drinks differing only in rate and extent of digestibility of carbohydrates. This was accomplished by comparing different glucose polymers: maltodextrin (rapidly digestible) versus medium-chain pullulan (slowly but completely digestible) versus long-chain pullulan (indigestible).

Subjects and Methods:

In a randomized double-blind balanced crossover design, 35 subjects received drinks with 15g test carbohydrate polymers. Key outcome measures were appetite scores, digestibility (in vitro test and breath hydrogen), and (in a subset) glucose and insulin levels.

Results: Digestibility, glucose and insulin data confirmed the rapid, slow, and non-digestible nature of the test carbohydrates. Despite its low digestibility, only long-chain pullulan reduced appetite versus the maltodextrin control, while the medium-chain pullulan did not.

Conclusions:

We conclude that glycemic responses per se have minimal effects on appetite, when tested in products only differing in carbohydrate digestibility rate and extent.

Introduction

Slowly digestible carbohydrates (or "slow carbs") are defined as 'carbohydrates that are likely to be completely digested in the small intestine but at a slower rate' [START_REF] Englyst | Classification and measurement of nutritionally important starch fractions[END_REF]. The use of slowly digestible carbohydrates, resulting in a lower or sustained postprandial glycemia, has been claimed to reduce appetite [START_REF] Bornet | Glycaemic response to foods: Impact on satiety and long-term weight regulation[END_REF][START_REF] Thomas | Low glycaemic index or low glycaemic load diets for overweight and obesity. Cochrane Database of Systematic Reviews CD005105[END_REF]. However, others find that the evidence that lowering of postprandial glycemia reduces appetite is inconclusive [START_REF] Pi-Sunyer | Glycemic index and disease[END_REF][START_REF] Van Dam | Carbohydrate intake and obesity[END_REF], that postprandial glycemia and appetite are not related [START_REF] Niwano | Is Glycemic Index of Food a Feasible Predictor of Appetite, Hunger, and Satiety?[END_REF][START_REF] Raben | Should obese patients be counselled to follow a low-glycaemic index diet? No[END_REF], or that blood insulin, but not glucose, is associated with increased short-term appetite reduction [START_REF] Flint | Associations between postprandial insulin and blood glucose responses, appetite sensations and energy intake in normal weight and overweight individuals: a meta-analysis of test meal studies[END_REF].

The inconsistencies between studies might be explained by a lower than expected energy availability of the carbohydrates tested or by other properties (nutritional, physical) differing amongst test products [START_REF] Alfenas | Influence glycemic index/load on glycemic response, appetite, and food intake in healthy humans[END_REF].

For example, many of these studies have used different dietary fibres, but it is generally not possible to distinguish effects of lowering postprandial glycaemia per se from other known effects of the fibres [START_REF] Bornet | Glycaemic response to foods: Impact on satiety and long-term weight regulation[END_REF][START_REF] Hlebowicz | Postprandial blood glucose response in relation to gastric emptying and satiety in healthy subjects[END_REF][START_REF] Van Dam | Carbohydrate intake and obesity[END_REF]. Indeed, recently it was concluded that the difference in appetite sometimes seen after low-glycemic foods is due to factors other than the difference in blood glucose [START_REF] Wolever | Day-to-day variation in glycemic response elicited by white bread is not related to variation in satiety in humans[END_REF].

One way to test this is to compare test foods differing only in the digestibility of carbohydrates, but with identical chemical makeup and physical properties, and evaluate effects on the postprandial glucose, insulin and appetite responses.

The comparison of maltodextrin to differing chain lengths of the glucose-polymer pullulan potentially provides a test of rapidly-to slowly-to non-digestible carbohydrate materials, differing only in digestibility. Pullulan is indigestible in its native (long-chain) state. We hypothesized that the use of smaller (thus slowly but fully digestible) pullulan fragments would result in a more sustained postprandial blood glucose and plasma insulin response, leading to a reduction in appetite as compared to the rapidly digestible control.

Subjects and Methods

Subjects

Subjects were recruited from local area of the research centre (Vlaardingen, Netherlands). Selection criteria were: age 18-60 years, Body Mass Index (BMI, kg/m 2 ) ≥21 and ≤32.0, apparently healthy, and not using medicines judged likely to influence the study results. Subjects with high dietary restraint scores [START_REF] Van Strien | The Dutch Eating Behavior Questionnaire (Debq) for Assessment of Restrained, Emotional, and External Eating Behavior[END_REF] and with tendencies toward diagnosable eating disorders [START_REF] Morgan | The SCOFF questionnaire: assessment of a new screening tool for eating disorders[END_REF] were excluded.

Thirty-five subjects (27 women) completed the study (there was one drop-out), with a mean age 47.5 (range 20-59) years and mean BMI 22.9 (range 20.0-25.3) kg/m 2 .

Study design

In order to test carbohydrates that differed only in digestibility we used sources of the glucose-polymer pullulan differing in chain length only (see below), based on the recognition that the rate and extent of carbohydrate hydrolysis could be controlled by varying these chain lengths. In this case, the long-chain would be largely indigestible; the medium-chain would be almost completely digestible, but at a slower rate (e.g., the "slow-carb"); and the maltodextrin glucose-polymer would be quickly and completely digestible. The use of maltodextrin as control versus pullulan or pullulan fragments ensured that all carbohydrates tested were solely based on glucose and only digestibility differed.

The study protocol was approved by the Wageningen Ethical Committee, The Netherlands. The study was designed according to a balanced cross-over design.

Over three weeks each subject visited the test facility 1 day per week, on the same weekday. During these test days subjects consumed a meal replacement drink (either control or one of the alternatives, see below) at 08.00 hours. Appetite scores (6 line scales), digestibility (breath hydrogen), gastro-intestinal (GI) symptoms and (in an n=12 subset) blood glucose and plasma insulin levels were measured for the subsequent 5 hours.

Test foods

Three products (all 325 ml) were evaluated (see Table 1): regular meal replacement drink (Slim•Fast Optima Chocolate ready-to-drink, Slim•Fast, Unilever, Covington, TN) in which the regular carbohydrates sucrose and lactose were replaced by 15g of either: 1) maltodextrin ("MDX");

2) long-chain pullulan ("LCP", molecular weight 200 kDa); or 3) medium-chain pullulan ("MCP", 22.6 kDa).

Preparation and measurement of pullulan fragments

Pullulan is a fermentation product of the yeast Aerobasidium pullulans. It is a water soluble, viscous polysaccharide consisting of basic unit of three α-1,4 linked glucose molecules that is repeatedly polymerized by an α-1,6 linkage on the terminal glucose [START_REF] Kimoto | Safety studies of a novel starch, pullulan: Chronic toxicity in rats and bacterial mutagenicity[END_REF][START_REF] Nakamura | Pullulan[END_REF]. Unhydrolyzed (native) pullulan has a molecular weight up to 500 kDa, is resistant to enzymatic hydrolysis by human intestinal enzymes and reaches the colon largely undigested [START_REF] Nakamura | Pullulan[END_REF]. To obtain slowly, but completely digestible carbohydrates, LCP (pullulan from Hayashibara Co, Ltd, Okayama, Japan) was splitted into smaller fragments (see Supplemental information for the preparation of the pullulan batches and the determination of their in vitro digestibility). As hypothesized, MCP showed slow and almost complete hydrolysis, while LCP was hardly hydrolyzed and MDX rapidly hydrolyzed. Viscosities of the products were similar (see Supplemental information).

Subjective feelings of appetite

Subjects arrived at the test facility at 07.30 and at 08.00 hours they received the test products which had to be eaten within 15 minutes. By means of a mark on 60-mm line scales using an Electronic Visual Analogue Scale (EVAS) [START_REF] Stratton | Comparison of the traditional paper visual analogue scale questionnaire with an Apple Newton electronic appetite rating system (EARS) in free living subjects feeding ad libitum[END_REF], subjects rated their appetite feelings ('prospective food consumption', 'desire for a snack', 'hunger', 'desire for a meal', 'satiety', 'fullness') just before consumption and every half hour from 08.00 hours till 13.00 hours. These 6 scales were anchored at the low end with the most negative feelings (e.g., "not at all"), and with opposing terms at the high end (e.g., "very high") as described by [START_REF] Flint | Reproducibility, power and validity of visual analogue scares in assessment of appetite sensations in single test meal studies[END_REF].

During each test day subjects were allowed to drink water or non-caloric drinks each hour (max 150 ml each hour) immediately after filling in the appetite questionnaires. Drinks consumed during the test session on the first day were recorded and repeated on the other test days.

Gastrointestinal disturbance & carbohydrate malabsorption

GI symptoms were scored every 2 hours from 08.00 hours until 13.00 hours on 4point scale (0=not, 1=mild, 2=moderate, 3=severe) using EVAS. Breath hydrogen method was used to assess carbohydrate malabsorption [START_REF] Bond | Use of Breath Hydrogen (H-2) in Study of Carbohydrate-Absorption[END_REF][START_REF] Strocchi | Detection of Malabsorption of Low-Doses of Carbohydrate -Accuracy of Various Breath H2 Criteria[END_REF]. Ten minutes before ingestion of the test meal and at 30-min intervals after ingestion for 5 hours, subjects provided a breath sample into a 20 ml syringe. The H 2 -enrichment of the breath samples, due to the colonic fermentation of the unhydrolyzed carbohydrates, was determined by injecting the end-expiratory breath sample into a H 2 breath test unit (Lactoscreen, Hoekloos, The Netherlands).

Blood glucose and plasma insulin

Because of concerns that blood draws could potentially affect the appetite measures, blood was obtained from a randomly selected subset of 12 subjects.

For blood sampling a flexible 1.0 mm intravenous cannula was inserted into an antecubital vein of one arm for blood sampling. Blood (5 ml) was collected before ingestion of the test drink and at 15-min intervals during the first hour, at 30-min intervals during the second, third and fourth hour, and at the end of the fifth hour after ingestion. The blood was collected into ice-chilled tubes (SST-BD Vacutainer; BD Diagnostics, Oxford, UK) containing EDTA. Immediately after sampling, blood glucose was measured by a hexokinase method (Roche Diagnostics, Basel, Switzerland). After the last sample, the tubes were centrifuged (3 000 rpm, 15 min at 4 o C). The supernatant plasma was stored at -20 o C until analyzed for insulin using an enzyme-linked immunosorbent assay (Mercodia, Uppsala, Sweden).

Background diet, physical activities and other measurements

The subjects were asked to avoid alcohol intake and sports activities on the evening before each test day. They could freely select their own evening meal, but this same meal was then consumed in the evening prior to every subsequent test day. Eating after 22.00 hour in that evening was not allowed and only noncaloric drinks were permitted. Subjects were asked not to change their life style during the study. These steps were taken to ensure roughly similar states of hunger and glycogen stores every test day [START_REF] Flint | Reproducibility, power and validity of visual analogue scares in assessment of appetite sensations in single test meal studies[END_REF]. Sleeping time, mode of transportation, menstrual cycle and incidental lifestyle changes were recorded. Body weight was assessed during each visit before the test meal was given.

Statistical analyses

Feelings of appetite scores were transformed to 100 mm for analysis and simplicity of presentation. In other studies we regularly observed a within-subject variance of about 85 mm•min for Area-Under-the-Curve (AUC) for appetite.

Power calculation based on this variance, using a power of 0.8 and a confidence limit of 0.05, showed that 18 subjects were required for this experiment. In case of dropouts 24 subjects were selected. As the blood draws could disrupt the appetite measures, an additional group of 12 subjects was tested, both for blood measurements and appetite. As analysis (ANOVA) showed that the characteristics of self-report scores of the 12 subjects who had blood drawn did not differ from the total group of subjects, all subjects were combined for the analyses of the self-report data. GI disturbance was analyzed using frequency of severity per time point and a standard ANOVA with the personal scores corrected for each subject's overall mean score.

We hypothesized that the use of smaller pullulan fragments would result in a more sustained postprandial blood glucose and plasma insulin response, thus behaving as a "slow carb", and would lead to a reduction in appetite as compared to a rapidly digestible control. The drinks differed only in the rate and extent of digestibility of the carbohydrates. The data were analyzed using analysis of covariance (ANCOVA) with baseline values as covariate, subjects as blocks and period and group (treatments and control) as factor using SAS version 8.2 (SAS Institute, Cary, NC). A criterion of p ≤ 0.05 was used for statistical significance. Given the specific test hypothesis, and to avoid inflation of experiment-wide error rate, we compared MCP and LCP only to MDX, and not to each other. The difference of each treatment versus MDX was estimated using the Dunnett multiple comparison test (2-sided). The primary analysis was focused on AUC, but to assess the significance of timeframes where differences were observed between treatments and control, further analysis was also done per time point. The incremental cumulative AUC was calculated using the values at t=0 min (just before consumption of the test drinks) as a covariate and using the trapezoid rule.

Correlations between appetite scores AUC and either plasma insulin or blood glucose responses were also calculated using conventional linear regression analysis.

Results

Blood glucose and plasma insulin

LCP produced the lowest and MDX the highest blood glucose excursions, while MCP showed an intermediate and more sustained pattern (Figure 1). AUC for blood glucose was significantly higher for LCP and MCP compared to MDX for the period t=0-150 min (4.78, 4.85, and 4.57 mmol•min for LCP, MCP and MDX, respectively). Blood glucose level dropped below 3.9 mmol/l (chosen as an arbitrary threshold for hypoglycaemia [START_REF] Childs | Defining and reporting hypoglycemia in diabetes -A report from the American Diabetes Association Workgroup on Hypoglycemia[END_REF]) in 10, 6 and 4 out of the 12 subjects during MDX, MCP and LCP, respectively.

MDX not only generated the most pronounced changes in blood glucose but also in blood insulin (Figure 2). The biggest rise in blood insulin was seen with MDX, while the smallest increase was observed for LCP. The relatively steep increases in insulin for MDX and MCP probably also explain the relatively steep decline in blood glucose 30 to 60 minutes after consumption of these drinks.

AUC for insulin was significantly lower for LCP compared to MDX for the period t=0-150 min (11.32,15.73 and 17.90 mmol•min for LCP,MCP and MDX,respectively). Although MCP showed a smaller insulin excursion than MDX, this was not significantly different.

In addition, there were no significant relationships between appetite scores AUC and either plasma insulin or blood glucose responses in the subset of subjects where these were measured (all explained variance was generally below 25%; P>0.05).

Subjective feelings of appetite

Results for 'prospective food consumption' and 'fullness' are shown in Figures 3 and4 (other appetite curves show comparable changes, data not shown). All self-report scores were significantly indicative of reduced appetite after LCP compared to MDX, and this is apparent from several different specific time points as well as a significantly different AUC for the time period t=0 to t=150 min. All significant differences were apparent during the first 150 min. MCP differed from MDX at some isolated time points, but not for AUC.

Carbohydrate malabsorption and gastro-intestinal symptoms

Breath hydrogen excretion after 4 and 5 hours was highest for LCP and lowest for MDX (Figure 5). The hydrogen excretion after MCP was significantly higher than after MDX. The number of subjects reaching 10 ppm or higher (a value considered indicative of true malabsorption and colonic fermentation [START_REF] Bond | Use of Breath Hydrogen (H-2) in Study of Carbohydrate-Absorption[END_REF][START_REF] Strocchi | Detection of Malabsorption of Low-Doses of Carbohydrate -Accuracy of Various Breath H2 Criteria[END_REF]) for MDX, MCP and LCP, respectively, were 2, 14 and 18 out of 35 subjects.

Although there were occasional reports of GI complaints, most of them were rated "mild" and a few "moderate" and they did not differ significantly from MDX (data not shown).

Discussion

These results cast further doubt on the notion that slowly digested carbohydrates may influence appetite via their effects on glycemic responses.

Differences in glycemic responses were unrelated to appetite scores following consumption of test products controlled in composition and differing only in carbohydrate digestibility rate and extent. Despite differing effects on plasma glucose levels following consumption of drinks containing rapidly or slowly digestible glucose polymers, appetite responses to these were not different. In contrast, a largely indigestible glucose polymer led to minimal changes in blood glucose, yet produced the largest reduction in appetite scores.

Literature on the effect of reduced or sustained blood glucose rises on appetite is inconsistent [START_REF] Bornet | Glycaemic response to foods: Impact on satiety and long-term weight regulation[END_REF][START_REF] Niwano | Is Glycemic Index of Food a Feasible Predictor of Appetite, Hunger, and Satiety?[END_REF][START_REF] Pi-Sunyer | Glycemic index and disease[END_REF][START_REF] Raben | Should obese patients be counselled to follow a low-glycaemic index diet? No[END_REF][START_REF] Thomas | Low glycaemic index or low glycaemic load diets for overweight and obesity. Cochrane Database of Systematic Reviews CD005105[END_REF][START_REF] Van Dam | Carbohydrate intake and obesity[END_REF]. These inconsistencies might be explained by a lower than expected energy availability of some of the carbohydrates tested or by other parameters that differed between the test products like taste, physical properties, structure, fibre type or content [START_REF] Bornet | Glycaemic response to foods: Impact on satiety and long-term weight regulation[END_REF][START_REF] Hlebowicz | Postprandial blood glucose response in relation to gastric emptying and satiety in healthy subjects[END_REF][START_REF] Van Dam | Carbohydrate intake and obesity[END_REF][START_REF] Wolever | Day-to-day variation in glycemic response elicited by white bread is not related to variation in satiety in humans[END_REF]. Thus, this literature does not provide consistent and direct evidence for the effects of glycemic responses per se on appetite. For these reasons we prepared a slowly digestible carbohydrate by splitting the fibre pullulan (consisting of glucose only) into smaller glucose-polymer fragments. By doing this we prepared test materials that differed only in the rate and extent of carbohydrate hydrolysis. Both the in vitro and in vivo tests (glucose and hydrogen) confirmed that controlling the chain length of pullulan also controlled the rate and extent of hydrolysis.

MCP produced a more sustained plasma glucose profile (and also a higher AUC and smaller peak, although interpretation of the blood glucose results is hampered by the blood glucose-suppressive effects of insulin). As such we believe it fulfils the criteria for "slow carbs" as defined by Englyst et al. [START_REF] Englyst | Classification and measurement of nutritionally important starch fractions[END_REF], namely 'completely digested in the small intestine but at a slower rate'. In contrast, LCP exhibited a more fibre-like behaviour as it was only about 23% digested. As colonic delivery and fermentation of fibre takes many hours [START_REF] Klein | Site-specific delivery of antiinflammatory drugs in the gastrointestinal tract: an in-vitro release model[END_REF][START_REF] Saito | Fecal Output, Gastrointestinal Transit-Time, Frequency of Evacuation and Apparent Excretion Rate of Dietary Fiber in Young Men Given Diets Containing Different Levels of Dietary Fiber[END_REF], LCP would be expected to provide only negligible amounts of available energy value during the first 4 to 5 hours after ingestion. One would therefore presume that the 'slow carbs' (MCP) provided more available energy in the 5 hour test period than the largely indigestible long-chain pullulan (LCP), yet the latter had the most robust effects on appetite.

One of the criticisms of previous studies testing the effect of low glycemic index products or 'slow-carbs' on appetite is that most studies compared products differing in ways other than just the carbohydrate composition, and thus included confounding variables affecting the interpretations with regard to blood glucose and/or appetite [START_REF] Alfenas | Influence glycemic index/load on glycemic response, appetite, and food intake in healthy humans[END_REF][START_REF] Raben | Should obese patients be counselled to follow a low-glycaemic index diet? No[END_REF]. Indeed, in related research on materials differing in glycemic index, no effect of glycemic index on appetite responses may be observed when controlled for nutritional composition [START_REF] Alfenas | Influence glycemic index/load on glycemic response, appetite, and food intake in healthy humans[END_REF].

LCP improved appetite control on all six scales when compared to MDX. MCP was better than MDX at some time points in a two scales, but this was not statistically significant for the summary measure of AUC. Contrary to expectations, all differences were apparent in the period up to 150 minutes, suggesting that it was not (or only partially) a 'slow-carb' effect. We expected that a slow-carb like MCP might have reduced appetite more than LCP, because the energy provided by the latter in the post-meal period should be small (most escaped to the colon). As the physical properties of all treatments were similar, other mechanisms could play a role here, e.g., effects on brush border enzymes [START_REF] Thomas | Low glycaemic index or low glycaemic load diets for overweight and obesity. Cochrane Database of Systematic Reviews CD005105[END_REF][START_REF] Wakabayashi | Effects of indigestible dextrin on postprandial rise in blood glucose levels in man[END_REF].

Gastric distension and gut hormones like GLP-1 have been mentioned as important determinants of appetite [START_REF] Naslund | Glucagon-like peptide 1 increases the period of postprandial satiety and slows gastric emptying in obese men[END_REF][START_REF] Peters | The role of the gastrointestinal tract in satiation, satiety and food intake: Evidence from research in humans[END_REF].

It is, however, unclear how either of these can explain the difference in appetite responses between LCP and MCP. LCP was hardly digestible and thus did not produce many glucose molecules that could have affected the release of gut hormones like GLP-1. It is possible that LCP might have been fermented in the colon and that the glucose molecules induced GLP-1 release there, but in that case any effects on GLP-1 and appetite should only become visible several hours after ingestion. Furthermore, if GLP-1 would explain the appetite-reducing effects then the MDX, by producing the fastest glucose availability and likely the most immediate rise in GLP-1, should have reduced appetite most. The immediate effect of ingesting the liquids will increase gastric distension and affect appetite, but we do not see how this would be different between the drinks. The effect of LCP on appetite is therefore intriguing but unexplained, and further research could be focused on this observation, including use of pullulan fragments of intermediate molecular mass (between LCP and MCP versions used here).

The immediate increase in postprandial glycemia was relatively modest compared with studies where much larger loads were used (50g) in drinks containing only carbohydrates and water. We used 15 g of the test carbohydrates in a drink containing also fat and protein. These are more realistic levels, especially for indigestible carbohydrates, in more realistic food formats.

Higher levels would have affected palatability and especially viscosity, while it was our intention to make products only differing in carbohydrate digestibility.

The insulin levels, actually, were more similar to other studies using higher carbohydrate levels. Apparently the protein levels in the drink increased insulin (explaining the insulin increase after ingestion of the long-chain pullulan drink) and this might have dampened the blood glucose response.

It has been proposed that solid meals generally produce more satiety than liquid meals, although there is currently no consensus on this [START_REF] Almiron-Roig | Liquid calories and the failure of satiety: how good is the evidence?[END_REF]. Solids meals produce different blood glucose effects than liquid meals (e.g. [START_REF] Brynes | Plasma glucagon-like peptide-1 (7-36) amide (GLP-1) response to liquid phase, solid phase, and meals of differing lipid composition[END_REF][START_REF] Leidy | Food Form and Portion Size Affect Postprandial Appetite Sensations and Hormonal Responses in Healthy, Nonobese, Older Adults[END_REF], while the effect of food form on gut hormones like CCK or GLP-1 is equivocal. Both a smaller and an equal increase of GLP-1 have been found after a solid versus a liquid meal [START_REF] Brynes | Plasma glucagon-like peptide-1 (7-36) amide (GLP-1) response to liquid phase, solid phase, and meals of differing lipid composition[END_REF][START_REF] Leidy | Food Form and Portion Size Affect Postprandial Appetite Sensations and Hormonal Responses in Healthy, Nonobese, Older Adults[END_REF]. Effects of a slowly digestible carbohydrate on appetite after a solid meal might therefore be different from the liquid meals used here, although the mechanism for this is unclear.

Based on the work of [START_REF] Wolf | Pullulan is a slowly digested carbohydrate in humans[END_REF], who found GI symptoms and malabsorption after consumption of a long-chain pullulan, we expected LCP to cause measurable GI disturbance and malabsorption (as it would be only partly hydrolyzed), while MCP (that would be hydrolyzed completely) would not. The poor digestibility of LCP is indicated by our in vitro results and hydrogen excretion after 4 and 5 hours, and also in the number of subjects excreting 10 ppm hydrogen or more. However, absolute levels of hydrogen excretion were relatively low, and GI disturbances were also low and not different from MDX. In their research, Wolf et al. [START_REF] Wolf | Pullulan is a slowly digested carbohydrate in humans[END_REF] used 50 g of pullulan, much higher than the 15 g used here. There is perhaps a threshold for occurrence of GI symptoms after long-chain pullulan, somewhere in between 15 and 50 g, although that might also be dependent on the product matrix.

In conclusion, our results in a study population of mostly women suggest that slowly (relative to rapidly) digestible carbohydrates will not have meaningful effects on acute appetite control when applied in food products at the levels tested here. A higher dose or a longer exposure may reveal the putative appetite effects of slow-carbs; however, this needs to be balanced against feasibility issues (especially product quality and GI complaints) to ensure that the results are relevant and practicable. While the slowly digestible carbohydrate did not meaningfully decrease appetite, the indigestible long-chain pullulan did and further research should be focused on this observation.

Supplementary information is available at The European Journal of Clinical

Nutrition's website.

Legends to Figures

Figure 1 .

 1 Figure 1. Blood glucose (LS means ± SE; n=12) after consumption of a meal

Table 1 .

 1 Composition of the test drinks containing either maltodextrin (MDX), or medium-chain (MCP) or long-chain (LCP) pullulan.

		MDX	LCP	MCP
		(g)	(g)	(g)
	fructose	2.5	2.5	2.5
	maltodextrin	15.0
	pullulan		15.0	15.0
	total sugars	17.5	2.5	17.5
	other soluble fibre	2.1	1.8	2.0
	insoluble fibre	3.1	1.0	2.7
	"total carbs"	24.3	21.9	24.0
	protein	10.0	10.0	10.0
	fat	5.1	5.1	5.1
	energy (kJ)*	766	728	758
	* based on 17 kJ/g for fibres (including LCP)

Acknowledgements

Tom Wiersma is acknowledged for statistical support. Research support was provided by Unilever.

Conflict of interest

None of the authors had any conflict of interest (all authors are employed by a commercial manufacturer of meal replacement products)


M F Romero

M M Sanz

I Tanarro
email: itanarro@iem.cfmac.csic.es

A Jiménez

E Muñoz

Plasma diagnostics and device properties of AlGaN/GaN HEMT passivated with SiN deposited by plasma-enhanced chemical vapour deposition

Keywords: High Electron Mobility Transistors (HEMT), AlGaN/GaN, silicon nitride (SiN) thin films, SiH 4 -NH 3 plasmas, plasma diagnostics, plasma enhanced chemical vapour deposition (PECVD)

In this work, silicon nitride thin films have been deposited by Plasma Enhanced Chemical Vapour Deposition (PECVD) on both silicon samples and AlGaN/GaN High Electron Mobility Transistors (HEMT) grown on sapphire substrates. Commercial parallel-plate RF plasma equipment has been used. During depositions, the dissociation rates of SiH 4 and NH 3 precursors and the formation of H 2 and N 2 have been analysed by mass spectrometry as a function of the NH 3 /SiH 4 flow ratio and the RF power applied to the plasma reactor. Afterwards, the properties of the films and the HEMT electrical characteristics have been studied. Plasma composition has been correlated with the SiN deposition rate, refractive index, H content and the final electric characteristics of the passivated transistors.

Introduction

Silicon nitride (SiN) thin films deposited by PECVD are widely used in the semiconductor industry as passivating layer [1][2][3], diffusion barrier [4], gate dielectric [5,6] or interlevel metal isolation. They are also currently employed as antireflection and protective coatings in solar cells [7,8], and have been investigated to fabricate membranes for micromechanical applications [9]. Silicon nitride can also be deposited by thermal CVD or catalytic CVD [10], but plasma enhancement renders uniform deposition over large areas and allows the use of much lower substrate temperatures [6], compatible with most of the steps in semiconductor processing.

At present, SiN thin films are increasingly used as passivating coatings of AlGaN/GaN High Electron Mobility Transistors (HEMT), which have proved to be excellent candidates for high-power and high-temperature requirements [11], from DC to high frequencies [12][13][14],

owing to the great thermal stability, large band offsets and high spontaneous and piezoelectric fields of the nitrides. These field effect transistors, which incorporate a junction between two materials with different band gaps, based on AlGaN/GaN heterostructures, provide huge sheetcarrier densities (∼10 13 cm -2 ), even for temperatures above 1000 K [15]. Nevertheless, the advantages of nitride-based devices are hindered by the large defect density of this material. So, AlGaN/GaN HEMT exhibit the instability phenomenon of current collapse, which seems to be related to surface effects [16]. Recently, it has been shown that the HEMT processing and, in particular, the SiN passivation process, have noticeable effects on minimizing current collapse and achieving a suitable passivation of these devices [17,18]. By this reason, a complete characterization of the SiN passivation process is desirable.

Plasma diagnostic, allowing to identify transient species, as well as stable products and other properties involved in plasma processing, has become a powerful method to understand the mechanisms which ultimately lead to the growth of films of the most diverse characteristics [19][20][START_REF] Sanz | Plasmas basic concepts and nitrogen containing plasmas[END_REF]. The diagnostic is mainly carried out with spectroscopic techniques like visible emission of excited species [6,[START_REF] Camero | [END_REF][23][24][25] or infrared absorption of molecular bands [7,[26][27][28][29][30]; by mass spectrometry of neutrals [1][2][3]6,31,32] and ions [33][34][35], and with Langmuir probes [36,37].

Many of these studies are usually performed on experimental plasma reactors, specially designed to allow the use of some of the former characterization techniques. Nevertheless, in commercial equipments, devoted specifically to optimize thin film production, the plasma diagnostic capabilities are often very restricted. The results found in experimental reactors cannot be always extrapolated directly to the commercial ones. Even the conditioning of the reactor surfaces with previous plasma treatments can influence the subsequent film properties [18]. Therefore, attempts for in-situ characterizing the plasmas generated in this kind of reactors during film processing are worthwhile, since they can be of great help to guide the improvement of the deposition processes and the quality of the films [38].

In order to produce SiN thin films by PECVD, gas mixtures of SiH 4 + NH 3 or SiH 4 + N 2 are commonly used. The composition of SiH 4 + NH 3 and SiH 4 + N 2 depositing plasmas under different conditions, and its influence on the properties of SiN films, have been studied by some authors in various types of reactors, always looking for an optimization of the characteristics of the films, depending on their further applications. The deposited SiN films do not consist of stoichiometric Si 3 N 4 crystals, but are more properly described as amorphous Si x N y H z . The hydrogen content, which is determinant in the film characteristics, is higher when NH 3 is used as precursor. Nevertheless, this molecule can be dissociated much more efficiently at electron energies remarkably lower than those needed to dissociate N 2 [3,6] and therefore is more widely used. To drive out the excess of hydrogen, substrate temperatures ∼300 ºC or higher are usually employed during deposition processes.

Smith and co-workers [1][2][3] studied SiH 4 + NH 3 and SiH 4 + N 2 plasmas generated in a parallel plate RF plasma reactor; characterized the plasmas by means of line-of-sight mass spectrometry, and studied the plasma composition for various plasma powers and gas mixture conditions, with the aim of minimizing the rate of charge trapping in Al/Si x N y H z /Si Metal-Insulating-Semiconductor (MIS) capacitors. They also found that in the case of SiH 4 + NH 3 plasmas, the main deposition precursor was the triaminosilane (Si(NH 2 ) 3 ) radical [1], whereas in the case of SiH 4 + N 2 plasmas, SiH n radicals and N atoms react directly at the substrate surface [2]. Kessels et al [26] confirmed and refined these last results after measuring by laser absorption spectroscopy and mass spectrometry the densities of SiH 3 and N in a SiH 4 + N 2 expanding thermal plasma, which was used to deposit SiN films at high deposition rates (>1 nm/s) for photovoltaic applications [7]. Oever et al [27] employed cavity ring-down absorption spectroscopy and threshold ionization mass spectrometry for the diagnostic of N, NH, and NH 2 radical densities in a remote Ar-NH 3 -SiH 4 expanding thermal plasma and inferred the possible role of these transients in silicon nitride deposition. Ohta et al [33] studied by mass spectrometry the influence of ions like NH 4 + on the growth of ultra-thin SiN films in SiH 4 + NH 3 electron cyclotron resonance plasmas, devoted to produce gate dielectric films in large scale integrated circuits. Flewitt et al [6] succeed in depositing SiN films with low H content at low temperature (80 ºC) using SiH 4 + N 2 + He electron cyclotron resonance plasmas, which would allow the use of plastic instead of glass substrates for liquid crystal displays, and inferred the relevance of gas phase reactions. So, in the previous studies, the main deposition mechanisms of silicon nitrides were quite thoroughly elucidated, and it was demonstrated that the plasma chemistry can be manipulated to control the film properties in a reproducible and predictable manner.

In this work, SiN thin films have been deposited on silicon samples (to test the film properties) and on High Electron Mobility Transistors (HEMT) previously processed on AlGaN/GaN heterostructures grown on sapphire substrates [START_REF] Tanarro | th International Symposium on Plasma Chemistry (ISPC)[END_REF]. To deposit the films, a commercial RF parallel-plate PECVD reactor has been used, and different NH 3 /SiH 4 flow ratios (ΦNH 3 /ΦSiH 4 ) and RF discharge powers (P RF ) have been tested. The dissociation of the precursors and the formation of hydrogen in the plasma have been observed in situ by mass spectrometry, and the properties of the films and of the HEMT have been characterized later. A high correlation has been found between the plasma composition under the different deposition conditions and the subsequent properties of the films and the HEMT. The data are compared with results previously reported in the literature [START_REF] Krämer | Gallium nitride-based microwave high-power heterostructure field-effect transistors design, technology and characterization[END_REF][START_REF] Kim | [END_REF].

Experiment

The SiN coatings were produced in a commercial RF planar parallel-plate reactor (Plasmalab μ80, from Plasma Technology) operating at 13.56 MHz. The reactor consists of a base grounded plate connected to the heater, and the upper plate connected to the RF power supply. The system is isolated within a cylindrical Pyrex chamber (see figure 1). SiH 4 and NH 3 were used as precursors (SiH 4 (99.994%); NH 3 (99.999%), both from Air Products). They were supplied to the reactor through two automatic gas flow valves. A vacuum valve at the reactor's output, in series with a rotary pump, regulated the gas exit. The samples were located on a wafer-plate with temperature control from 20 to 400 ºC, and were maintained at 300 ºC in all the cases. Increasing this temperature would render a reduction of the SiN film hydrogen content [3]; nevertheless, when applied to passivate AlGaN/GaN HEMT, the use of higher substrate temperatures could damage the metal based Schottky gate contacts previously done [42].

Plasmas were characterized by mass spectrometry. A Stanford Research System quadrupole mass spectrometer (SRS-RGA100) with a Faraday cup as a detector was employed.

It was located in a vacuum chamber differentially pumped up to 10 -4 Pa by a turbomolecular pump and a rotary pump. Since no extra vacuum ports in the commercial PECVD reactor other than its gas output were available, the mass spectrometer system was connected to this point, before the gas exit valve of the reactor, through a vacuum "tee" piece. The gas sampling flow to the spectrometer's chamber was controlled by means of a fine needle valve (in series with a ball valve). Pressure ∼ 2•10 -3 Pa was maintained in this chamber during the characterization of the plasma.

The refractive indexes and growth rates of the films deposited by PECVD were subsequently analysed by ellipsometry with a PlasMos 2302 equipment, based on a He-Ne laser (λ = 632.8 nm, 45º incident angle). A Fourier Transform Infrared (FTIR) Spectrometer Nicolet

Magna IR 760 working in the range 400 -4000 cm -1 , by using a EverGlo IR source, a KBr beamsplitter and a MCT detector cooled with liquid nitrogen, allowed estimating the amplitudes of the Si-H and N-H stretching bands and inferring the hydrogen content in the SiN films. The HEMT devices passivated with these films were characterized by DC and pulsed I-V measurements (gate pulsewidth of 500 μs and a period of 10 ms) by using an Agilent 4156c semiconductor parameter analyzer.

Experimental results and discussion

3.a Characterization of the plasma

Figure 2 shows the two mass spectra of the mixed NH 3 and SiH 4 precursors in the reactor, with discharge off and with discharge on in the steady state. In this figure, the RF power was P RF = 30 W and the gas flow rates, 3.1 sccm and 1.7 sccm, respectively. The background spectrum was subtracted previously. The three panels display the regions of interest. Note the different scales in the intensity of the signals (vertical axis) of the left panel and the other ones, which is due, not only to the efficient production of H 2 as major stable product of the discharge, but also to the higher detection efficiency at low masses, commonly found in quadrupole mass spectrometers [34,43]. In what follows, only relative variations of signal intensities are taken into account and, hence, the diverse efficiencies for the various species are not significant. In the With discharge on, H 2 was generated as major gas product, only a small proportion of ammonia (∼10%) remained in the plasma, leading to the corresponding disappearance of the above mentioned contribution to m = 28 a.m.u signal in the quadrupole, and silane was almost completely dissociated (remaining SiH 4 ~ 1%), even for the low RF power applied in this case, leading to the deposition process. As it has been previously commented, and according to bibliographic results [3,26], the N and Si species liberated from the precursors' dissociation are generally assumed to be deposited in the walls by processes involving species such as disilane, at relatively low discharge powers, or Si(NH 2 ) 4 and Si(NH 2 ) 3 radicals, at the higher ones.

In a first series of measurements, the SiN films were deposited on silicon samples at different ΦNH 3 /ΦSiH 4 values from 0.9 to 3, with ΦSiH 4 = 1.7 sccm and P RF = 60 W. In this case, the reactor pressures changed between 88 and 236 Pa, respectively. From the subsequent characterization of the films, ΦNH 3 /ΦSiH 4 = 1.8 was selected as the most appropriate for the deposition conditions (see below).

In a second series of measurements, the RF power was varied between 30 and 250 W, for ΦNH 3 /ΦSiH 4 = 1.8 (ΦSiH 4 = 1.7 sccm). A total pressure of 70 Pa was maintained in this case. At these conditions, SiN films were grown independently on silicon samples and, finally, on AlGaN/GaN HEMT. Plasma exposures were determined, either by fixing the deposition time (15 min) when applied to silicon substrates, or the desired final film thickness (120 nm), when applied on HEMT. In the last case, the required deposition times to obtain this thickness were previously estimated from the growth rate obtained on Si substrates for each condition.

In figures 3(a) and 3(b), the remaining NH 3 and SiH 4 fractions, and the signals corresponding to H 2 and N 2 produced in the plasma for the different ΦNH 3 /ΦSiH 4 values at P RF = 60 W are depicted. The remaining fractions of NH 3 and SiH 4 were estimated from the intensities ratio between discharge on (in the steady state) and discharge off, for 16 and 31 a.m.u, respectively. At these masses, the background contributions were lower than at the other representative masses of the fragmentation patterns, minimizing possible errors. Linearity of the mass spectrometer was tested from its response to the different NH 3 gas flows without discharge.

As can be seen, the remaining fraction of SiH 4 was very small and nearly constant, and neat increases with ΦNH 3 /ΦSiH 4 in the remaining NH 3 fraction and in the H 2 and N 2 signals was appreciated, as could be expected from the gradual excess in NH 3 precursor. and N 2 produced in the plasma, for different RF discharge powers, at ΦNH 3 /ΦSiH 4 = 1.8, during film depositions on HEMT. Between 30 and 125 W, the dissociation of both precursors increased with power, but afterwards, their concentrations clearly stabilized. In all cases, the remaining fraction of NH 3 was noticeably higher than that of SiH 4 . The increase in H 2 and N 2 signal with P RF was quite small. The results were very similar (under experimental errors) when the SiN films were deposited on Si substrates. They are not displayed for the sake of simplicity.

3.b SiN film properties

The thickness and refractive indexes of the SiN films grown at the different plasma conditions were measured by ellipsometry, after extracting the samples from the plasma reactor.

From film thickness and deposition times, the deposition rates were directly estimated. The changes in deposition rate and refractive index of the SiN films as a function of ΦNH 3 /ΦSiH 4 are displayed in figure 4(a). Figure 4(b) displays these changes as a function of the applied RF power. By increasing ΦNH 3 /ΦSiH 4 from 0.9 to 3 (figure 4(a)), the refractive index decreased slightly (note the small spread of the vertical scale at the left axis), whereas the deposition rate almost duplicated its value. The decrease in refractive index can be an indication that SiN film became more rich in nitrogen [6,[START_REF] Kim | [END_REF], giving place to an increase in the deposition rate. At the higher range of NH 3 /SiH 4 flow ratios, both magnitudes varied more slowly. This may suggest a tendency to saturation in the deposition process with the gradual excess of NH 3 supply. These results were all in agreement with previous literature data [START_REF] Krämer | Gallium nitride-based microwave high-power heterostructure field-effect transistors design, technology and characterization[END_REF][START_REF] Kim | [END_REF], where similar variations were found. This behaviour, and especially, the evolution of the H content with ΦNH 3 /ΦSiH 4 determined afterwards (see figure 6 According to the literature [6,45], low H concentrations in the SiN films are highly convenient and determinant of their passivation properties in HEMT. Figure 6 displays the decreases in H content of the SiN films by increasing ΦNH 3 /ΦSiH 4 (a) and RF power (b), up to reaching minimum stationary values for ΦNH 3 /ΦSiH 4 ~ 1.8 and P RF ~ 125 W, respectively. The initial decrease in H content was remarkably greater for the case of ΦNH 3 /ΦSiH 4 variation than that registered by changing P RF . In any case, the regions of minimum stationary H content in the films correspond in both cases to the higher H 2 gas concentrations observed in the plasma (see figure 3(b) and 3(d)). Moreover, concerning P RF , the minimum H content also corresponds to the region where the dissociation degrees of NH 3 and SiH 4 reached the steady state (figure 3(c)).

These results deserve also to be compared to the intervals of ΦNH 3 /ΦSiH 4 and P RF values where some tendencies to saturation were found in the refractive index and deposition rate of the films (figure 4(a,b)), and are in agreement with the observations reported in references [1,45]. To further investigate the influence of P RF during SiN film deposition in the trapping of charges, the effect of current collapse, defined as I DS (DC)/I DS (pulsed) at V DS =5 V, was estimated from the output characteristic at V GS = 0V (see figure 8) for the different P RF values. Although a 500μs pulse width was quite long to extract the current collapse, which affects most of this kind of devices for radiofrequency applications, it was short enough to allow an estimation of the quality of the device at moderate high frequencies. The results displayed in figure 9 indicate that current collapse is reduced when high P RF are applied to the plasma during SiN deposition, implying a reduction of slow trapped charges that degrade the electrical behaviour of this kind of devices [46,47]. This is in good agreement to previous results [START_REF] Krämer | Gallium nitride-based microwave high-power heterostructure field-effect transistors design, technology and characterization[END_REF] and shows that SiN films with a lower H content are more effective to mitigate current collapse effects.

3.c Characterization of HEMT

Summary and conclusions

In this work, the composition of plasmas generated in a commercial RF discharge reactor containing NH 3 and SiH 4 for PECVD of SiN films was studied by mass spectrometry, as a function of the NH 3 /SiH 4 flow ratios and the RF power applied to the reactor. The SiN films were grown on silicon samples and, as passivating coatings, on high electron mobility transistors. The properties of the films and of the HEMT were studied afterwards by different complementary techniques.

The dissociation degree of the precursors and the concentration of H 2 and N 2 produced in the plasma were related to the deposition rate and refractive index of the films, and, fundamentally, to their H content and to the electric response of the passivated transistors.

The studies varying ΦNH 3 /ΦSiH 4 allowed selecting an intermediate value for this magnitude, where the H content of the films got minimum values and stabilized. Besides, at higher ΦNH 3 /ΦSiH 4 than this value (1.8), NH 3 was in excess, and its dissociation efficiency decreased noticeably, whereas the H 2 (and N 2 ) gas content in the plasma increased markedly.

The studies varying P RF demonstrated that the H content of the SiN films decreased further with growing RF power, and reached minimum stationary values for P RF higher than 125 W, corresponding to minimum and stationary remaining concentrations of the precursors. The decrease in the H film content and in the remaining plasma precursors coincided too with the improvement of the HEMT electrical characteristics. These results confirm that the NH 3 /SiH 4 gas flow ratio and the RF power are critical values during SiN film deposition for the effective passivation of AlGaN/GaN HEMT, in agreement with previous literature data. These results also suggest that the properties of the film and the passivated HEMT are closely related with the dissociation efficiency of the precursors in the depositing plasmas, and their H 2 content. So, efforts for in-situ characterization of the plasma during the depositing process in commercial reactors like the one employed here can guide encountering the best film growth conditions, saving great time and effort in finding these conditions by later ex-situ characterization of the devices.

Aknowledgements

Figure 1 .

 1 Figure 1. Experimental set-up. Connections between the commercial PECVD system and the Quadrupole Mass Spectrometer (QMS) chamber are shown.

Figure 2 .

 2 Figure 2. Mass spectra of the mixed precursors for SiN coating without discharge (grey line) and with a 30 W RF discharge (black line). Substrate temperature = 300 ºC. Reactor pressure = 0.7 mbar, ΦNH 3 /ΦSiH 4 = 1.8. The typical dissociation patterns of NH 3 and SiH 4 are shown (bars).

Figures 3 (

 3 Figures 3(c) and 3(d) show the remaining NH 3 and SiH 4 fractions, and the signals of H 2

Figure 3 .

 3 Figure 3. (a) Remaining fractions of SiN precursors, and (b) signals of H 2 and N 2 produced in the steady state discharge, as a function of the NH 3 /SiH 4 gas flow ratios. Lines are only to guide the eyes. (c,d) The same data as a function of the applied RF power. N 2 signals in (b) and (c) are magnified by factor 3.

  (a)), led us to select an intermediate value, ΦNH 3 /ΦSiH 4 = 1.8, for the studies at diverse P RF values.As P RF increased, at ΦNH 3 /ΦSiH 4 = 1.8 (figure4(b)), the deposition rate multiplied its value by two, and the refractive index increased slightly, until both magnitudes reached a tendency to saturation. These dependences were also in agreement with the results of references[1,[START_REF] Krämer | Gallium nitride-based microwave high-power heterostructure field-effect transistors design, technology and characterization[END_REF].

Figure 4 .Figure 5 .

 45 Figure 4. (a) Influence of ΦNH 3 /ΦSiH 4 on the refractive index (left axis) and the deposition rate (right axis) of the SiN films. (b) The same, as a function of P RF .

Figure 6 .

 6 Figure 6. (a) Variation of H content (atoms per surface unit) in the SiN films as a function of ΦNH 3 /ΦSiH 4 for P RF = 60 W. (b) Variation of the H content with the RF power for reactor pressure = 0.7 mbar and ΦNH 3 /ΦSiH 4 = 1.8. The film thickness was 120 nm.

Figure 7 Figure 7 .

 77 Figure 7 illustrates schematically a HEMT device with (upper panel) and without (lower panel) conduction, depending on the potential applied to the gate, G, being D the drain and S, the source of the transistor.

Figure 8 .

 8 Figure 8. Output characteristic of AlGaN/GaN HEMT for DC (continuous lines) and pulsed signals (dashed lines), after pasivation with SiN films deposited at 30 W (left) and 205 W (right).

Figure 9 .Figure 10 .

 910 Figure 9. Variation of the ratio I DS (DC)/I DS (pulsed) on AlGaN/GaN HEMT with the RF power applied to the plasmas during SiN deposition. The higher proximity of this value to unity for the higher P RF values indicates a lower current collapse.

  This work was supported in part by the KORRIGAN project (EDA-04/102.052/032 CA 2157v7) and in part by the projects ICTS-2007-05, MAT2007-65965, FIS 2007-61686 and CSD2009-00038 of the MICINN of Spain.


Zaher ; Toumi

Annabel ; Kesterton

Arnab ; Bhowmick

A J Beveridge

N A Scott

Nigel Mr

Scott

Nonagenarian Surgical Admissions for the acute abdomen: Who benefits?

Keywords: Emergency Surgery, Nonagenarian, acute abdomen

Methods and Materials.

Surgical management of 49 consecutive nonagenarian admissions (median age 92yrs) with an acute abdomen compared to the management and outcome of 50 younger patients (median age 53.5) admitted with a suspected acute abdomen over the same period.

Results

Nonagenarian group were mainly female (71% v 50% p=0.003). The use of laboratory investigations and imaging was similar for the patients aged over 90 and the younger patients -although proportionately fewer nonagenarians were investigated by abdominal CT scan (8% v 24%).

Of the 49 nonagenarian patients admitted, only 4% (n=2) were operated on.

By contrast, 38% (n=19) of patients aged 50-59 (P=0.0001) underwent a surgical intervention.

A much greater proportion of nonagenarians died in hospital than patients in the 50-59 comparator group (16% nonagenarians versus 4% comparator patients; p=0.04). The very large majority of survivors in both age groups were

Conclusions

In this study, when compared with younger patients very few nonagenarian patients (2%) with a suspected acute abdomen benefited from surgical admission. Instead the large majority of nonagenarians either died or were discharged back to their home address without surgery. -Selected patients in their nineties can be successfully operated on as emergencies and discharged from hospital alive.

What does this study add?

-Most Nonagenarians are unlikely to benefit from hospital surgical admission.

-Palliative treatment must remain a major consideration for nonagenarians with significant comorbidity and/or severe surgical illness.

-Future admission protocols for nonagenarians with a suspected acute abdomen should usefully incorporate assessment of "illness severity" before the decision to admit.

INTRODUCTION

The number of nonagenarians in England and Wales continues to increase (1). An inevitable consequence of this increase in life expectancy is an increasing workload of surgical illness amongst the very elderly. (2) While the outcomes of surgery in selected elderly patients are well documented [START_REF] Cohen | Surgical procedures in patients during the tenth decade of life[END_REF][START_REF] Damhuis | Postoperative mortality after cancer surgery in octogenarians and nonagenarians: results from a series of 5 390 patients[END_REF][START_REF] Arenal | Abdominal Surgery in Nonagenarians: Short-Term Results[END_REF][START_REF] Arenal | Mortality associated with emergency abdominal surgery in the elderly[END_REF], less clear is whether the overall management of the nonagenarian acute abdomen, including the frequency of the decision to operate, is the same as in younger patients.

In this study we documented the surgical management of nonagenarians and a younger (50-59 years old) comparator population admitted with a diagnosis of an acute abdomen to the same hospital over the same time period. Our aim was to determine if the management and outcomes of the nonagenarian acute abdomen differ significantly from those of younger patients.

METHODS AND MATERIALS

49 consecutive patients aged 90 years or over with a clinical diagnosis of acute abdomen, were admitted during a nine month period (2007) to the Surgical Assessment Unit at Royal Preston Hospital. Over the same period 306 patients aged between 50 and 59 years of age were also admitted with an acute abdomen. For the purposes of this study, a "young" comparator population (n=50; median age 53.5 yrs) was selected from every sixth admission in this latter age group. Each patient had details of age, gender and pre-admission domicile recorded.

In addition details of the use of laboratory and radiological investigations, surgical operations, length of stay, outcome and discharge destination were collected. The nonagenarian population and 50-59 year comparator population were compared, to determine any differences in the use of investigations, surgical intervention and outcome, including final discharge address from the hospital. Chi square test was used for comparison between the two groups.

RESULTS

Patients and Management.

The nonagenarian group had significantly more females (71%) than the comparator group (50%). The frequency of haematological and biochemical investigations was the same for patient groups as was the use of chest radiographs, abdominal films and abdominal ultrasound. However, significantly fewer nonagenarians underwent CT scan. (Table 1) Of the 49 nonagenarian patients admitted, only 4% (n=2) were operated on, one had a Hartmann's procedure for perforated diverticular disease and one died after a repair of an incarcerated femoral hernia. By contrast, 38% (n=19) of patients aged 50-59 (P=0.0001) underwent a surgical operation.

Outcome

The median hospital stay for the nonagenarians was very similar to that of the 50-59 age group (Table 2). However, a much greater proportion of nonagenarians died in hospital than patients in the 50-59 comparator group 3 summarises the preadmission and post-discharge domicile of the nonagenarian group. The discharge diagnoses of the nonagenarian group are summarised in Table 4.

DISCUSSION

Not surprisingly, female patients predominate amongst very elderly patients admitted with a suspected acute abdomen [START_REF] Arenal | Mortality associated with emergency abdominal surgery in the elderly[END_REF]. In addition, we found the use of laboratory and most radiological investigations in nonagenarians, to determine the cause of the acute abdomen, was both similar to their use in the younger comparator population and to their use in previously reported elderly surgical groups [START_REF] Geloven | Hospital Admissions of Patients aged over 80 with acute abdominal complaints[END_REF]. An exception was that significantly fewer nonagenarians had an abdominal CT scan.

Previous studies tend to emphasise that selected patients in their nineties can be successfully operated on as emergencies and discharged from hospital alive [START_REF] Warner | Surgical procedures among those > 90 years of age. A population-based study in Olmsted County, Minnesota, 1975-1985[END_REF][START_REF] Cohen | Surgical procedures in patients during the tenth decade of life[END_REF][START_REF] Damhuis | Postoperative mortality after cancer surgery in octogenarians and nonagenarians: results from a series of 5 390 patients[END_REF][START_REF] Arenal | Abdominal Surgery in Nonagenarians: Short-Term Results[END_REF][START_REF] Arenal | Mortality associated with emergency abdominal surgery in the elderly[END_REF]. In favourable reports, the operative mortality of emergency surgery in nonagenarians is between 20 and 30% [START_REF] Cohen | Surgical procedures in patients during the tenth decade of life[END_REF][START_REF] Damhuis | Postoperative mortality after cancer surgery in octogenarians and nonagenarians: results from a series of 5 390 patients[END_REF][START_REF] Arenal | Abdominal Surgery in Nonagenarians: Short-Term Results[END_REF][START_REF] Arenal | Mortality associated with emergency abdominal surgery in the elderly[END_REF]. By contrast, the striking finding here was the rarity of surgical operation amongst the nonagenarians (4% v 38% of comparator group; p=0.001) -despite the higher nonagenarian death rate after admission (16% v 4% of comparator group; p=0.04). Others have also found that a smaller proportion of very elderly with an acute abdomen are suitable for surgical intervention when compared to younger patients (8). Catastrophic outcomes after abdominal surgery in the elderly are closely related to advanced comorbidity (6, 9) -NCEPOD (10) described 82% of nonagenarian surgical deaths as being associated with ASA III or worse.

Thus significant comorbidity and poor performance status (11) means that surgical intervention for the acute abdomen in many very elderly patients is unlikely to be of benefit. This perception of poor patient outcomes in our experience, led to 98% of nonagenarians admitted with an acute abdomen either dying in hospital without surgical intervention or after a median stay of 4 days, being discharged back to their admission address.

It is strongly our view that neither age alone nor subjective rating systems (12, 13) can determine the appropriateness of surgical intervention in the individual elderly patient. However, the place of palliative treatment must remain a major consideration for nonagenarians with significant comorbidity and/or severe surgical illness (9). Future admission protocols for nonagenarians with a suspected acute abdomen would usefully incorporate assessment of "illness severity" before the decision to admit -the aim being to avoid the upset and distress of admission for the very many elderly patients who are unlikely to benefit from hospital surgical admission. We plan to study prospectively and comprehensively the management and outcome of this growing group of patients in order to help in creating appropriate admission protocols.

  and older, form an increasing proportion of the general population. Outcomes of their acute surgical admissions are not well documented.

  their pre-admission domicile (39 (95%) nonagenarians versus 46 (96%) comparator 50-59 year group).

  What is known about the topics?-Nonagenarians represent a growing part of the population.-Nonagenarian acute surgical admissions have increased and are likely to increase further.

  versus 4% comparator patients; p=0.04). The same proportion of surviving nonagenarians and younger comparator patients were discharged back to their original home address. Table

8

  Walsh TH. Audit outcome of major surgery in the elderly. Br J Surg 1996; 83(1):92-7 9) Zerbib P, Kulick JF, Lebuffe G, Khoury-Helou A, Plenier I, Chambon JP. Emergency major abdominal surgery in patients over 85 years of age. World J Surg. 2005 Jul;29(7):820-5 10) Extremes of Age -The 1999 Report of the National Confidential Enquiry inot Perioperative Death. NCEPOD Published 17 November 1999 by the National Confidential Enquiry into Perioperative Deaths 35-43 Lincoln's Inn Fields, London WC2A 3PN 11) Masuo K, Kumagai K, Tanaka T et al "Physiological" age as an outcome predictor fo abdominal surgery in elderly patients. Surgery Today 1998:28(10): 997-1000. 12) Farquharson SM, Gupta R, Heald RJ, Moran BJ. Surgical decisions in the elderly: the importance of biological age. J R Soc Med 2001: 94;232-235 13) Seymour DG Letter "Surgical decisions in the elderly" J R Soc Med 2001:

Table 1 -

 1 Investigation and Management

		International Journal of Clinical Practice	Page 12 of 15
		Nonagenarians	Comparator Group	p
		n=49	n=50
	Gender	14M:35F	25M:25F	0.003
	Age
	Median (range)	92 (90-99)	53.5 (50-59)	<0.0001
				(Mann
				Whitney)
	Biochemical	44 (90%)	47 (94%)	ns
	Investigations
	Haematological	45 (92%)	48 (96%)	ns
	Chest Radiograph	26 (53%)	25 (50%)	ns
	Plain abdominal	34 (69%)	26 (52%)	ns
	film
	Ultrasound scan	9 (18%)	10 (20%)	ns
	CT abdomen and	4 (8%)	12 (24%)	0.03
	pelvis
	Surgical Operation	2 (4%)**	19(38%)	0.0001
	(** 1 patient died after surgery)
		International Journal of Clinical Practice

Table 3 -

 3 Pre-admission and post-discharge domicile of the nonagenarian

					Page 14 of 15
	group
	Pre-admission	Number	Outcome
	domicile	of	Death	Discharge destination
		patients		Pre-admission	Higher level of
				address	care
	Nursing home	3	1	2	0
	Residential home	15	2	13	0
	Sheltered housing 3	1	2	0
	Patient's own	28	4	22	2
	home
	Total	49	8	39	2

Table 4 -

 4 Final diagnoses of discharged nonagenarians*

	Method of	Number of	Diagnosis
	diagnosis	patients
	CT**	4	2 diverticular disease, 1
			cholangiocarcinoma, 1 small bowel
			obstruction
	USS**	5	3 cholelithiasis, 1 pancreatic Ca, 1 normal
	Endoscopy**	2	1 Sigmoid volvulus, 1 colon cancer
	Operation**	1	1 Perforated diverticular disease
	Laboratory	3	3 Pancreatitis
	investigations**
	Plain imaging**	2	1 Pseudo-obstruction, 1 constipation
	Clinical	10	4 uncomplicated hernia, 4 rectal prolapse, 2
	assessment only		haemorrhoids
	Total	27 *
	*14 patients did not have investigations to positively confirm the discharge
	diagnoses (6 non-specific abdominal pain, 4 diverticular disease, 2
	constipation, 1 biliary colic, 1 adhesions)
	** In combination with clinical assessment

Page 15 of 15 International Journal of Clinical Practice International Journal of Clinical Practice

No funding was sought or received.

Conflicts of interest:

The authors confirm that they do not have any potential or actual personal, financial or political interest in the material.


Edzard Ernst

E Ernst

 Moreover, CAM often claims to be holistic, person centred, enabling, relying on observation, self-knowledge, human awareness

Criticism of mainstream medicine

Several of the attractors to CAM can also be seen as an implicit criticism of mainstream medicine. Even our definition of CAM cited above echoes this theme. Defining CAM as "satisfying a demand not met by orthodoxy…" 1 implies that conventional medicine is not perfect and leaves important demands unmet. Similarly, the view that CAM is natural and safe implies that mainstream medicine has neither of these qualities. An Italian study suggested that the main reason for employing CAM was "concern about potential toxicity of conventional medicine". [START_REF] Menniti-Ippolito | Use of unconventional medicine in Italy: a nation-wide survey[END_REF] Stressing that CAM is humane, patient-centred and holistic, implies that conventional medicine is inhumane, technology-centred and reductionist. 31 36 A Germany survey of CAM users showed that 68% of them had negative opinions concerning mainstream doctors, [START_REF] Mitzdorf | Why do patients seek treatments in hospitals of complementary medicine?[END_REF] and a similar UK survey demonstrated that almost all patients consulting a CAM clinic stated that "failure of conventional medicine" was their reason for attending. [START_REF] Moore | Why do people seek treatment by alternative medicine[END_REF] Most of these issues somehow relate to the central theme of therapeutic relationship. [START_REF] Andritzky | Wer nutzt unkonventionelle Heilweisen und was sind die Motivationen?[END_REF] Sixtyeight percent of patients reported a more satisfying relationship with their CAM practitioner than with their GP. [START_REF] Finnigan | The Centre for the Study of Complementary Medicine: an attempt to understand its popularity through psychological, demographic and operational criteria[END_REF] In the eyes of these patients, CAM practitioners were friendlier, more personal, they treated the relationship with their patients more like a partnership and provided more time for the consultation. Similar findings emerged from our survey of UK arthritis sufferers. Satisfaction with the therapeutic encounter was markedly greater with CAM practitioners than with GPs. [START_REF] Resch | Use of Complementary Therapies by Individuals with 'Arthritis[END_REF] Again, satisfaction with the time spent on the patient was higher with CAM practitioners. Similar results were found in a study of Spanish CAM users suffering from somatoform disorder. [START_REF] Garcia-Campayo | The use of alternative medicines by somatoform disorder patients in Spain[END_REF] A comparison of US physician homeopaths with doctors practising mainstream medicine showed that the former dedicated more than twice the time on patient consultations. [START_REF] Jacobs | Patient Characteristics and Practice Patterns of Physicians Using Homoeopathy[END_REF] Surveys from Australia, the UK and the US confirmed the fact that CAM users tend to be dissatisfied with mainstream medicine. [START_REF] Mcgregor | The choice of alternative therapy for health care: testing some propositions[END_REF] , [START_REF] Correa-Velez | Use of complementary and alternative medicine and quality of life: changes at the end of life[END_REF] , [START_REF] Djuric | Why do patients seek therapies based on complementary medicine?[END_REF] , [START_REF] Shahrokh | Elderly herbal supplement users less satisfied with medical care than nonusers[END_REF] , [START_REF] Nayak | The use of complementary and alternative therapies for chronic pain following spinal cord injury: a pilot survey[END_REF] Delegation of core values Such findings imply that patients' requirements for a satisfying therapeutic relationship with their clinician are better met during consultations with CAM practitioners. If that is true, it would explain why many patients seek these qualities when visiting a CAM practitioner.

Patients seem to be aware of the constraints under which mainstream medicine has to operate and thus seek from CAM practitioners what they cannot get from conventional clinicians. To put it bluntly, they might see their doctor for specific therapeutic effects (i.e. the science of medicine) and their CAM practitioner for the non-specific therapeutic effects (i.e. the art of medicine). If that is so, mainstream physicians are in danger of delegating 'the art of medicine' to CAM practitioners.

The way forward

If these assumptions are correct, we should ask whether this "division of labor" is desirable. I have repeatedly argued that the art and science of medicine must not be separated, e.g. 48 ; both are core values for any good healthcare. Such a separation would mean that patients might receive ineffective treatments plus the benefits of a good therapeutic relationship from CAM practitioners or effective therapies plus inadequate therapeutic relationships from conventional clinicians. This would clearly be wrong; it not only means that healthcare is suboptimal but it also implies that patients are at risk. Good healthcare must incorporate both and the art the science of medicine.

To improve the current situation, we should consider ways of maximising the benefits of nonspecific therapeutic effects within the realm of mainstream medicine. A recent systematic review qualitatively synthesised the relevant evidence in relation to cancer care. [START_REF] Schofield | Effectively discussing complementary and alternative medicine in a conventional oncology setting: communication recommendations for clinicians[END_REF] The authors recommended to elicit patients' understanding of their own situation, to respect diversity, to explore relevant details and listen actively to what patients tell us, to respond to their emotions, to respect their beliefs and to provide advice that is based on sound evidence. [START_REF] Schofield | Effectively discussing complementary and alternative medicine in a conventional oncology setting: communication recommendations for clinicians[END_REF] This may not be the full solution to the complex problems, but it seems like a good start.

Conclusion

Complementary and alternative medicine is popular. An analysis of the reasons why this is so points towards the therapeutic relationship as a key factor. Providers of CAM tend to build better therapeutic relationships than mainstream healthcare professionals. In turn, this implies that much of the popularity of CAM is a poignant criticism of the failures of mainstream healthcare. We should consider it seriously with a view of improving our service to patients.

(

  The public's enthusiasm for complementary and alternative medicine amounts to a critique of mainstream medicine Invited MS for Int J Clin Pract)The public's enthusiasm for complementary and alternative medicine amounts to a critique of mainstream medicine

  /ew/2009/CAM-Nov09-11 08/03/2010

JM/PC1/ew/2009/CAM-Nov09-11 08/03/2010 31, 32, 33 and spirituality.[START_REF] Feldman | The use of complementary and alternative medicine practices among Australian university students[END_REF] These claims may be exaggerated or even false but they

JM/PC1/ew/2009/CAM-Nov09-11 08/03/2010


PhD Lisette Van Den Bemt

PhD Tjard R J Schermer

Multicomponent staging indices for COPD in daily patient care: what's the yield? Word count: 1954

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is not fully reversible [START_REF]Global Initiative for Chronic Obstructive Lung Disease (GOLD)[END_REF]. For years the focus of COPD disease management has been to delay the progression of airflow obstruction. However, this mission was rarely successful since the current pharmacotherapy (i.e., inhaled corticosteroids and bronchodilators) does not result in relevant protective effects in terms of lung function decline (2;3). The only way accelerated lung function decline can successfully be prevented is to persuade and support patients to quit smoking. Unfortunately, many patients with COPD are reluctant or unable to do so [START_REF] Anthonisen | The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial[END_REF]. Presently COPD is no longer considered to be almost synonymous to chronic progressive airflow obstruction, but is considered to be a multicomponent disease that involves extrapulmonary effects like decreased exercise capacity and peripheral muscle depletion as well. These extrapulmonary effects of COPD also contribute to the progressive nature of the disease (5;6). Moreover, the levels of functional impairment may differ substantially between patients with COPD who have the same level of airflow obstruction [START_REF] Van Den Bemt | Low body mass index, airflow obstruction, and dyspnoea in a primary care COPD patient population[END_REF]. To be able to translate this present-day understanding of the disease to daily practice requires a multicomponent staging index that produces a 'composite picture' of COPD disease severity (8). In this perspective paper we discuss the latest developments with regard to staging indexes for COPD and their value for primary care.

Six years ago a first prognostic multicomponent staging index for use in COPD patient management was published, the so-called BODE (Body Mass Index, Obstruction, Dyspnoea, and Exercise tolerance) index [START_REF] Celli | The Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity Index in Chronic Obstructive Pulmonary Disease[END_REF]. The BODE index was originally based on an analysis of components that predict prognosis of COPD in terms of mortality, but more recently it has been shown that it also predicts hospitalizations and exacerbations (10;11). After the initial publication of the BODE index various other composite indices that predict COPD prognosis have emerged, like the ADO (Age Dyspnoea Airflow obstruction), the TARDIS (Tayside Allergy and Respiratory Disease Information System) [START_REF] Schembri | A predictive model of hospitalisation and death from chronic obstructive pulmonary disease[END_REF], and CPI (COPD Prognostic Index) indices (13) (Table 1). Although among researchers there is no consensus yet about which index is to be preferred or which scoring weights should be applied for different components [START_REF] Puhan | Expansion of the prognostic assessment of patients with chronic obstructive pulmonary disease: the updated BODE index and the ADO index[END_REF], the multicomponent staging tools -especially the BODE index -have been received with great enthusiasm by health care professionals, and have resulted in renewed optimism about COPD patient management. The notion that not only the level of airflow obstruction is related to prognosis, but that other aspects like exercise tolerance and nutritional status are too may encourage But is this enthusiasm justified? Should researchers who develop these multicomponent staging indices already be recommending their application in daily patient care, or is it too early for that? And, maybe the most important point to consider, should we guide disease management for patients with COPD on an index that predicts disease progression or should we also take current health state into account?

Application of prognostic multicomponent staging indices in COPD care

It has been suggested that the prognostic multicomponent staging indices can be used to select patients that qualify for intensive treatment (e.g., multidisciplinary pulmonary rehabilitation) [START_REF] Puhan | Expansion of the prognostic assessment of patients with chronic obstructive pulmonary disease: the updated BODE index and the ADO index[END_REF].

Except for the BODE index, all prognostic indices mentioned above consist of one or more components that are fixed demographic characteristics which are not directly related to COPD severity (age, gender). Selection of patients for intensive treatment based on these prognostic staging indices presents a fundamental problem: patients are more likely to qualify for intensive treatment just because they are older. It is true that the risk of dying from COPD or other causes increases with age, but should we really 'bother' patients of advanced age with intensive treatment for their COPD just because they are old? We believe that the opposite should be the case, i.e. that younger age combined with an already severe stage of the disease in terms of airflow obstruction and/or functional limitations should justify intensive treatment.

Another concern about selecting patients for intensive treatment based on prognostic indices is that all mentioned indices were developed to predict mortality in COPD patients, although some instruments also reflect the risk of exacerbations or hospital admissions in the near future. Although COPD is one of the leading causes of mortality worldwide, for patients it is first and foremost an incapacitating disease that has a strong negative impact on their daily lives [START_REF] Rennard | Impact of COPD in North America and Europe in 2000: subjects' perspective of Confronting COPD International Survey[END_REF]. Limiting intensive treatment to patients with a high mortality risk will exclude many patients with COPD who experience the progressive nature of this debilitating disease and will continue to do so for many years.

Staging indices could also be used to select specific interventions when the index provides insight in 'alterable' determinants of disease progression. The components of the instruments that are eligible for change are usually related to lifestyle, like improving nutritional status, reducing lung function (outpatient) pulmonary rehabilitation. Even while some promising short term results have been reported with regard to improving exercise tolerance [START_REF] Wetering | Short-and longterm efficacy of a community-based COPD management programme in less advanced COPD: a randomised controlled trial[END_REF], reality is that many COPD patients fail to achieve or maintain these essential lifestyle changes. Even when COPD patients are confronted with their degree of airflow obstruction, this does not result in a higher success rate of a smoking cessation intervention [START_REF] Kotz | Efficacy of confronting smokers with airflow limitation for smoking cessation[END_REF]. The challenge for the upcoming years will be to develop strategies that result in permanent lifestyle changes. This should be a top priority for scientists and health care providers. But even then, it remains to be seen if lowering the 'score' on any staging index wards off the unfavourable future COPD-related events or postpones death.

In contrast, a clear advantage of using the multicomponent staging indices in COPD patient care is that they provide insight in the clinical course of the disease, which is informative for health care professionals (e.g., physicians, nurses, physiotherapists) as well as for patients and their relatives. It should be decided whether or not the value of this prognostic information offsets the efforts and additional medical procedures and costs that are needed to collect the required information. The effort to collect information on the components of the various staging indices varies widely, from just asking some additional (standardized) questions to a six minute walking test. The set up of a walking test track can be a problem when space is limited, like it often is in primary care practices. Therefore, the value of exercise tests -or indices that include the result of such a test -needs to be well established before it should be recommended for use in regular COPD management.

Prognostic multicomponent staging indices in primary care

Based on just their lung function the majority of patients (~80%) is classified as having mild-tomoderate COPD (7;18). It is important to keep in mind that these patients are usually treated by primary care physicians and are not (yet) managed by respiratory specialists. Therefore, the majority of COPD patients are treated in primary care. The current prognostic multicomponent staging indices -except for the TARDIS -have not included primary care COPD patients in their development, and the predictive capacity of the instruments for primary care patients has not been established yet.

Because mortality rates of patients with mild to moderate COPD are generally low [START_REF] Hoogendoorn | Severity distribution of chronic obstructive pulmonary disease (COPD) in Dutch general practice[END_REF], it is questionable if mortality should be the outcome of choice when developing tools to guide treatment of patients in primary care. Moreover, we previously examined the coexistence of three severity components that are often part of prognostic indices (i.e., BMI, level of dyspnoea, and airflow obstruction) in a primary care COPD population [START_REF] Van Den Bemt | Low body mass index, airflow obstruction, and dyspnoea in a primary care COPD patient population[END_REF]. In this population, the spectra of the severity components was strongly skewed toward mild outcomes, and the concurrent occurrence of these components was low. This makes it highly unlikely that the current multicomponent staging indices will be applicable for primary care.

Isn't it time for another approach?

COPD disease management is not only directed towards the prevention of disease progression, but also on the alleviation of manifestations of the disease. All aforementioned multicomponent staging indices predict future events (i.e., are 'prognostic' instruments), while other indices have already been developed to collect information on aspects of the current disease state of the patient. For instance, the COPDSS (COPD Severity Score) index has been shown to be able to discriminate between patients with varying degrees of dyspnoea and numbers of exacerbations [START_REF] Miravitlles | Validation of the COPD severity score for use in primary care: the NEREA study[END_REF]. Moreover, a higher score on the COPDSS was associated with lower quality of life and more impairment in activities of daily live. Another example of an instrument that gathers information about several aspects of COPD and the impact of the disease on a patients' health status is the Nijmegen Integral Assessment Framework (NIAF). This instrument provides a detailed assessment of the health status of a COPD patient, which includes physiological functioning, complaints, functional impairment, and quality of life [START_REF] Vercoulen | An Integral assessment framework of health status in chronic obstructive pulmonary disease (COPD)[END_REF]. Some of the concerns that apply for the prognostic indices also apply to the aforementioned 'health state assessment' instruments. Most importantly, it should be established if these instruments can be used to select specific interventions. Moreover, it is sometimes difficult to make a clear distinction between the different types of instruments, since prognostic instruments may also collect information on current health state and vice versa. However, there seems room for both types of instruments for use in COPD patient care. It can be argued that 'health state assessment' instruments are more appropriate for patients with less advanced COPD because the outcomes that are predicted by the prognostic instruments (i.e., mortality, exacerbations, and hospitalisations) are rather uncommon in a The development of prognostic multicomponent staging indices and health state assessment instruments is an interesting and promising new development in the management of COPD, but several issues need to be addressed before the widespread and possible costly implementation of these instruments in daily patient care can be justified. It is especially important to gain insight in the effectiveness and local availability of disease management options that could be selected based on the outcome of the indices and that result in relevant improvement of the disease state or prognosis of the patient. For instance, if access to pulmonary rehabilitation for COPD patients is not guaranteed the yield of using any multicomponent staging index is very limited [START_REF] Schermer | Prevention and management of chronic obstructive pulmonary disease (COPD) in primary care: position paper of the European Forum for Primary Care[END_REF]. If indices cannot be used to guide COPD disease management, its added value for daily patient care is limited to providing information on the risk for unfavourable events. This seems inappropriate when managing patients with a chronic condition who have to face the consequences of their incapacitating disease today, tomorrow and for years to come. The majority of COPD patients are treated in primary care and many of the selected components and outcomes of the current prognostic indices do not frequently occur in this part of the patient population. It is therefore rather unlikely that these instruments are useful in primary care. The development of prognostic multicomponent indices currently dominates the scientific COPD literature, and outshine the attention for the development of instruments that assess the current disease state (or stage) of patients. In our view COPD patient management decisions should not be based on predicting future clinical events alone, but should also contribute to alleviation of current disease manifestations. 'health state assessment' instruments could be useful for this purpose. Therefore, it may be that we are looking in the wrong direction with the current strong focus on prognostic indices, while many patients with COPD and the professionals who provide the health care for them may benefit from another -or at the least a wider -approach.

  in their efforts to prevent disease progression in their patients with COPD.

  smoking cessation interventions, and improving exercise tolerance through

  the patient population. In patients with advanced COPD both types of instruments could be used side by side, because predicting prognosis as well as assessing health status are indicated.