Future Trends in NHS

The future of health care is often conceptualised in terms of improved treatments emerging from the bio-medical science base – for instance increasing the precision with which particular therapies can be targeted. Many of these advances in the effectiveness of care will have supply side consequences in terms of cost and some will require service re-configuration – regenerative medicine and bed-side diagnostics, for example. However the larger challenges are likely to originate from increased demand. The service will have to adapt to these supply and demand side changes. This blog considers the role of applied research in informing these adaptations in order to improve the overall effectiveness and efficiency of services.

We discern three trends which, absent a major perturbation such as international conflict, will alter demand over the medium to long term. The time horizon for our analysis is the next quarter century, given that the longer the time horizon the wider the variance in any predictions.

The trends are as follows:

  1. The population demographic will continue towards higher proportions of elderly people.
  2. The dependency ratio (ratio of working age to young and retired people) will become increasingly adverse.
  3. Demand for services per capita will increase.

None of these assumptions is unarguable as they involve outcomes that have not yet been observed. They are ordered from least to most contentious.

  1. That the population will continue to age is almost a given, but the rate at which it will do is less certain. Some predict that over a third of children alive now will reach a century. However, the rate of increase in life expectancy may slow as the large reductions in smoking related deaths are absorbed into the base-line. Immigration could affect population projections in ways that are hard to predict. The recent sudden increase in mortality among white middle-aged males in the USA,[1] but improvement in survival of low socio-economic group children in the same country,[2] shows how difficult projections can be. A recent demonstration of trends over two decades suggests that age-specific prevalence of dementias are reducing, arguably because risk factors for cardiovascular disease are also risk factors for dementia. This will not reduce the total prevalence of dementia, of course, if life expectancy continues to increase.[3] [4]
  2. The worsening of the dependency ratio is almost a corollary of an ageing society, but again the extent to which this happens is less certain as the work force gradually internalises the notion that 65 years of age is not a biological watershed but a social convention.[5] But delayed retirement will not solve the problem of a deteriorating dependency ratio; absent a method to delay ageing, many types of work, such as aviation and mining, are simply not suitable for older people. In addition, as people work longer at the end of life; so policies are encouraging longer leaves of absence from work outside the home to care for young children. So, all things considered, the dependency ratio will become more adverse as a function of increased longevity. Note, Britain appears to be at an earlier stage in this transition than many other high-income countries, such as Japan and Germany, and the opportunity for immigration to mitigate the tendency is likely to be accentuated given recent events.
  3. Demand for services contingent on an ageing population is somewhat controversial. A reasonable planning assumption is that people will be healthier at a given age but this will not completely mitigate the frailty of older people at a given age. In that case we must assume a rise in demand as the population ages, even if age-specific morbidity declines to some extent.

Implications for the NHS flow from the above. Demand for services will increase relative to resources. That is to say there will be more old people relative to working age people and there will be more frail people relative to the population and demand will outpace economic growth. All of this may be compounded by a tendency for old people to live in remote areas at a distance from major conurbations where health services are concentrated. However, this problem will be less acute than in most other countries.

There are many possible mitigations and the NIHR has a role in all of them; these are listed in the table below.

Factors to help the service cope with increasing demand.

                  Mitigating factor How it might work Caveats Potential impact
Major technical advances that might affect demand. A ‘cure’ or prevention for dementia would both improve the economy (and hence supply) while supressing demand. Probably lies outside our 25 year time horizon. Will prolong life and hence increase the proportion of frail elderly people. Potentially very high but out of scope. Medical advances more generally likely to increase demand by increasing longevity.
Self-care An ‘extreme’ form of skill substitution. Unlike other mitigations there is an extensive research literature. Beneficial for capable patients minimal impact on global demand. The correct answer to improving care, reducing demand will require development of interventions and further research.
Information technology Can make care safer and supply more efficient. Full electronic notes disrupt patient communication in their current form. A lot more needs to be learned about the design and implementation of this deceptively complex technology. Huge benefits in prospect but the socio-technical aspects require extensive development and research.
Robotics May substitute for expensive/scarce human resources.[6] Humans require the care and attention of other humans. Moderate. Likely to assist rather than replace clinical input.
Skill substitution Less expensive staff (physician’s assistants) substitute for more expensive (doctors). Increasingly feasible as health care increasingly codified. Limited by the complexity of decision making in patients with many diseases. Very hard to say without more research. May be modest.
Pro-active community services Prevent deterioration to improve health and decrease admissions. Existing research disappointing – may actually increase demand by identifying self- correcting illness. Potentially great but we are in the foothills of discovery.

Mitigating demand is not easy in the face of the demographic factors mentioned above. It is often argued, even in official enquiries, that prevention is the key to reducing demand. While prevention may reduce demand arising from particular diseases, such as diabetes, survivors go on to develop further diseases on their trajectory to death.[7] It is therefore not at all clear that prevention will reduce total demand and it may even be the case that deferred demand is augmented demand. There are some potential mitigating possibilities. A prevention or cure for Alzheimer’s disease would make a massive difference. Less distant is an ‘artificial pancreas’ that might massively simplify diabetes care. Methods to make people independent, such as home telemetry, have had nugatory impact on demand to date,[8] but this may change in the future. Patient self-care is beneficial in improving healthcare and satisfaction,[9] but effects on total demand have been modest.

If supply side measures might help services cope with the consequences and demand continues to rise, then two points should be noticed. First, efficiency gains are notoriously difficult to achieve in service industries. Second, the likely increasingly adverse dependency ratio is likely to limit expansion in skilled staff. Partial solutions may lie in manufacturing, including robotics and information technology. Skill substitution is a future area where it may be possible to improve efficiency.[10] In particular, physicians assistants may reduce costs overall.[11] The research for skills or system substitution is not entirely positive – for example, substituting nurses for doctors may not improve efficiency because consultation times had to increase.[12] There is an international trend to provide more care at ‘grass roots’ by means of Community Health Workers (CHWs) – an area where high-income countries are learning from low- and middle-income countries.[13] CHWs have a large potential role in improving care – helping patients to adhere to medications, providing preventative services, identifying deteriorating patients. Their effect on reducing demand is less certain, and on occasion they may actually increase it.[14]

Readers may think that the CLAHRC WM Director can be rather pessimistic, even nihilistic. Not so, CLAHRC WM has recently conducted an overview (umbrella review) across 50 systematic reviews of different methods to integrate care across hospitals and communities.[15] Discharge planning with post-discharge support is highly effective. Multi-skill teams are much more effective if they include hospital outreach than if they are entirely community-based. Self-management is effective but mainly for single diseases. Case management is of minimal value. Across all intervention types, length of stay was reduced in over half, emergency admissions were reduced in half, and readmissions were reduced in nearly half. In almost no case did the intervention make any of the above outcomes worse. Costs to the service were reduced in over a third of intervention types, but the quality of evidence is poor on this point – a topic that is being addressed across all CLAHRCs. And here is the CLAHRC WM Director’s point; there are no quick wins and no silver bullets. And the solutions are not self-evident. Only by patiently trying out new things and evaluating them methodologically can things improve. It may sound self-serving, but that does not mean it is incorrect – CLAHRCs have an immense contribution to make to improve the effectiveness and cost-effectiveness of health services.

— Richard Lilford, CLAHRC WM Director

I acknowledge advice from Prof Peter Jones (University of Cambridge), Director of CLAHRC East of England, but the views expressed are entirely my own.

References:

  1. Deaton A, Lubotsky D. Mortality, inequality and race in American cities and states. Soc Sci Med. 2003;56(6):1139-53.
  2. Chetty R HN, Katz LF. The Effects of Exposure to Better Neighbourhoods on Children: New Evidence from the Moving to Opportunity Experiment. Am Econ Rev. 2016.
  3. Matthews FE, Stephan BC, Robinson L, Jagger C, Barnes LE, Arthur A, Brayne C; Cognitive Function and Ageing Studies (CFAS) Collaboration. A two decade dementia incidence comparison from the Cognitive Function and Ageing Studies I and II. Nat Commun. 2016; 7: 11398.
  4. Matthews FE, Arthur A, Barnes LE, Bond J, Jagger C, Robinson L, Brayne C; Medical Research Council Cognitive Function and Ageing Collaboration. A two-decade comparison of prevalence of dementia in individuals aged 65 years and older from three geographical areas of England: results of the Cognitive Function and Ageing Study I and II. Lancet. 2013; 382(9902): 1405-12.
  5. Lilford R. Robotic hotels today – nursing homes tomorrow? NIHR CLAHRC West Midlands News Blog. March 6 2015.
  6. Lilford R. Medical Technology – Separating the Wheat from the Chaff. NIHR CLAHRC West Midlands News Blog. February 26 2016.
  7. Lilford R. Improving Diabetes Care. NIHR CLAHRC West Midlands News Blog. November 11 2016.
  8. Henderson C, Knapp M, Fernández J-L, Beecham J, Hirani SP, Cartwright M, et al. Cost effectiveness of telehealth for patients with long term conditions (Whole Systems Demonstrator telehealth questionnaire study): nested economic evaluation in a pragmatic, cluster randomised controlled trial. BMJ. 2013; 346: f1035.
  9. Tricco AC, Ivers NM, Grimshaw JM, Moher D, Turner L, Galipeau J, et al. Effectiveness of quality improvement strategies on the management of diabetes: a systematic review and meta-analysis. Lancet. 2012; 379: 2252–61.
  10. Lilford R. The Future of Medicine. NIHR CLAHRC West Midlands News Blog. October 23 2015.
  11. Lilford R. Improving Hospital Care: Not easy when budgets are pressed. NIHR CLAHRC West Midlands News Blog. January 23 2015.
  12. Laurant M, Reeves D, Hermens R, Braspenning J, Grol R, Sibbald B. Substitution of doctors by nurses in primary care. Cochrane Database Syst Rev. 2005; 2(2).
  13. Lilford R. Lay Community Health Workers. NIHR CLAHRC West Midlands News Blog. April 10 2015.
  14. Roland M, Abel G. Reducing emergency admissions: are we on the right track? BMJ. 2012; 345: e6017.
  15. Damery S, Flanagan S, Combes G. Does integrated care reduce hospital activity for patients with chronic diseases? An umbrella review of systematic reviews. BMJ Open. 2016; 6: e011952.

Business Schools Collaborate on Large Cluster RCT

CLAHRC WM News Blog readers know that we like to find interesting examples of RCTs outside healthcare. How about randomising small- and medium-size enterprises (SMEs) to different types of industrial policy. Business school colleagues have done just that, and randomised over 200 firms to receive an industrial policy intervention consisting of a voucher and some help or control.[1] Curiously it is quite hard from the paper to work out exactly how many firms were randomised in this parallel group, cluster RCT. There is no CONSORT type diagram. They call the study an RCT+, to signify that the study included in-depth qualitative studies to better understand pathways to success or failure. Our CLAHRC collaborates with one of the business schools involved (Warwick Business School) and we thoroughly applaud combining mixed methods research within the framework of large RCTs, especially in the usual situation where results are partly context dependent.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Bakhshi H, Edwards JS, Roper S, Scully J, Shaw D, Morley L, Rathbone N. Assessing an experimental approach to industrial policy evaluation: Applying RCT+ to the case of Creative Credits. Research Policy. 2015; 44: 1462-72.

Does Being a Guide or Scout as a Child Promote Mental Health in Adulthood?

The CLAHRC WM Director heard of this report on the radio and read the paper by Dibben, et al. with interest.[1] The study is based on nearly 10,000 fifty year old people from the 1958 birth cohort – the National Child Development Study. Twenty-eight percent had participated in the Guides or Scouts as children, and they scored highly significantly better on the Mental Health Index than those who did not. The standard deviation is not given, so it is hard to judge how important this is. However, the odds of a score indicative of a clinical disorder was 18% lower in the Guide/Scout group. The authors adjusted for the obvious confounders, of course, but the CLAHRC WM Director was worried that the differences between ‘intervention’ and ‘control’ group are much wider when the social class of the father was low – a small amount of residual confounding would eliminate the difference. That said, the results are consistent with other literature; exercise, contact with nature, and social interaction have all been individually shown to be associated with better mental health outcomes in children. Could this all result from systematic bias across all studies resulting from confounders hidden from view?

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Dibben C, Playford C, Mitchell R. Be(ing) prepared: Guide and Scout participation, childhood social position and mental health at age 50 – a prospective birth cohort study. J Epidemiol Community Health. 2016. [ePub].

Does Use of e-Cigarettes Increase Quit Rates in People Trying to Stop?

CLAHRC WM News Blog readers know that we have been following the literature on e-cigarettes. In a recent post we said that the jury is still out on whether they (e-cigarettes) improve quit rates. We, the jury, are filing back in and it looks as though e-cigarettes do indeed increase quit rates, other things being equal.[1] The authors piggy-backed these observations on ongoing studies of smokers.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Beard E, West R, Michie S, Brown J. Association between electronic cigarette use and changes in quit attempts, success of quit attempts, use of smoking cessation pharmacotherapy, and use of stop smoking services in England: time series analysis of population trends. 2016; 354: i4645.

Financial Crisis and Health

The gradual improvement in health across Europe was not perturbed by the financial crisis of 2008, and the effect on suicide is unclear, but there may be a slight increase.[1] The studies were generally of indifferent quality, however. People in the Second World War were generally healthy unless they got shot. In countries that are already rich a temporary drop in GDP is bearable. People who lose their jobs are obviously at risk of deterioration in mental health, but employment rates held up in many countries, even those like the UK and Ireland that had a big recession compared to others.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Parmar D, Stavropoulou C, Ioannidis JPA. Health outcomes during the 2008 financial crisis in Europe: systematic literature review. BMJ. 2016; 354: i4588.

Physics and Chemistry and Mystical Thinking

The poor CLAHRC WM Director encounters mystical types who believe in all manner of paranormal and supernatural phenomena. Sometimes, such people are borne to high positions in society. Do they have two mind-sets; being able to understand maths, physics and biology, and also believing in mystical things? Or are the two ways of thinking broadly incompatible? The latter according to Lindeman and Svedholm-Häkkinen.[1] In an interesting article they correlate mathematical ability and knowledge of biology and physics with results of a supernatural belief scale – yes one does exist. Sure enough, the better a person’s knowledge of the physical world, the lower their belief in the supernatural. Which way round cause and effect is working is not entirely clear. But ancient people who know no physics and chemistry tend to have strong supernatural beliefs, so the CLAHRC WM Director hypothesises that education really does dispel nonsense thinking.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Lindeman M, & Svedholm-Häkkinen AM. Does Poor Understanding of Physical World Predict Religious and Paranormal Beliefs? Appl Cognit Psychol. 2016; 30: 736-42.

Let the Second Sanitary Revolution Begin

Despite the gains in recent years, far too many children still die before their fifth birthday. Childhood mortality in low income countries is 76 per thousand live births compared with 7 per thousand in high income countries.[1] Now that pneumococcal vaccine is in a widespread use we may expect diarrhoea to take over from pneumonia as the number one killer of children. Certainly in slums – soon to be home to over 1 billion people – diarrhoea is the greatest threat not just to life, but also to child health. Diarrhoea predisposes to chronic enteropathy, especially in malnourished children, which in turn predisposes to stunting and perhaps reduced cognitive development.[2]

But it does not have to be this way. The first ‘sanitary revolution’ in the second half of the 19th century in Europe and North America yielded massive gains in child survival.[3] Less than 4% of all development assistance has been allocated to urban water and sanitation improvement over the last few decades, according to Prof David Satterthwaite. Moreover, it is not as though Europe and America were awash with money; the per capita GDP of Britain in the 1860s ($703.1)[4] was roughly equivalent to that of Rwanda today ($697.3).[5] This suggests that a lack of political will is also to blame for poor sewage and water installations in modern day slums. And the pitiful state of sanitation in modern slums has been thoroughly documented.[6] Hardly surprisingly, improving sanitation is the number one priority for people who live in slums.[7] Water and sanitation is not a middle-class concern foisted on slum dwellers; it is a critically important issue that results in millions of child deaths and that local people want tackled.

There are of course barriers to tackling this problem relating to relative powerlessness of people in slums, poor local governance, immature financial markets, and so on. But there is another problem that is created entirely by a certain type of armchair academic – this is the pernicious idea that nothing can be done pending improvements in local and national governance. Such people argue that it is first necessary to improve security of tenure, functioning financial markets, and so on. An extension of this argument, for which empirical support is absent, is that water and sanitation is not enough; it must be part of an improvement in the whole slum ‘nexus’ to include solid waste disposal, street drainage, home improvement, etc. We cannot wait for extractive elites to disappear, the judiciary to be made independent, or every slum holder to achieve title before acting; Paris famously installed a functioning sewage system during the dictatorship of Napoleon the third following his coup d’état. Fortunately water and sanitation was prioritised at a recent WHO Technical Working Group on “Addressing Urban Health Equity Through Slum Upgrading” attended by the CLAHRC WM Director.

So, let the water and sanitation revolution begin. Let it be driven by political and social zeal but do not let it be undisciplined, and let us never forget that water and sanitation is a socio-technical innovation – it needs to be supported (ideally initiated) by local people themselves. Ensuring proper use and maintenance of sanitary facilities requires alignment of supply and demand.

A number of international organisation promote water and sanitation in low- and middle-income countries, for example the UN-HABITATs Water and Sanitation Trust Fund. But good intentions are not enough when it comes to sanitation – even where sanitation and water have been improved, the benefits on health are often nugatory.[8] [9] This is because the installations are inadequate, and/or because facilities are underused or poorly maintained. It is thus crucially important that interventions meet local needs, that they can be maintained, and that their effects in reducing exposure to infection and improving health are evaluated. Installation of improved water and sanitation utilities needs to be accompanied by research into how to make this socio-technical intervention work well and also summative evaluation of the effects on health and well-being.

— Richard Lilford, CLAHRC WM Director

References:

  1. World Health Organization. Under-five mortality. WHO, 2016.
  2. Grantham-McGregor S, Cheung YB, Cueto S, Glewwe P, Richter L, Strupp B. Developmental potential in the first 5 years for children in developing countries. Lancet 2007; 369: 60–70.
  3. Szreter S. The Population Health Approach in Historical Perspective. Am J Public Health. 2003; 93(3): 421-31.
  4. Broadberry S, Campbell B, Klein A, Overton M, van Leeuwen B. British economic growth and the business cycle, 1700-1870. 2011. Working Paper.
  5. The World Bank. GDP per capita (current US$). 2016.
  6. Ezah A, Oyebode O, Satterthwaite D, et al. The history, geography, and sociology of slums and the health problems of people who live in slums. Lancet. 2016. [ePub].
  7. Parikh P, Parikh H, McRobie A. The role of infrastructure in improving human settlements. Urban Design Planning, 2012; 166; 101-18.
  8. Wolf J, Prüss-Ustün A, Cumming O, et al. Assessing the impact of drinking water and sanitation on diarrhoeal disease in low- and middle-income settings: systematic review and meta-regression. Trop Med Int Health. 2014; 19(8): 928-42.
  9. Fewtrell L, Kaufmann RB, Kay D, Enanoria W, Haller L, Colford JM, Jr. Water, sanitation, and hygiene interventions to reduce diarrhoea in less developed countries: a systematic review and meta-analysis. Lancet Infect Dis. 2005; 5(1): 42-52.

Accountable Care Organisations

Accountable Care Organisations have been introduced in many settings in the USA. Evaluations are few and far between, but a recent overview [1] finds that while they do not save money, they are associated with improved processes of care (e.g. increased rates of cancer screening), and intermediate outcomes (e.g. HbA1c and blood pressure in people with diabetes). Attempts to create something similar in the UK by merging hospital and primary care budgets are underway in England, notably in Manchester. Before and after studies, such as those typically used in evaluations, are prone to exaggerate effectiveness of quality improvement initiatives,[2] thanks to the rising tide phenomenon.[3] Moreover, merging budgets is not the only way to improve coordination of care across providers, as discussed in a previous post.[4] That said, merged budgets do align provider financial incentives with patient need and core professional values, and we have not reached the end of history on this topic – not nearly.

— Richard Lilford, CLAHRC WM Director

References:

  1. Song Z, Fisher ES. The ACO Experiment in Infancy – Looking Back and Looking Forward. JAMA. 2016; 316(7): 705-6.
  2. Eccles M, Grimshaw J, Campbell M, Ramsay C. Research designs for studies evaluating the effectiveness of change and improvement strategies. Qual Saf Health Care. 2003; 12: 47-52.
  3. Chen YF, Hemming K, Stevens AJ, Lilford RJ. Secular trends and evaluation of complex interventions: the rising tide phenomenon. BMJ Qual Saf. 2015. [ePub].
  4. Lilford RJ. Polycentric Organisations. NIHR CLAHRC West Midlands. 25 July 2014.

A Fascinating Account of the Opening Up of an Area of Scientific Enquiry

News Blog readers may have seen previous posts on synaptic pruning.[1] Synaptic pruning involves the elimination of synapses with weak connections between brain neurons. Pruning is especially exuberant after periods of rapid neuronal multiplication (in mid-gestation, around the age of two years, and in late adolescence). Over-exuberant synaptic pruning is associated with schizophrenia. It may also play a crucial role in degenerative brain diseases, such as Alzheimer’s, and in people with memory loss after West Nile fever. The biochemical trigger arises from products of the complement cascade. Astrocytes induce neuronal cells to make the protein C1q, which triggers the complement cascade in neurons. Complement factors, such as C3 attach to weak synapses, and micro-glia (the macrophages of the brain) then ingest the tagged synapses. This process can be visualised by staining living brain cells – bits of synapse end up in the micro-glia. A genetic predisposition to over-express certain complement components increases the risk of schizophrenia markedly, as reported in a previous post.[2] As brains age C1q levels increase four-fold, and this likely predisposes to degenerative diseases, such as Alzheimer’s. Drugs to dampen down this cascade are entering clinical trials. For a lively account if the human story behind one of the leading scientists involved in unravelling this story, see an article by Emily Underwood.[3]

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Psychiatry Comes of Age. NIHR CLAHRC West Midlands. 11 March 2016.
  2. Lilford RJ. Molecular Diagnostic Testing, Including Whole-Exome Sequencing, in Children with Autism Spectrum Disorder. NIHR CLAHRC West Midlands. 23 October 2015.
  3. Underwood E. This woman may know a secret to saving the brain’s synapses. Aug 18 2016.

Did You Ever Want to Know What Bugs Were Actually in Diarrhoea?

Maybe not, but the CLAHRC WM Director is fascinated by stool and its contents. He shares this scatological interest with the 51-odd authors of the Global Multicenter Enteric Study who collected stool specimens from 9,439 children with diarrhoea, and no less than 13,129 control children.[1] Then they used quantitative PCR (polymerase chain reaction) to analyse the samples. Children in low- and middle-income countries (LMICs) often harbour asymptomatic enteropathogens. However, there was evidence that the level of pathogen-derived nucleic acid could distinguish between infection and asymptomatic shedding.

The authors found:

  1. Types of organism that were highly prevalent with strong quantity-dependent associations with symptoms – these include rota-virus, adenovirus 40/41, Shigella spp, Cryptosporidium spp, and some types of E. coli.
  2. Organisms like Salmonella spp, norovirus, V.  cholerae, and E. histolytica that showed strong quantitative associations with diarrhoea, but which had low prevalence.
  3. Organisms, such as various Campylobacter spp and other types of E. coli that were highly prevalent, but only moderately associated with diarrhoea – they are frequently found in the stool of asymptomatic people.
  4. Organisms that were only associated with diarrhoea in specific contexts, such as Aeromonas spp and enteroaggregative E. coli.
  5. Organisms that showed no association with diarrhoea, such as T. trichiura and A. duodenale.

A microbiological cause for diarrhoea could be found in 90% of cases when quantitative PCR was used, while a cause was found in only half of cases of diarrhoea using traditional methods. This is because some organisms, such as Shigella spp, are difficult to grow in culture. It had previously been thought that bloody diarrhoea is the hallmark of Shigella infection, but this study shows that many cases are associated with watery diarrhoea, rather than dysentery, at least in children. Future development of rapid quantitative assays should help identify cases that need antibiotics, and gene sequencing should also provide evidence on antibiotic resistance. Most important, we need improved sanitation to get rid of this lethal disease.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Liu J, Platts-Millsa JA, Juma J, et al. Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study. Lancet. 2016; 388: 1291-301.