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Best practice in primary care pathology: review 12
  1. W S A Smellie1,
  2. C A M McNulty2,
  3. P O Collinson3,
  4. N Shaw4,
  5. R Bowley4
  1. 1Department of Chemical Pathology, Bishop Auckland General Hospital, Bishop Auckland, UK
  2. 2Health Protection Agency Primary Care Unit, Department of Microbiology, Gloucester Royal Hospital, Gloucester, UK
  3. 3Department of Chemical Pathology, St Georges Hospital, London, UK
  4. 4Sowerby Centre for Health Informatics, All Saints Business Centre, London, UK
  1. Correspondence to W S A Smellie, Department of Chemical Pathology, Bishop Auckland General Hospital, Cockton Hill Road, Bishop Auckland, County Durham DL14 6AD, UK; info{at}


  • Funding This work has been supported (in alphabetical order) by the Association of Clinical Biochemists*, Association of Clinical Pathologists*, Association of Medical Microbiologists, British Society for Haematology, Royal College of General Practitioners, Royal College of Pathologists* and the Sowerby Centre for Health Informatics in Newcastle (SCHIN), representatives of whom have contributed to the reviewing process (*these organisations contributed direct funding to support the project start-up). The opinions stated are however those of the authors.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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This is the twelfth in a planned series of reviews to answer a number of questions which arise in primary care use of pathology. Each subject is introduced with a brief summary of the type of information found. While the individual subjects are not related as they cover the disciplines of clinical biochemistry, microbiology, immunology, haematology and cellular pathology, they are designed once completed to form a resource which will be indexed and cover a wide range of the most common primary care laboratory issues, to be made available to users. Where the new UK General Medical Services (GMS) contracts make specific reference to a laboratory test, the indicator or target is appended at the end of the answer.

Antiepileptic drug monitoring (WSAS, IDW)

Concentrations of many of the anti-epileptic drugs (AEDs) can be measured, although only a few of these drugs meet the criteria for effective therapeutic drug monitoring and for those that do, monitoring is usually only recommended in specific situations. These questions cover the more commonly used agents for epilepsy (and do not refer to the use of monitoring of these drugs in situations outside of epilepsy).

When should anti-epileptic drug levels be routinely measured in fit-free stable patients?

  • Routine measurement is not required for any anti-epileptic drugs in fit-free stable patients.

Routine measurement of AEDs is not required in any situation. Measurement is only indicated to answer specific questions.1 Routine AED measurement is not advocated by the National Institute of Health and Clinical Excellence (NICE) guideline for management of epilepsy in adult and children in primary and secondary care2 and the Scottish Intercollegiate Guidelines Network (SIGN) guidelines for adults3 and children.4 These guidelines recommend that AEDs should only be measured ‘if clinically indicated’ (see below) and are likely to influence patient management.5

When should anti-epileptic drug levels be measured?

Box 1 summarises the situations in which therapeutic drug monitoring may be useful. Phenytoin has been highlighted in particular because of its saturation kinetics and lack of predictable dose response. Valproate does not have an established therapeutic range, and so measurement is only of value in cases of suspected overdose or non-adherence. Of the newer agents, the SIGN document specifically indicates that routine monitoring is not necessary for lamotrigine, vigabactrin, gabapentin, topiramate, tiagabine, oxcarbazepine and levetiracetam. While a relationship does exist between blood levels and response for carbamazepine, SIGN does not advocate routine monitoring for this. SIGN comments that the value of plasma AED monitoring in pregnancy is questionable, although again suggests that plasma monitoring may be of use when concern about toxicity or therapy adherence is present, and for adjustment of phenytoin dose.

Box 1 Examples of situations where therapeutic drug monitoring may be clinically useful

  • Detection of non-adherence.

  • Suspected toxicity or overdose.

  • Phenytoin dose adjustment.

  • Management of pharmacokinetic interactions.

  • Specific clinical conditions (eg, status epilepticus, organ failure and pregnancy).

A Cochrane review found no evidence that monitoring of AED levels improved outcome.6

Large changes in lamotrigine concentrations have been described in pregnancy and there may be a possible role for monitoring in pregnancy.7 Therapeutic drug monitoring may also have a possible role as a guide to re-establishing the correct dose after pregnancy if AED doses have been increased during pregnancy.8

All of the guidance however is consistent in recommending that monitoring in general be limited to the specific situations described above.

In relation to dose, what time should anti-epileptic drug levels be measured?

  • At any time for suspected acute toxicity.

  • Generally before the next dose, if levels are being monitored to detect change, as this value produces the most consistent result over time.

  • Most AED levels vary little during the 2–3 h pre-dose.

Measurement of trough concentrations eliminates variation due to individual differences in absorption kinetics. Plasma phenytoin concentrations however vary little over the 24 h period.9 According to a review by Eadie,10 most AEDs which are measured vary little in concentration in the 2–3 h period before dosing, and so some flexibility in blood sampling time may be acceptable, given practical patient constraints.

Sampling times are also governed by the clinical question being answered. If acute toxicity is suspected, in order to obtain a result as quickly as possible, it would be inappropriate to delay sampling. Similarly, if adherence problems are suspected, it would appear logical to take the sample opportunistically rather than introduce a delay during which a patient may take a dose of the drug which may confuse interpretation.

How long after changing a dose should a drug level be measured if necessary?

  • Under normal circumstances, wait until predicted steady state has been reached; if practical, allow some additional time for individual variability.

Predicted steady state times are shown in table 1 (from Eadie's review).10 Carbamazepine, phenytoin and valproate are all subject to autoinduction, over a period of 2–3 weeks after dosage change. Because of its unpredictable kinetics however, phenytoin may be subject to accumulation; if a large rise in serum concentrations is found after an initial test after changing a phenytoin dose, the test should be repeated to ensure further accumulation does not occur.

Table 1

Predicted time to reach steady state in patients without impaired clearance mechanisms

GMS contract indicator: none.

Faecal samples and infectious diarrhoea

These question–answer sets are extracted from the Health Protection Agency (HPA) quick reference guide for infectious diarrhoea.11

Acute diarrhoea can be defined as three or more stools per day for less than two weeks; the sample taking the shape of the collection pot.12 13 Most cases are self limiting and are usually viral; the incidence of infectious diarrhoea in the general population has been estimated to be 20% per year.14 Identifiable pathogens are only found in a small proportion of specimens submitted,15 and it is appropriate therefore to be selective when submitting faecal specimens for microbiology.

When should a faecal specimen be sent for bacteriological analysis?

Patients who:

  • Are systemically unwell requiring hospital admission or antibiotics.

  • Have blood or pus in their stool.

  • Have diarrhoea after foreign travel.

  • Have persistent diarrhoea, suspected as being giardiasis.16

  • Have diarrhoea post-antibiotics or after hospitalisation (Clostridium difficile).

  • Require reassurance to exclude other causes.

Or on specific advice from health protection units:

  • For a suspected public health hazard or outbreak.

  • Family or community outbreaks.

  • Contacts of patients with specific organisms, eg, E coli 157, or in areas with high endemic levels of specific pathogens.

These groups of patients are identified as those at greatest risk of bacterial or parasitic diarrhoea potentially requiring additional treatment other than supportive. Most laboratories will routinely investigate specimens for Campylobacter, cryptosporidium, Escherichia coli 0157, Salmonella and Shigella. Of these, approximately 90% of infections are caused by Campylobacter or Salmonella.

Clostridium difficile is an increasing problem in the community and should always be considered, particularly if the patient has recently received antibiotics or proton pump inhibitors, or been hospitalised.

The microbiological examination of stool specimens is complex, and depending on the clinical history, laboratories may examine for additional pathogens; it is therefore important that samples are accompanied by details of relevant history (systemic illness symptoms; abdominal pain; immunosuppression if present; epidemiological setting; suspected incriminated food; recent foreign travel; recent antibiotics or hospitalisation; residential contacts, eg nursing home; contact with other individuals). Samples sent at the request of community health protection units should be notified as such.

What sample should be sent?

  • A single pea sized specimen (1 ml) is the minimum required for routine investigation.

  • If diarrhoea is recurrent, send three larger (5 ml) specimens taken 2–3 days apart, requesting ova, cysts and parasite analysis.

While a single specimen may be sufficient for bacterial and viral analysis, protozoan cysts are shed intermittently, therefore three specimens are needed for the reliable diagnosis of these infections.17

Faecal samples should not be mixed with urine. Stools should be passed on to a potty container, newspaper or plastic wrap and small scoops of stool should be transferred into the collection pot including scoops from parts of stool which appear bloody, slimy or watery. A detailed patient instruction sheet is available on the HPA website (

Repeat specimens after treatment are usually unnecessary.1

How is a faecal culture result interpreted?

  • The laboratory report will usually list the pathogens detected and those pathogens tested for and not detected.

  • Most laboratories will routinely investigate specimens for Campylobacter, cryptosporidium, Escherichia coli 0157, Salmonella, Shigella and Clostridium difficile. Of these, approximately 90% of infections are caused by Campylobacter or Salmonella.

  • Other enteropathogens which may looked for (depending on history):

    • Noroviruses

    • Rotavirus

    • Giardia lamblia

    • Entamoeba histolytica

    • Vibrio

    • Yersinia enterocolitica

    • Cyclospora

    • Toxin-producing Clostridium perfringens

    • Bacillus cereus

    • Staphylococcus aureus toxin

  • A negative report does not indicate that all pathogens have been excluded.

  • No routine methods are available to detect enterotoxigenic E coli, which is the commonest cause of traveller's diarrhoea.

When is treatment recommended?

  • Most patients with detected pathogens, eg, Salmonella, Shigella and E coli, will not require specific antibiotic treatment unless systemically unwell.

  • Antibiotic therapy has little effect on duration of Campylobacter diarrhoea unless administered early in the illness.18

  • G lamblia and E histolytica infections should be treated.16

  • Local microbiologist advice is recommended before starting treatment, unless specifically recommended by the laboratory report.

Most patients with detected pathogens will not require specific treatment unless systemically unwell or on specific microbiologist or health protection unit advice. Clostridium difficile is an increasing cause of diarrhoea in the community setting. Most patients will have had a recent course of antibiotics or have been hospitalised.

  • C difficile: stop unnecessary antibiotics and/or proton pump inhibitors to re-establish normal flora. Recommended treatment is metronidazole 400 or 500 mg oral three times daily. Seventy per cent of patients respond after 5 days; 94% in 14 days. If severe (characterised by temperature >38.5°C, white cell count >15, rising creatinine or signs/symptoms of severe colitis) or third episode, vancomycin 125 mg oral four times daily 10–14 days is recommended.

Do I send a repeat specimen?

  • Repeat specimens are usually unnecessary except on specific microbiological advice.

GMS contract indicator: none.

Methicillin-resistant Staphylococcus aureus (CAMM)

These question–answer sets are extracted from the HPA quick reference guide for methicillin-resistant Staphylococcus aureus (MRSA) screening in primary care.19 These questions and answers relate to the screening and suppression, but not specific treatment of MRSA, for which local microbiology advice should be obtained.

MRSA colonised patients are at risk of developing infection, particularly of the surgical site, which is associated with increased mortality. The main purpose of screening is to reduce prevalence, limit clinical impact and avoid spread to MRSA free areas.20 These questions and answers relate to the screening and suppression for MRSA carriers but not specific antibiotic treatment of MRSA infection.

Who should be screened for MRSA?

Considerable efforts are being made in the UK to reduce MRSA prevalence and it is usual for all elective surgical patients to be screened prior to admission. In England, since 2009 the Department of Health (DH) has required mandatory screening of all elective admissions and most day cases (unless the day case is not receiving medical or surgical treatment). This will be extended to cover all emergency admissions by 2011. (FAQs for screening of elective patients for MRSA are available on the DH website:

We recommend screening as a minimum in:

  • Patients at high risk of suffering serious MRSA infections (including elective surgery such as joint replacement).

  • Patients being admitted to units with a high prevalence of MRSA.

  • Patients at higher risk of MRSA carrier status due to frequent previous hospital attendance.

  • Patients being readmitted to hospital who have previously tested positive for MRSA.

Patients who do not need screening within the DH guidelines (unless at risk for another reason) include:

  • Ophthalmic day cases.

  • Termination of pregnancy.

  • Radiological patients.

Categories of patients who most justify screening for MRSA are those at risk of suffering severe consequences from MRSA infections, such as those prior to major surgery. Local arrangements vary: GPs may be asked to screen patients as part of a pre-surgical assessment; alternatively, in some trusts screening may be performed in pre-admission clinics or on admission. The prevalence of MRSA is approximately 1% in patients living at home,21 22% in care home residents22 and 40% in S aureus positive blood cultures.23 Most MRSA positive patients are over 60 years old.24 Those at greatest risk have had frequent hospital admissions, past colonisation or are resident in homes or units known to have high MRSA prevalence.25

How should a patient be screened for MRSA?

We recommend:

  • Using a swab moistened with sterile water or saline.

  • Swab anterior nostrils by wiping the swab around the rim of the patient's nose for 5 seconds.

  • Also swab any skin wounds.

Screening should be performed as close to an elective hospital admission as possible, or as an alternative in sufficient time to allow the patient to follow a decolonisation regime with subsequent post-decolonisation screening before elective admission. If this alternative strategy is used, a repeat test at admission may be required in patients coming from an area of high MRSA prevalence (eg, care home) in case interim colonisation has occurred.20

Recommendations on swab sites vary and some trusts ask clinicians to swab nose, throat, axilla, groin and wounds. However, most patients who are positive for MRSA on sites other than the nares are also positive in the nares.26 Most guidelines recommend swabbing both nostrils with the same swab even though it only produces a slight increase in sensitivity.27–30

MRSA should be requested specifically on the laboratory request form; results are generally reported as MRSA isolated or MRSA not isolated. Antibiotic susceptibilities are usually only reported on the first swab sent.

How should MRSA be suppressed?

  • Suppression should ideally take place in the five days before surgery.

  • Treat underlying skin conditions.

  • Remove or replace invasive devices.

  • Systemic treatment should only be prescribed in line with local policies.

  • Admitting wards must always be informed of prior positive MRSA status.

  • If, for some reason, the patient does not receive MRSA suppression treatment in hospital, this should be undertaken on discharge.

Nasal and skin regimens to suppress MRSA are shown in table 2, which is taken from the HPA quick reference guide based on a Cochrane review.31 The instructions are in the right hand column.

Table 2

Methicillin-resistant Staphylococcus aureus (MRSA) suppression regimens

Chlorhexidine may not be suitable for patients with underlying skin disease. Chlorhexidine 4% produces the highest incidence of contact dermatitis.32 Chlorhexidine is applied to all skin, but particular attention should be given to applying it to all moist areas where MRSA is usually found, that is, the axillae, groin and perineum.

Dermatological advice may be required in patients with ongoing skin conditions.

As nasal and skin decontamination may only suppress and not abolish MRSA, admitting wards must always be informed of a patient's status in order to take appropriate preventive and prophylactic actions.

Should patients be screened after treatment?

Units and hospitals vary in their advice about screening for MRSA post-treatment. For most elective screening in England, the DH does not recommend or require re-screening post-treatment.

Testing for MRSA suppression is performed by submitting up to three screens one week apart, starting 48 h or more after completing antiseptic and, where applicable, antibiotic therapy. If suppression fails, further advice should be sought from the hospital infection control service.

What should be done for patients who are MRSA positive when discharged from hospital?

  • Most MRSA positive patients do not require special management.19

  • The DH advises that patients found to be screen-positive but not given suppression/decolonisation before discharge should be given this after discharge if possible.

  • Standard infection control procedures should be followed.

  • The primary management issue is to avoid other patients being contaminated.

  • Clinical procedures in primary care, such as dressings or minor surgery, should be performed at the end of a patient list.

  • Give patients an information leaflet (

What else can be done to reduce the risk of MRSA in patients?

  • It is important for all staff to stringently follow infection control procedures in all patients.

  • Hand hygiene is the mainstay of reducing spread of infection in all healthcare settings.

  • Alcohol hand rub has reduced the incidence of MRSA bacteraemia in English hospitals.

  • Prudent antibiotic prescribing also reduces the acquisition of antibiotic resistant organisms. This includes:

    • avoiding unnecessary antibiotics

    • using delayed antibiotic prescriptions whenever appropriate

    • avoiding first-line use of broad-spectrum antibiotics, including quinolones, cephalosporins and co-amoxiclav.

When and how should treatment with antibiotics be performed?

Table 3 summarises antibiotic treatment of MRSA. Specific advice should be sought from a microbiologist for immunocompromised patients or in those who are deteriorating clinically.

Table 3

Recommended antibiotic regimens to treat methicillin-resistant Staphylococcus aureus (MRSA) (from Health Protection Agency guidance19

GMS contract indicator: none.

Brain natriuretic peptide (POC, WSAS)

Two types of natriuretic peptide are produced by the heart in response to an increase in wall tension in the chambers of the atria and the ventricles: atrial natriuretic peptide (ANP) and B type natriuretic peptide (BNP). They are part of the natural counter-regulatory mechanisms for the rennin–angiotensin system, producing vasodilatation and increasing sodium excretion in the urine. It is now possible for BNP to be measured in the routine laboratory. BNP is initially produced as a prohormone, proBNP. This is then cleaved into the N-terminal portion of the prohormone (NTproBNP) and BNP itself. Both of these can be measured and provide accurate assessment of the amount of proBNP produced.

Clinically, measurement of NTproBNP or BNP is equivalent. Whether NTproBNP or BNP is used will depend on the local laboratory services. There are two differences between NTproBNP and BNP. First, NTproBNP is a much more stable molecule, whereas BNP needs to be measured within 4–24 h (according to method) or the sample stored frozen. NTproBNP can be measured in serum, whereas BNP requires EDTA plasma. This means that measurement of NTproBNP is simpler for a primary care service. Second, measurement of NTproBNP can be performed on a number of instruments and the results harmonised. Values for BNP will differ between different laboratories according to what equipment they have. To avoid confusion, the term NTproBNP/BNP is used when the text refers to either of the methods interchangeably, although assay performances and result action limits differ.

How useful is the NTproBNP/BNP as a predictor of cardiac failure?

We recommend using age-related cut-off values:

  • A low NTproBNP/BNP to exclude heart failure.

  • A greatly raised NTproBNP/BNP to diagnose heart failure.

Intermediary values require further investigation.

All BNP results must be interpreted in the context of the clinical features of the patient. Measurement is supported by NICE,33 appears in the European Society of Cardiology34 guidelines as an initial test to exclude heart failure and is supported by the recent Health Technology Appraisal35 as a rule out test for heart failure.

Reference values of both NTproBNP and BNP are affected by the patient's age, sex and BMI. Values are higher in women than in men, although thresholds for exclusion of heart failure are not sex dependent. A value below the appropriate cut-off for the age of the patient excludes cardiac failure with a very high negative predictive value. Very high values of BNP/NTproBNP do occur in primary care patients and suggest (rule in) a diagnosis of acute cardiac failure. Measurement of BNP/NTproBNP has been shown to be an excellent diagnostic test for both echocardiographically proven systolic dysfunction as well as a clinical diagnosis of heart failure.35 36

There are a range of causes of moderate increase of NTproBNP/BNP (between the rule in and the rule out limits). These may be due to milder grades of heart failure, other forms of cardiac disease, or occasionally other medical conditions. An increased NTproBNP always indicates that there is something wrong with the patient and is associated with a reduced long-term survival.37 All values above the rule out cut-off require further investigation by echocardiography and referral to a heart failure service for assessment. Table 4 shows examples of cut-off values for BNP and NTproBNP.

Table 4

Sample cut-off values for B type natriuretic peptide (BNP) and the N-terminal portion of the prohormone (NTproBNP) in the diagnosis or exclusion of heart failure

What is the role of an ECG as a tool to screen out those who should be sent for echocardiography—how does this tie in with NTproBNP/BNP measurement?

We recommend:

  • ECG and NTproBNP/BNP should be used jointly in the initial assessment of possible heart failure, although NTproBNP/BNP is the superior diagnostic test.

Current guidelines recommend a combination of an ECG and/or measurement of BNP. An entirely normal ECG also has a strong negative predictive value for heart failure. However, when comparing the diagnostic power of the ECG with BNP measurements, the ECG has been found to be inferior in routine clinical practice.36 38 If both tests are normal, heart failure is unlikely. If the NTproBNP/BNP is increased but ECG is normal, the NTproBNP/BNP result should be used to guide further action.

What is the prognostic value of NTproBNP/BNP in established heart failure?

  • NTproBNP/BNP has strong prognostic value, increases correlating with risk of death, whether or not the patient has heart failure.

The magnitude of increase of NTproBNP/BNP is prognostic in patients with cardiac failure and indeed across the entire spectrum of individuals both with39 and without40 cardiac disease. The degree of increase is proportional to the degree of risk of premature death. In a three-year study in primary care patients with suspected heart failure (average age 73 years), values in the fourth decile range of NTproBNP (83–118 ng/l) were found to be associated with a 90% increased risk of hospitalisation for cardiovascular disease, and values in the seventh decile (229–363 ng/l) were found to be associated with an 80% increased risk of mortality after adjusting for potential confounding variables.37

Does the NTproBNP/BNP level fall with treatment of cardiac failure?

  • NTproBNP/BNP levels fall with successful treatment of heart failure, although measurements are not currently recommended to monitor response to treatment.

Successful treatment of heart failure results in a fall in NTproBNP/BNP. Failure of NTproBNP/BNP to fall in response to treatment is associated with a much worse long-term outcome. Studies which have been done which have used measurement of NTproBNP/BNP to both monitor and to direct treatment have shown overall that active treatment to reduce the level of the hormone is associated with a better outcome.41 However, there is currently insufficient evidence to recommend the use of NTproBNP/BNP as the sole means of monitoring treatment. Monitoring should be based on clinical response, together with appropriate monitoring of renal function and electrolytes depending on the drugs used.42

What can cause a greatly increased NTproBNP/BNP in the light of a normal echocardiogram?

  • Heart failure with preserved systolic function.

  • Structural heart disease (eg, valvular or cardiomyopathy).

  • Renal failure.

  • Sepsis.

An increased NTproBNP/BNP indicates atrial and ventricular dysfunction from any cause. Echocardiography is very good at showing impaired systolic function by measurement of the ejection fraction. As well as systolic dysfunction, there may be diastolic dysfunction which is difficult to diagnose on the echocardiogram but also causes a rise in the NTproBNP/BNP. In addition, other causes of cardiac structural dysfunction such as cardiomyopathy or valvular disease, and rhythm disturbances such as atrial fibrillation may cause a rise in BNP/NTproBNP. Renal failure (often with fluid overload) and infective conditions such as pneumonia may also cause a rise in NTproBNP/BNP. Any raised value requires further investigation and explanation as it will be associated with disease involving the heart.

GMS contract indicator: none.


This twelfth review brings the running total of question and answer sets written in order to provide an overview of current advice in use of laboratory tests in primary care to approximately 135. An index of the first 11 reviews is available with the eleventh review.43 They have all used a common search methodology,44 although where recent systematic reviews have been performed, the guidance also relies heavily on the findings of these reviews. For authors wishing to consult the UK General Medical Services contract and related quality and outcomes framework, the guidelines for these can be found in NHS Confederation.45

Take-home messages

  • Most antiepileptic drugs do not require routine monitoring in primary care. The main uses of monitoring are in suspected toxicity or overdose, possible pharmacokinetic interactions, dose adjustment for phenytoin, and specific clinical situations, for example, organ failure.

  • The main groups of patients in whom stool culture is indicated in primary care are those at greatest risk of bacterial or parasitic diarrhoea, potentially requiring additional treatment other than supportive.

  • The main purposes of methicillin-resistant Staphylococcus aureus (MRSA) screening in primary care are to reduce prevalence, limit clinical impact and avoid spread to MRSA-free areas.

  • The main role of B type natriuretic peptide in primary care at present is to rule out heart failure to avoid the need for echocardiography, although further potential uses are emerging.


We are most grateful to Mrs Gillian Eddleston for helping to prepare this manuscript, and to the following people who kindly reviewed the work: Dr J Cabrera-Abreu and Dr WG Simpson (Association for Clinical Biochemistry), Professor R Gama and Dr WA Telfer Brunton (Association of Clinical Pathologists) and Dr N Campbell (Royal College of General Practitioners).


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  • Funding This work has been supported (in alphabetical order) by the Association of Clinical Biochemists*, Association of Clinical Pathologists*, Association of Medical Microbiologists, British Society for Haematology, Royal College of General Practitioners, Royal College of Pathologists* and the Sowerby Centre for Health Informatics in Newcastle (SCHIN), representatives of whom have contributed to the reviewing process (*these organisations contributed direct funding to support the project start-up). The opinions stated are however those of the authors.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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