BREATH ANALYSIS DEVICE

Cross-Reference To Related Applications

This application claims benefit to EP 17386013.1, filed March 24, 2017 which claims the benefit of GB 1607272.0, filed April 26, 2016, which is incorporated by reference in its entirety.

Field of the Invention

This invention relates to a device for measurement of exhaled breath. In particular, but not exclusively, the present invention relates to a portable breath analysis device suitable for use in indirect calorimetry. The invention also relates to a method of analysing a subject's exhaled breath.

Background of the Invention

Exhaled breath analysis has gained a lot of interest during recent years since it is a non-invasive technique that has many promising results. Since ancient times, physicians have been aware of the relationship between the odour of a person's breath and certain diseases. Since then it has been recognised that breath could give insight into physiological and pathophysiological processes of the human body (see, for example, W. Ma, W, Liu X and J. Pawliszyn, "Analysis of human breath with micro extraction techniques and continuous monitoring of carbon dioxide concentration", Analytical and Bioanalytical Chemistry, (2006)).

The human breath is a mixture of inorganic gases (NO, C0 ₂ , CO, nitrogen), volatile organic compounds (VOCs) (isoprene, ethane, pentane, acetone) and other non-volatile substances (isoprostanes, peroxynitrine, cytokines). Generally, the components of human breath have endogenous and exogenous origins and an analysis of their composition can be related to the physiological processes that have taken place as well as to the pathways of ingestion or absorption (see K. Kim, J. Shamin and E. Kabir, "A review of breath analysis for diagnosis of human breath", Trends in Analytical Chemistry, (2012)). As a result, breath can be regarded as a fingerprint of the human health and its analysis has significant medical applications.

Generally, the advantages of breath analysis tests can be identified in their safety and non-invasive nature. The simplicity of breath analysis is particularly interesting for patients who have to monitor their health daily such as patients who are diabetic, have to monitor their urea etc. (G. Guilbault, G. Palleschi and G. Lubrano, "Non-invasive biosensors in clinical analysis", Biosensors and Bioelectronics, (1995)).

As a result, there is a great demand for hand-held devices that can help people monitor their health in a domestic environment. Moreover, one of the major goals of recent medicine is early detection that dramatically increases the chances of a successful treatment, and breath analysis can help in this.

Indirect calorimetry is used to measure the human metabolism by the amounts of 0 ₂ and C0 ₂ that are found in the exhaled human breath. A human's energy expenditure is divided into resting metabolic rate (RMR), physical activities and thermogenesis that is induced by food intake. RMR represents the largest percentage of the total energy expenditure (>75%) (W. McArdle, F. Katch and V. Katch, "Exercise physiology: nutrition, energy and human performance", 7 ^th ed. Lippincott Williams & Wilkins, (2010)). Determining RMR has improved our understanding of the pathophysiology of obesity and it can help patients undergoing weight loss due to malnutrition, especially in intensive care units. Currently RMR is determined by whole body respiratory chambers and metabolic carts but such methods are costly and require trained technicians. Moreover, mathematical models that have been developed for the prediction of RMR fail by a rate of 50% to 70% and are often found to be inaccurate in cases of obesity, anorexia nervosa and other illnesses. Thus, there is a need for an inexpensive, handheld and easy to use device to perform indirect calorimetry measurements and determine accurately the RMR of a person.

Apart from the numerous fitness applications, a hand-held breathalyser that measures the human metabolism also finds use in controlling the diet of obese individuals. Obesity is currently a major problem and a 2014 report by the Health & Social Information Centre reported that only 32.1% of men and 40.6% of women in England have a normal Body Mass Index (BMI) (Statistics on Obesity, Physical Activity and Diet, Health & Social Care Information Center, (2014)). Moreover, obesity is related to type II diabetes, coronary heart disease, different types of cancer (breast cancer, bowel cancer etc.) and stroke according to a report of the National Health Service

(http://www.nhs.uk/conditions/obesity/Pages/lntroduction.asp x accessed on 6 April 2016).

Currently there are just two hand-held breathalysers on the market, sold under the trade names MedGem (by Microlife Medical Home Solutions Inc. of 2801 Youngfield St., Suite 241 Golden, CO 80401, USA) and Breezing (by Breezing, Co. of 2601 N 3rd St, Suite 108, Phoenix, AZ, 85004). The MedGem device measures only the exhaled oxygen in the breath and assumes that the expired carbon dioxide has a constant ratio of 0.85 when compared to oxygen. That of course is only an assumption and, as it is very often not a correct assumption, it leads to erroneous measurements. The MedGem device is unable to measure both 0 ₂ and C0 ₂ on a breath-by-breath basis in order to deliver the required accuracy. In fact, the ratio of exhaled carbon dioxide to exhaled oxygen is defined as the respiratory quotient (RQ) and varies between 0.6 and 1.0. Based on the RQ measured, it can be determined whether the individual burns mainly fat (RQ = 0.7), protein (RQ= 0.8) or carbohydrates (RQ = 1.0). The accuracy of the determination of the RQ is thus very important. The accurate determination of the RQ is a metric equally important to measurement of the metabolism. Measuring both the RQ and the metabolism of an individual enables one to take a more holistic approach to the treatment of the user. Moreover, there are certain information that can be drawn from the RQ, such as the overfeeding or underfeeding of an individual, that the MedGem device is unable to track. Also, by measuring only the exhaled oxygen and neglecting the sensing of the carbon dioxide, the MedGem device cannot determine whether protein, fat or carbohydrates have been metabolised by an individual. Moreover, RQ changes significantly in many medical cases of pulmonary diseases (COPD, asthma etc.) and this restricts MedGem from being used widely in a medical environment. The second device that is currently available in the market place is sold under the trade name Breezing. This device senses both oxygen and carbon dioxide. It uses consumable sensors which is disadvantageous in many settings. It means that each test requires a consumable sensor that costs approximately 5$ (USD). Use of disposable parts is inconvenient and costly. There are many cases in which an individual may need to measure his metabolism / RER numerous times during the day and this of course increases significantly the cost with the Breezing device. Moreover, in clinical settings the cost of such a device again increases significantly because each patient's measurement requires the usage of costly consumables.

Despite the burning need to create a low-cost, hand-held breathalyzer that measures both the human metabolism and the respiratory quotient (RQ) without using consumable components, there is currently no device available with such a specification. The invention described in this patent application solves this problem and is able to measure the metabolism with a gold-standard accuracy.

Summary of the Invention

In a first aspect, the present invention provides a portable breath analysis device comprising: a gas flow pathway for passage of exhaled breath from an inlet to an outlet; a breath sampling bag for collecting exhaled breath, located between the inlet and the outlet and partitioning the gas flow pathway into an upstream portion between the inlet and the sampling bag and a downstream portion between the sampling bag and the outlet; a flow sensor arranged to allow measurement of the gas flow in the upstream portion; and at least one further sensor arranged in the downstream portion to take measurements of the exhaled breath in that portion. The invention allows a sample of multiple exhaled breaths to be collected together and subsequently analysed in a portable, low-cost and convenient manner.

The device may also comprise an exhaust pathway branched from the gas flow pathway at a branching point between the inlet and the breath sampling bag, for the passage of a portion of exhaled breath away from the gas flow pathway. This allows for a portion of each exhaled breath to continue along the gas flow pathway to the sampling bag, while the remainder of each exhaled breath exits the device via the exhaust pathway. By reducing the volume collected from each breath, the presence of an exhaust also allows samples of more breaths to be collected without the sampling bag filling to its capacity too quickly.

The present invention also provides a portable breath analysis device comprising: a gas flow pathway for passage of exhaled breath from an inlet to an outlet; a breath sampling bag for collecting exhaled breath, located between the inlet and the outlet and partitioning the gas flow pathway into an upstream portion between the inlet and the sampling bag and a downstream portion between the sampling bag and the outlet; an exhaust pathway branched from the gas flow pathway at a branching point between the inlet and the breath sampling bag, for the passage of a portion of exhaled breath away from the gas flow pathway; a flow sensor arranged to allow measurement of the gas flow in the upstream portion or arranged to allow measurement of the gas flow in the exhaust pathway; and at least one further sensor arranged in the downstream portion to take measurements of the exhaled breath in that portion.

The device may comprise an interruption means for interrupting fluid connection between the sampling bag and the downstream portion. In this case, the breath sample is collected in the sampling bag and held there by the interruption means, before being allowed to continue to the downstream portion where it is analysed by the sensors. Alternatively, no interruption means may be present, and the sampling bag may be in constant fluid connection with the downstream portion. In this case, exhaled breath collects in the sampling bag and the downstream portion, and only once the desired volume of breath has been collected do the sensors take any measurements of the breath.

Where an interruption means is present, it may be a valve movable between at least a first and second position, wherein in the first position, the sampling bag is in fluid connection with the downstream portion of the pathway, and in the second position, the sampling bag is not in fluid connection with the downstream portion of the pathway. This allows control over the number of breaths to be collected in the sampling bag before analysis by the at least one sensor(s) takes place. Closing the valve to hold the breaths in the sampling bag before analysis allows equilibration of the multiple exhaled breath samples inside the bag before proceeding to the sensors to be analysed.

The device may comprise a carbon dioxide sensor. The device may also or alternatively comprise an oxygen sensor. Preferably, the device comprises both a carbon dioxide sensor and an oxygen sensor and is preferably an indirect calorimeter, to allow a user to use the device for the monitoring of their metabolism. Such a device according to the invention allows the precise measurement of the consumed oxygen and produced carbon dioxide via a fully portable and low-cost device. As both the oxygen consumption and carbon dioxide production are measured by the device, the respiratory quotient (RQ) that determines whether an individual metabolises fat, protein or carbohydrates can be accurately measured. In a preferred embodiment, the device does not use consumables.

The oxygen sensor and the carbon dioxide sensor may for example be arranged for in-line gas measurement. The oxygen sensor and the carbon dioxide sensor may for example be arranged side-by-side in the downstream portion. Alternatively, the oxygen sensor and the carbon dioxide sensor may be arranged in the downstream portion in sequence.

The invention allows the precise measurement of the consumed oxygen and produced carbon dioxide via a fully portable and low-cost device. As both the oxygen consumption and carbon dioxide production are measured by the device, the respiratory quotient (RQ) that determines whether an individual metabolises fat, protein or carbohydrates can be accurately measured, rather than relying on assumptions for fixed values of the RQ. In a preferred embodiment, the device does not use consumables and that reduces the cost of running the device.

Preferably, the device is an indirect calorimeter. Indirect calorimetry is a useful tool for analysing the metabolism of a subject which may be useful for medical reasons, or for diet and lifestyle reasons. Indirect calorimeters have several medical applications in the assessment of diabetes, obesity, anorexia, cardiovascular diseases etc., but existing indirect calorimeters are bulky and cost approximately $30,000. The functioning of a device of the present invention as an indirect calorimeter is thus advantageous as it provides a portable, hand-held indirect calorimeter device that can be used by an individual in a domestic environment.

The oxygen sensor or the carbon dioxide sensor, when present, may be a thermal conductivity detector. This allows measurement of the carbon dioxide and oxygen levels of the exhaled breath by measuring only the thermal conductivity of the exhaled breath.

Whilst in some embodiments the device does not comprise a dehumidifying means, in other preferred embodiments the device may comprise a dehumidifying means positioned along the gas flow pathway. A dehumidifying means reduces the humidity of exhaled breath, which contains a lot of moisture, to reduce condensation on the sensors and thus enable accurate measurements by the sensors. The humidity of exhaled breath can also adversely affect the accuracy of sensor measurements aside from by causing condensation.

The sampling bag of the device may for example comprise such a dehumidifying means. This allows compact incorporation of the dehumidifying means in the device, such that the exhaled breath is dehumidified while it is being stored in the sampling bag.

The device may comprise a pump for drawing exhaled breath from the breath sampling bag along the downstream portion. After being stored in the storage bag, in particular where an interruption means is present, this ensures the exhaled breath passes steadily across the sensors in the downstream portion.

The device may comprise a pump to draw a sample of exhaled breath along the gas flow pathway. The presence of a pump helps to ensure a constant flow rate through the pathway and across the sensors. Where an exhaust pathway is also present, a pump will create a steady flow of a portion of the exhaled breath down the gas flow pathway, while the remainder of the breath passes along the exhaust pathway.

Alternatively, the device may not comprise a pump, and the flow of gases through the sensors can be controlled by the dimensions and configuration of the components of the gas flow pathway and the exhaust pathway, where present; for example, tubes of smaller diameter may be used along the gas flow pathway to reduce the flow rate of the exhaled breath as it passes through the device. Regulation of the flow rate to a steady flow is desirable both to ensure accurate readings of the sensors and that the

dehumidifying means, where present, functions efficiently.

Preferably, the device further comprises a one-way valve positioned between the inlet and the sampling bag, through which gas may pass in a direction from the inlet to the sampling bag only. Such a valve requires a user to breathe out through the mouth and in through the nose, and does not allow the user to inhale by way of the gas flow pathway, in situations where this is desirable. The one-way valve prevents exhaled breath present in the sampling bag from escaping the sampling bag.

The device may also comprise an air circulating means within the sampling bag for circulating exhaled breath collected in the breath sampling bag (and downstream portion where relevant, such as where no interruption means is present). Such an air circulating means creates a flow inside the sampling bag such that the collected exhaled breath in the bag equilibrates more rapidly than would be the case if no fan were present.

The device may further comprise an exhaust valve for the passage of exhaled breath from the interior to the exterior of the breath sampling bag. This allows a certain portion of the exhaled breaths collected in the sampling bag to be released. For example, where it is desired to collect a large number of exhaled breaths, the presence of an exhaust valve allows a portion of the collected breaths to be released so that a bag of extremely large volume does not need to be used.

The device may further comprise a humidity sensor. This allows measurements by the other sensors to be compensated for changes in humidity.

The device may further comprise a temperature sensor. This allows

measurements by the other sensors to be compensated for changes in temperature.

The device may further comprise a pressure sensor. This allows measurements by the other sensors to be compensated for changes in pressure.

The device may further comprise one or more further sensors. This allows the device to measure additional parameters that may be of interest. For example, the device may include a sensor of acetone, nitric oxide, sulphur compounds, pentane, ethanol and/or hydrocarbons. In particular, when a pentane and ethanol sensor are present, oxidative stress may be monitored.

Preferably, the device comprises a microcontroller. The microcontroller carries out the data processing of the device, such as receiving the measurements from each of the sensors, determining the mode to be used from the flow sensor measurements, and may control the interruption means and the exhaust valve. The microcontroller may also power the pump.

Preferably, the device comprises a communication means for communication between the microcontroller and a mobile phone or other device. This allows the user to review the collected data in a convenient and user-friendly manner.

According to a further aspect of the invention, there is provided a method of analysing exhaled breath of a subject comprising the step of the subject breathing into a breath analysis device, wherein the device comprises: a gas flow pathway for passage of exhaled breath from an inlet to an outlet; a breath sampling bag for collecting exhaled breath, located between the inlet and the outlet and partitioning the pathway into an upstream portion between the inlet and the sampling bag and a downstream portion between the sampling bag and the outlet; a flow sensor arranged to allow measurement of the gas flow in the upstream portion; and at least one further sensor arranged in the downstream portion to take measurements of the exhaled breath in that portion.

The present invention also provides a method of analysing exhaled breath of a subject comprising the step of the subject breathing into a breath analysis device, wherein the device comprises: a gas flow pathway for passage of exhaled breath from an inlet to an outlet; a breath sampling bag for collecting exhaled breath, located between the inlet and the outlet and partitioning the pathway into an upstream portion between the inlet and the sampling bag and a downstream portion between the sampling bag and the outlet; an exhaust pathway branched from the gas flow pathway at a branching point between the inlet and the breath sampling bag, for the passage of a portion of exhaled breath away from the gas flow pathway; a flow sensor arranged to allow measurement of the gas flow in the upstream portion or arranged to allow measurement of the gas flow in the exhaust pathway; and at least one further sensor arranged in the downstream portion to take measurements of the exhaled breath in that portion.

It will of course be appreciated that features described in relation to one aspect of the present invention may be incorporated into other aspects of the invention. For example, the first aspect of the invention may incorporate any of the features described with reference to the other aspects of the invention and vice versa.

Description of the Drawings

Figure 1 shows a schematic diagram of a first embodiment of the invention.

Figure 2 shows a schematic diagram of a second embodiment of the invention. Figure 3 shows a schematic diagram of a third embodiment of the invention. Figure 4 shows a schematic diagram of a fourth embodiment of the invention. Detailed Description

According to a first aspect of the invention, the breath analysis device comprises a gas flow pathway for passage of exhaled breath from an inlet to an outlet.

When using the device, a subject breathes into the device at the inlet of the gas flow pathway. Preferably, the entire exhaled breath of the user is led to the gas flow pathway when the user exhales into the device.

To facilitate the user exhaling entirely into the device, the gas flow pathway may include at the inlet a facemask or a mouthpiece, for example.

The device comprises a breath sampling bag along the gas flow pathway, between the inlet and the outlet, and partitioning the gas flow pathway into an upstream portion between the inlet and the sampling bag and a downstream portion between the sampling bag and the outlet. This allows the collection of multiple exhaled breaths in the bag, where they may equilibrate, before being measured by the sensors in the downstream portion (which are discussed further below). The breath sampling bag may be constructed from any suitable material which is non-permeable to gas and not chemically reactive with the gases of the human breath, for example plastic or latex. The volume of the bag used may depend on the number of exhaled breaths it is desired to collect and measure at a time. For example, the bag used may have a volume of between 1 and 6 litres. The sampling bag may be interchangeable in a device with others of a different volume, to allow use of the device with bags of multiple volumes for analysis of different numbers of exhaled breaths.

Preferably, the bag is formed from a material which is deformable such that the bag may be collapsed to a reduced volume when the device is not in use, to allow convenient transport and storage of the device.

The device comprises a flow sensor which in some embodiments is located in the upstream portion and arranged to allow measurement of the gas flow in the upstream portion. The flow sensor may be the only sensor of the device that is located in the upstream portion with all the other sensors, discussed below, located in the downstream portion. When the breath of the user is exhaled into the gas flow pathway of the device, the flow sensor measures the flow rate of the breath, preferably in mL/min. Preferably, the flow sensor measures instantly the entire flow of the exhaled breath. The flow sensor may be a hot film anemometer, a micro-thermal conductivity detector, a thermal sensor element, a thermal mass flow sensor, an ultrasonic transit time flow meter or any other appropriate sensor that can sense rapidly the flow rate of a gas mixture.

The presence of a flow sensor which measures on a constant basis also allows the device to be used as a spirometer. Spirometry is the most common lung function test, which involves measurement of the volume of air inspired and expired by the lungs when a patient blows into a spirometer.

The device also comprises at least one further sensor, in addition to the flow sensor, arranged to take measurements of the exhaled breath in the downstream portion. Exhaled breaths collect in the sampling bag and downstream portion, and are then measured collectively by the one or more sensors in the downstream portion. The one or more further sensors allow measurement of whatever feature of the exhaled breath is desired, for example the concentration of one or more gases. A subject may use the breath analysis device of the first embodiment by holding it in his hands and exhaling from his mouth into the device, via a mouthpiece or facemask when present. When a user exhales into the device, the exhaled breath passes along the gas flow pathway, where its flow rate is measured by the flow sensor, and enters the breath sampling bag. Breaths may also collect at the same time in the downstream portion, or may collect in the sampling bag first before continuing to the downstream portion (as described further below). Once the desired number of breaths have been collected the collected breath is analysed by the one or more sensors present in the downstream portion.

The device may further comprise an exhaust pathway which is branched from the gas flow pathway at a branching point between the inlet and the sampling bag. This allows the fragmental sampling of each breath. When a subject exhales into the device, the exhaled breath enters the gas flow pathway and a portion of the breath continues along the gas flow pathway beyond the branching point. The remainder of the exhaled breath, which does not continue along the gas flow pathway, exits the device via the exhaust pathway. In one embodiment, the exhaust pathway is connected to the gas flow pathway at a branching point by a T-connector. In another embodiment, the T-connector forms part of the exhaust pathway and part of the gas flow pathway itself.

In some embodiments of the invention, the exhaust pathway may also be used for the passage of air to be inhaled; as the subject inhales, ambient air is drawn in the reverse direction to that of the exhaled breath, through the exhaust pathway towards the subject. In alternative embodiments, the user does not inhale through the mouth when using the device, and so ambient air to be inhaled does not pass through the exhaust pathway to the user.

Where the device comprises an exhaust pathway which is branched from the gas flow pathway at a branching point between the inlet and the sampling bag, in some embodiments as discussed above the flow sensor may be located in the upstream portion and arranged to allow measurement of the gas flow in the upstream portion. In some other embodiments, however, the flow sensor may be located in the exhaust pathway and arranged to allow measurement of the gas flow in the exhaust pathway.

Where the device comprises an exhaust pathway, and the branching point in the gas flow pathway is before the flow sensor (i.e. where the flow sensor is located in the exhaust pathway), the flow measurement may take into account the change in flow due to the sampling flow (i.e. the flow of gas to the breathe sampling bag) as well as the flow through the exhaust pathway.

The exhaust pathway may exit to the atmosphere outside of the device, or it may exit to another part of the device or to another breathing apparatus used by the user/patient. This could be a breathing apparatus of an intensive care unit, for example, where metabolism may be monitored because patients could suffer from malnutrition.

The device may also comprise an interruption means for interrupting fluid connection between the sampling bag and the downstream portion. This ensures that, as a user is breathing into the device and the exhaled breaths are collected into the device, the exhaled breaths do not pass into the downstream portion and the sensors until all the desired exhaled breaths are collected. The desired number of exhaled breaths are collected in the sampling bag, since they cannot pass into the downstream portion when the interruption means is closed, where they equilibrate before continuing on to the sensors for analysis when the interruption means is opened.

In alternative embodiments, no interruption means may be present and the sampling bag is instead in constant fluid communication with the downstream portion.

Where an interruption means is absent, the sensors only take measurements of the collected breath once the desired number of exhaled breaths have been collected. In such an embodiment, the sensors may be heated to reduce condensation of the moisture in exhaled breath on them. Alternatively, the breath may be dehumidified by the presence of an alternative dehumidifying means upstream of the sensors, as discussed further below.

The interruption means for interrupting fluid connection between the sampling bag and the downstream portion may be a valve movable between at least a first and second position. In the first position, the sampling bag is in fluid connection with the downstream portion of the pathway, and the exhaled breaths held in the bag may pass through to the downstream portion to be analysed by the sensors. In the second position, the sampling bag is not in fluid connection with the downstream portion of the pathway, and exhaled breaths are prevented from passing into the downstream portion. In some preferred embodiments, the valve is electrically operated for this purpose. In alternative embodiments, the interruption means may be a compressible portion of a tube and it may be operable by the user pinching it closed (to interrupt the fluid connection) and releasing it (to open the fluid connection).

The device may comprise an oxygen sensor arranged in the downstream portion to take measurements of the exhaled breath in that portion. The oxygen sensor may be an electrochemical partial pressure oxygen sensor, a paramagnetic oxygen sensor, fuel cell technology oxygen sensor, a light sensor that uses the fluorescence quenching properties of dye (e.g. a ruthenium based dye), a thermal conductivity detector (preferably a micro-thermal conductivity detector) (as described further below), a metal oxide semiconductor sensor, a polymer sensor or any other sensor type that is able to sense oxygen. As exhaled breaths are analysed collectively, a sensor may be used that has any practically useful response time; it is not essential that the sensors used have an especially low response time.

A carbon dioxide sensor may also be present in the device, and is also arranged in the downstream portion to take measurements of the exhaled breath in that portion. The carbon dioxide sensor may be a non-dispersive infrared sensor (NDIR) that uses the strong and unique infrared absorption of the carbon dioxide in a gas mixture, a metal oxide semiconductor sensor, a solid state sensor that uses a potentiometric measurement, a thermal conductivity detector (preferably a micro-thermal conductivity detector (as described below)), a polymer sensor or any other carbon dioxide sensor. As exhaled breaths are analysed collectively, a sensor may be used that has any practically useful response time; it is not essential that the sensors used have an especially low response time. As mentioned above, either the oxygen or the carbon dioxide sensor of the device may be a thermal conductivity detector, preferably a micro-thermal conductivity detector. This type of sensor is known for its low response time but lacks on selectively detecting oxygen or carbon dioxide in a three gas mixture such as 99% of the human breath (0 ₂ , N ₂ , C0 ₂ ). A micro-thermal conductivity detector measures the thermal conductivity of the gas mixture. Thus if the precise concentration of two of the gases in a three gas mixture is known, then a measurement of the thermal conductivity of the three gas mixture allows the concentration of the third gas component to be calculated. In the case of the human breath the concentration of nitrogen is always constant at 78.08% whereas the concentrations of oxygen and carbon dioxide vary. Thus, if the oxygen concentration is measured by a selective oxygen sensor as described above, and it is known that nitrogen with a concentration of 78.08% is always present in the exhaled human breath, the thermal conductivity of the three gas mixture (nitrogen, oxygen, carbon dioxide) of the exhaled breath can be used to calculate the concentration of carbon dioxide. The same holds when carbon dioxide is measured with a sensor that selectively measures carbon dioxide and the signal of the thermal-conductivity detector is used to calculate the oxygen of the exhaled breath. Thus, a thermal-conductivity detector can be used as the sensor of either oxygen or carbon dioxide.

Alternatively, a thermal conductivity sensor may be used on its own to measure both carbon dioxide and oxygen, when a constant respiratory quotient (RQ) is assumed. RQ is defined as the ratio of oxygen consumed to the carbon dioxide produced by a user.

In some embodiments, a nitrogen sensor may also be present to enhance the accuracy of a thermal conductivity detector used.

In some embodiments, where both an oxygen sensor and a carbon dioxide sensor are present, the oxygen sensor may be positioned upstream of the carbon dioxide sensor in the downstream portion. In alternative embodiments, the carbon dioxide sensor may be positioned upstream of the oxygen sensor.

In some embodiments, the oxygen and carbon dioxide sensors may be separate components. In alternative embodiments, the oxygen and carbon dioxide sensors may be combined as a single unit sensor, capable of sensing both oxygen and carbon dioxide. For example, an array of carbon nanotubes (CNTs) can be used for the simultaneous detection of oxygen and carbon dioxide among other breath biomarkers. In this case the oxygen and carbon dioxide sensor are combined in one array of carbon nanotubes (CNTs).

In some preferred embodiments, the device is an indirect calorimeter. Indirect calorimetry is used to measure the human metabolism based on the amounts of 0 ₂ and C0 ₂ that are found in the exhaled human breath.

In some preferred embodiments, devices of the invention comprise a dehumidifying means for reducing the humidity of an exhaled breath passing through the device. The dehumidifying means is positioned between the inlet and the at least one sensor. Where an exhaust pathway is present, the dehumidifying means is not located solely along the exhaust pathway. It is known that the exhaled breath has a high relative humidity (RH) (often up to 100% RH) and this can lead to condensation forming in the sensors. The sensors used may be less accurate under condensed conditions and this is why the relative humidity of the breath is reduced prior to passage across the sensors.

In some embodiments, the upstream portion comprises a dehumidifying means. Alternatively, or in addition, a portion of the downstream portion which is upstream of the sensors may comprise one or more dehumidifying means. Alternatively or in addition, the dehumidifying means may be located in the breath sampling bag, or the sampling bag itself may comprise one or more dehumidifying means. For example, the bag may have Nafion ^® on its interior surface such that exhaled breath is dehumidified while it is held in the bag.

In one preferred embodiment, the dehumidifying means is a Nafion ^® tube. A Nafion ^® tube is used to dry the exhaled human breath. The exhaled breath is dried as it passes through a series of one or more Nafion ^® tubes along the gas flow pathway and reaches the humidity of ambient air.

Alternative means of dehumidifying the breath may also be used, instead of or in addition to a Nafion ^® tube. For example, in some embodiments, a chamber containing a wet sponge may be located along the gas flow pathway in-line with a further chamber containing one or more chemical substances with the ability to absorb moisture and reduce humidity. Such chemicals may be chosen from, but are not limited to: magnesium perchlorate, Sodium chloride (halite) (NaCI), Calcium chloride (CaCI2), Sodium hydroxide (NaOH), sulfuric acid (H2S04), Copper sulphate (CuS04), phosphorus pentoxide (P205 or more correctly P4O10), silica gel, hydrated salts such as Na2SO4-10H2O, LiBr, LiCI and amines. In such embodiments, the exhaled breath will pass first through the wet sponge where its humidity may rise, and it will then be dried after passing through the chamber of the silica gel, calcium chloride and/or magnesium perchlorate etc.

The dehumidifying chamber containing chemicals may comprise a valve at its inlet and/or a valve at its outlet. Having a valve at both the inlet and the outlet of the dehumidifying chamber would allow the chamber to be closed off when the device is not in use, to prevent ambient air contacting the chemicals and thus prolong the lifetime of the chemicals.

In some embodiments, only the chamber with the chemical compounds could be used (silica gel, calcium chloride, magnesium perchlorate etc.) for drying the breath. In some embodiments, a combination of a Nafion ^® tube, a wet sponge and a chamber with chemical compounds (silica gel, calcium chloride, magnesium perchlorate etc.) may be used. In some embodiments a combination of a Nafion ^® tube and only the chamber with the chemical compounds could be used, without a wet sponge. In some embodiments, only a wet sponge and the chamber of chemical compounds could be used, only the chamber of chemical compounds, or only the Nafion ^® tube.

In alternative embodiments, a dehumidifying means is not present. The sensors may, for example, instead be heated to avoid condensation forming.

In some embodiments, the device comprises a dehumidifying means and the sensors are heated.

In some embodiments, a facemask or mouthpiece is connected to the inlet of the gas flow pathway, and, while the flow sensor proximal section of the upstream gas flow pathway and exhaust pathway may remain in proximity to the mouthpiece or facemask, a length of tubing may form the portion of the gas flow pathway extending from the branching point. In this way, the remainder of the device at the end of the long tube opposite the facemask, flow sensor, proximal section of the upstream gas flow pathway and exhaust pathway may be kept, for example, in a pocket, bag or otherwise strapped to the user, whilst the user is using the device. The facemask may be strapped to the head of the user. In some embodiments, the tubing may comprise the dehumidifying means, for example if the tubing comprises a Nafion ^® tube drying mechanism. Such embodiments may be used in V02 max testing, anaerobic threshold identification and several others fitness applications.

In some embodiments, the device comprises a pump for drawing exhaled breath from the breath sampling bag along the downstream portion, to be analysed by the sensors. A pump assists in ensuring a steady stream of exhaled breath through the sensors.

In some embodiments, the device comprises a pump for drawing exhaled breath along the gas flow pathway. The pump regulates the flow rate through the gas flow pathway to ensure a constant steady flow. Where an exhaust pathway is present, such a pump may, for example, operate to ensure a constant flow of a portion of the exhaled breath is drawn down the gas flow pathway rather than exiting through the exhaust pathway. The pump may operate at a constant flow, drawing through the gas flow pathway a sample of the exhaled breath when it enters the gas flow pathway.

One particularly preferred type of pump for use in devices of the invention is a rotary vane pump, since it can produce a steady flow without causing any turbulence, which is advantageous for accurate measurement by the sensors.

In alternative embodiments, the device does not comprise a pump. In such an embodiment, the gas flow may instead be controlled by the diameter and configuration of the gas flow pathway, and the exhaust pathway where present. For example, tubes of smaller diameter may be used along the gas flow pathway to reduce the flow rate of the exhaled breath as it passes through them. ln some embodiments, the device further comprises a one-way (non-rebreathing) valve positioned between the inlet and the breath sampling bag, through which gas may pass in a direction from the inlet to the breath sampling bag only.

Where a non-rebreathing valve is used, it may be present for example in a mouthpiece or a facemask of the gas flow pathway. In this case, the user must inhale through the nose and exhale through the mouth.

In embodiments where an exhaust pathway is present, the one-way valve may be positioned in the upstream portion, downstream of the branching point of the exhaust pathway and the upstream portion. This allows the user to inhale through the mouthpiece, by way of the exhaust pathway through which ambient air is drawn in towards the user when the user inhales, without collected exhaled breath being removed from the sampling bag. Alternatively or in addition, the one-way valve may be present in the upstream portion, upstream of the branching point, so that a user may not inhale through the device and must, for example, inhale through the nose.

Alternatively or in addition, a one-way valve may be present in the exhaust pathway, to prevent ambient air being drawn in through the exhaust pathway when a user inhales.

Alternatively, the one-way valve may be absent. In this case, the user may inhale and exhale from his mouth while his nose is closed with a nose-clip. In situations where inhaling and exhaling needs to be done through the mouth and this can be achieved by using a mouthpiece or facemask without a non-rebreathing valve.

In some embodiments, the device includes an air circulating means for circulating the exhaled breath collected in the breath sampling bag. This may be, for example, a small pump, fan or any other suitable device that is capable of creating a flow inside the sampling bag in order to accelerate the rate at which the breath in the bag reaches equilibrium.

Alternatively, the device may not include an air circulating means. In this case, the exhaled breath sample inside the breath sampling bag may reach equilibrium by simple diffusion of the gases present. ln some embodiments, the device may include an exhaust valve in the sampling bag, for the passage of exhaled breath from the interior to the exterior of the breath sampling bag. The exhaust valve may allow a fraction of the exhaled breath collected to be removed from the sampling bag. This allows different sampling methods of the exhaled breath. For example, the valve could open to allow 80% of the collected breath to escape, retaining only 20% of the collected sample. Alternatively, the valve could be closed and the entire breath may fill the breath sampling bag.

The presence of an exhaust valve may allow a smaller bag to be used even in situations where it is desired to collect and analyse a large number of exhaled breaths. By retaining only a portion of each exhaled breath, samples of a number of exhaled breaths may be collected without the need to use a very large volume breath sampling bag.

If the exhaust valve is electrically operated, it may be controlled by the microcontroller to determine to what degree it is opened.

In some embodiments, the device includes a barometric pressure sensor, a relative humidity sensor and/or a temperature sensor. The signals of these sensors may be communicated to a micro-controller (discussed further below) in order to compensate for changes in the ambient barometric pressure, relative humidity and temperature. These signals enable the readings of the other sensors present, in particular the oxygen and/or carbon dioxide sensors when present, to be converted accurately into readings of the concentration of the gases in the exhaled breath. The also facilitate the usage of the device in any condition of humidity, any altitudes and in different climates.

The barometric pressure sensor, relative humidity sensor and/or temperature sensor may be arranged to take measurements in the upstream portion or the downstream portion. Preferably, they are arranged to take measurements in the downstream portion.

In some embodiments, one or more further sensors may be present. For example, one or more of an acetone, nitric oxide, sulphur compounds, pentane, ethanol, nitrogen and hydrocarbons sensor may be present in the device. If an acetone sensor is added to the device, the glucose level of a patient can be monitored in a non-invasive way. This is particularly interesting for patients that are diabetic since they need to monitor their glucose level on a day-to-day basis. It is known that the level of acetone concentration that is found in the exhaled breath is correlated to the blood glucose level. However, it is extremely difficult to determine the baseline of an individual's glucose level. In this device, by combining the information gathered about the metabolism level of an individual and/or his respiratory quotient (RQ) with the concentration of acetone that is found in his exhaled breath, it is possible to determine the baseline level by a suitable algorithm.

If a nitric oxide sensor is added to the device of the invention the device can provide information regarding the user's asthma medication. The nitric oxide levels that are found in the breath can give to a physician information about the effectiveness and the dose needed for the asthmatic patient, which can be used to regulate the medication for an asthma patient.

If a sensor that measures sulphur compounds and/or hydrocarbons is added to the device, then information about mouth hygiene and information about mouth odour can be provided to the user of the device.

If a pentane sensor and an ethanol sensor is added to the device, then oxidative stress can be measured.

The one or more further sensors may be arranged to take measurements in the upstream portion or the downstream portion. Preferably, they are arranged to take measurements in the downstream portion.

Preferably, devices of the invention comprise a microcontroller. The microcontroller may be used to power any pump present in the device when the pump is supplied with power from the micro-controller. The microcontroller also carries out the data processing of the device: the flow-rate sensed by the flow sensor, the concentration of oxygen measured in the exhaled breath by the oxygen sensor when present, and the concentration of carbon dioxide sensed by the carbon dioxide when present each create an electrical signal that is communicated to the micro-controller. The microcontroller may control the interruption means, in particular a valve, to determine when the valve should be opened to allow the exhaled breaths to pass from the bag to the downstream portion to be analysed by the sensors. For example, the microcontroller may control the means for interrupting such that the exhaled breaths are released into the downstream portion after a certain number of exhaled breaths have been collected in the breath storage bag.

The flow rate measured by the flow-sensor is translated to an electrical signal which is fed to the micro-controller of the device, which accordingly may, in some embodiments, determine the mode of operation of the device by controlling the interruption means, in particular a valve, as described above. The flow rate measurement from the flow-sensor is supplied to the microcontroller and allows the microcontroller to determine the breathing frequency (breathing rate). Depending on the breathing frequency measured, the micro-controller may control the interruption means to determine whether the device will analyse the user's exhaled breath once a certain number of exhaled breaths have been collected in the sampling bag, for example two exhaled breaths, three exhaled breaths, four exhaled breaths etc. i.e. it selects which mode the device operates in. By synchronising the flow sensor with an electronically operated interruption means in this way, the expired breath sample is then guided either to the sensors in the downstream portion only once the desired sample size has been collected.

The microcontroller may also be used to control the extent to which the exhaust valve in the bag, where present, is open or closed, to control how many breath samples may be collected in the bag at once.

In some preferred embodiments, the device comprises a communication means for communication between the microcontroller and a mobile phone or other external device. For example, the communication means may be a Bluetooth connection via the microcontroller, to enable communication with a mobile phone. The device may be used for remote medical monitoring. The communication means allows data collected by the microcontroller to be sent directly to a remotely located device, for example via the internet. Data collected may be displayed on a computer or, for example, a smartphone application. Alternatively or in addition, a communication means may be a USB connector, a removable memory card, a cable, a wireless unit, an Ethernet shield, or a mobile broadband unit, for example.

The operation of a device of the invention as an indirect calorimeter is based on the determination of the oxygen consumption, carbon dioxide production and the flow rate that can be determined by the exhaled breath of the user. In a preferred embodiment, when a subject exhales into the device, the entire exhaled breath enters the gas flow pathway. Upon entering the gas flow pathway, the entire flow rate of the expired breath is preferably instantly measured.

The exhaled human breath consists mainly (~99%) of nitrogen, oxygen and carbon dioxide. The Haldane transform assumes that nitrogen is physiologically inert. This means that the volume of inspired nitrogen must be the same with the volume of expired nitrogen.

This can be seen from the following equations:

VJFJN ₂ = V _E F _E N ₂ V _I = V _E f-i (1)

F _E N ₂ = 0.99063 - (F _E 0 ₂ + F _E C0 ₂ ) (2)

F _j N ₂ = 0.7808 (3) 0.99063 - (F _E 0 ₂ + F _E C0 ₂ )

0.7808

where: V| = Inhaled flow rate V _E = Exhaled flow rate

F _E N ₂ = Fraction of expired nitrogen

F|N ₂ = Fraction of inspired nitrogen

F _E 0 ₂ = Fraction of expired oxygen

F _E C0 ₂ = Fraction of expired carbon dioxide

Equation 1 describes that nitrogen is inert and the volume of inspired nitrogen is equal to the volume of the expired nitrogen which is the Haldane approximation. Equation 2 describes that the fraction of exhaled nitrogen equals to the 99.063% of the exhaled breath minus the fraction of expired oxygen and carbon dioxide. Equation 3 describes that the fraction of inspired nitrogen equals to 78.08%, which is the percentage of nitrogen in ambient air. Equation 4 is the equation used to calculate the inspired flow rate when the expired flow rate, the fraction of expired oxygen and the fraction of expired carbon dioxide are known from the various sensors in the device.

After entering the upstream portion (in which the flow rate of the expired breath is measured), the whole of the breath (or a portion of the breath where an exhaust pathway is present) continues to the breath sampling bag. This may be assisted by the presence of a pump in the in the upstream portion or the breath sampling bag to draw the breath or a sample of the breath down the gas flow pathway, as described above. The remainder of the exhaled breath, which does not enter the breath sampling bag, exits the device via the exhaust pathway where an exhaust pathway is present.

Along the upstream portion and/or along the downstream portion, the expired breath passes through a series of Nafion ^® tubes, which reduces the humidity of the exhaled breath. The relative humidity of the exhaled breath is reduced through the Nafion ^® tube until it reaches the ambient relative humidity. Alternatively or in addition, Nafion ^® may be present on the interior surface of the breath sampling bag. Alternatively or in addition, the sensors may be heated to prevent condensation of humid breath on them. The microcontroller may determine the extent to which an exhaust valve, where present, is open, and as such how much of the expired breath is retained in the bag.

The flow rate measurement from the flow-sensor is supplied to the microcontroller and may allow the microcontroller to determine the breathing frequency (breathing rate) and to control the interruption means, where present, as described above.

Once a sample of expired breath has passed from the sampling bag through the interruption means, where present, it continues to the downstream portion including the network of sensors of the device. Where an interruption means is not present, exhaled breath collects in both the sampling bag and the downstream portion at the same time. In a preferred embodiment, the sensor network of the device includes a flow sensor, an oxygen sensor, a carbon dioxide sensor, a temperature sensor, a barometric pressure sensor and a humidity sensor. The temperature sensor, barometric pressure sensor and the humidity sensors are used to compensate the measurements of the oxygen and carbon dioxide sensors.

A human's energy expenditure is divided into resting metabolic rate (RMR), physical activities and thermogenesis that is induced by food intake. The device is able to measure the oxygen consumed and the carbon dioxide produced by an individual. By determining the instant flow of the exhaled breath and the fraction of expired oxygen F _E 0 ₂ as well as the fraction of expired carbon dioxide F _E C0 ₂ , the resting energy expenditure (REE) or resting metabolic rate (RMR) in kCal/day of an individual can be calculated through the Weir equation.

REE = 1.44[3.9(VO ₂ ) + 1-1(VC0 ₂ )] (5)

V0 ₂ = V _j F^ - V _E F _E 0 ₂ (6) VC0 ₂ = ½F ₇ C0 ₂ - V _E F _E C0 ₂ (7) where

V| = Inhaled flow rate

V _E = Exhaled flow rate

F|0 ₂ = Fraction of inspired oxygen

F|C0 ₂ = Fraction of inspired carbon dioxide

F _E 0 ₂ = Fraction of expired oxygen

F _E C0 ₂ = Fraction of expired carbon dioxide The inhaled flow rate is calculated by equation (4), as described previously. The fraction of inspired oxygen (F|0 ₂ ) is constant at 0.2005 since it is the fraction of inspired oxygen from ambient air. Similarly, the fraction of inspired carbon dioxide (F|C0 ₂ ) is constant at 0.00039 since it is the fraction of inspired carbon dioxide from ambient air. Thus, the energy expenditure of an individual is calculated by measuring the exhaled flow rate (V _E ), the fraction of inspired oxygen (F _E 0 ₂ ) and the fraction of inspired carbon dioxide (F _E C0 ₂ ).

Apart from the energy expenditure of an individual, it is possible to measure his respiratory quotient that is defined as:

VC0 ₂

^RQ = ToT ⁽⁹⁸ The respiratory quotient (RQ) is usually between 0.7 - 1.0 for aerobic metabolism. When the RQ is closer to the value of 0.7, the user of the device is metabolising fat. Whereas, when the RQ is closer to the value of 1.0, the user is metabolising carbohydrates. The medium value of RQ = 0.8 shows that the user is metabolising protein.

In addition to metabolism by indirect calorimetry, various other functions may be measured by the device. These include, but are not limited to, the calories burned during exercise, in which instance a facemask may be used as part of the primary pathway to facilitate use of the device while exercising. The device may also be used to calculate body mass index (BMI, a measure of the fat-free mass of an individual), may track the history of the user with corresponding software (such as a smartphone application) to draw conclusions about the health status of the user, and may be used as a spirometer.

The operation of the device is conducted through the micro-controller and the data measured can be transmitted to a smartphone or computer for example.

According to a second aspect of the invention, there is provided methods of analysing exhaled breath of a subject comprising the step of the subject breathing into a breath analysis device of the invention, as described above. Example 1

An example of a device according to the invention is shown schematically in Figure 1 as device 100. The device comprises a gas flow pathway 112, which is formed of the upstream portion 112a, the breath sampling bag 104, and the downstream portion 112b. The upstream portion 112a comprises a mouthpiece 101 connected to a flow sensor 102. Flow sensor 102 measures the flow rate of exhaled breath when a user exhales into the mouthpiece. A non-rebreathing valve 103 is also present; air may pass through the valve in a direction from the mouthpiece 101 to the sampling bag 104 only. A user must therefore exhale into the device through the mouth into the mouthpiece 101, and inhale through the nose.

The exhaled breath passes through the upstream portion and enters the breath sampling bag 104. Multiple breaths collected in the sampling bag are equilibrated by the presence of a fan 105 in the sampling bag. A portion of the exhaled breaths are released via the exhaust valve 111 to allow more breath samples to be collected in a bag of smaller volume than would otherwise be required if the entirety of each breath were being collected. The collected exhaled breath is prevented from passing into the downstream portion by the interruption means 113.

Once the desired number of exhaled breaths have been collected in the breath sampling bag, the interruption means is arranged to open the fluid connection between the sampling bag and the downstream portion, allowing the collected exhaled breath to pass from the sampling bag to the downstream portion. The exhaled breath is drawn from the sampling bag by a pump 114.

On its passage along the downstream portion, the exhaled breath passes through a Nafion ^® tube 110 where it is dehumidified before it reaches the sensors.

The exhaled breath then reaches the sensor network, where it is analysed by an oxygen sensor 106, a carbon dioxide sensor 107, and one or more further sensors 108 that may be present.

The measurements from the flow sensor 102 are translated into electrical signals which are delivered to the micro-controller 109. The measurements from the sensor network, including the oxygen sensor 106, the carbon dioxide sensor 107, and the further sensors 108, are also delivered to the micro-controller, which conducts the data processing of the device.

In the embodiment of Figure 2, the device 200, additionally includes an exhaust pathway 215. Exhaled breath entering the device through the mouthpiece 201 passes through the flow sensor 202 where the flow rate is measured, and then reaches a branching point where the exhaust pathway 215 meets the gas flow pathway 212. A portion of the exhaled breath is removed via the exhaust pathway, whilst the remaining exhaled breath continues along the upstream portion 212a of the gas flow pathway. The sample of exhaled breath that is drawn along the gas flow pathway, rather than being removed via the exhaust pathway, is drawn down the gas flow pathway by a pump 216 present in the upstream portion.

In this embodiment, a non-rebreathing valve 203 is present in the upstream portion, downstream of the branching point with the exhaust pathway. Exhaled breath entering the breath sampling bag 204 first passes through the valve. However, the presence of the exhaust pathway allows a user to inhale as well as exhale through the mouthpiece of the device; when the user inhales, ambient air is drawn through the exhaust pathway towards the user, while the presence of the one-way valve prevents air being instead drawn from the sampling bag to the user. Flow sensor 202 measures the flow rate of exhaled and/or inhaled breath when a user exhales and inhales via the mouthpiece.

As the exhaled breath passes through the upstream portion towards the bag 204, it passes through a Nafion ^® tube 210 where it is dehumidified. In an alternative embodiment, the exhaled breath is passed through a chemical substance which can absorb moisture (e.g. a desiccant) to dehumidify the sample of breath.

The embodiment shown does not comprise a fan or an exhaust valve (however alternative embodiments may comprise a fan and/or an exhaust valve). This

embodiment also does not comprise an interruption means (but in an alternative embodiment an interruption means may be present). In this embodiment where no interruption means is present, exhaled breath entering the breath sampling bag 204 also enters the downstream portion 212b at the same time, and the sensors (including the oxygen sensor 206, carbon dioxide sensor 207 and the one or more additional sensors 208) only take measurements once the desired amount of exhaled breath has been collected. The microcontroller 209 operates as described above for Figure 1.

A further example of a device 300 according to the invention is shown in Figure 3. In the device of Figure 3, all the components are the same as in the device of Figure 2 (e.g. mouthpiece 301, non-rebreathing valve 303, Nafion ^® tube 310, pump 316, breath sampling bag 304, oxygen sensor 306, carbon dioxide sensor 307, microcontroller 309), except that the flow sensor 302 is located in the exhaust pathway, i.e. the branching point in the gas flow pathway is before the flow sensor.

A further example of a device 400 according to the invention is shown in Figure 4. In the device of Figure 4, all the components are the same as in the device of Figure 2 (e.g. mouthpiece 401, flow sensor 402, non-rebreathing valve 403, Nafion ^® tube 410, pump 416, breath sampling bag 404, other sensors 408, microcontroller 409), except that the oxygen sensor 406 and carbon dioxide sensor 407 are arranged in series rather than side-by-side. Whilst the present invention has been described and illustrated with reference to particular embodiments, it will be appreciated by those of ordinary skill in the art that the invention lends itself to many different variations not specifically illustrated herein.

Where in the foregoing description, integers or elements are mentioned which have known, obvious or foreseeable equivalents, then such equivalents are herein incorporated as if individually set forth. Reference should be made to the claims for determining the true scope of the present invention, which should be construed so as to encompass any such equivalents. It will also be appreciated by the reader that integers or features of the invention that are described as preferable, advantageous, convenient or the like are optional and do not limit the scope of the independent claims. Moreover, it is to be understood that such optional integers or features, whilst of possible benefit in some embodiments of the invention, may not be desirable, and may therefore be absent, in other embodiments.