MRCOphth Tiarnan D L Keenan
email: tiarnan.keenan@doctors.org.uk

Fiona Carley

Frcophth

PhD David Yeates

MSc Mark N A Jones

BSc Sally Rushton

FFPHM Michael J Goldacre

Trends in corneal graft surgery in the United Kingdom Authors

Keywords: Penetrating keratoplasty, lamellar keratoplasty, deep anterior lamellar keratoplasty, endothelial keratoplasty

Aims

The aims of this study were to examine trends over time and regional variation in rates of corneal graft surgery in the United Kingdom (UK).

Methods

The hospital in-patient enquiry (HIPE) and hospital episode statistics (HES) were analysed for keratoplasty admissions in England from 1971-2006. NHS Blood and Transplant (NHSBT) data were analysed for keratoplasty operations in the UK from 1999-2009.

Results

Annual rates of penetrating keratoplasty (PK) under HIPE and HES increased from 0.7 per 100 000 population (1971) to 3.9 (1992), then decreased to 3.1 (2006). Rates of lamellar keratoplasty (LK) increased from 0.1 (1971) to 0.9 (2006). Annual PK operations under NHSBT decreased from 1901 (1999/00) to 1473 (2008/9). Over the same period, deep anterior lamellar keratoplasty operations increased from 91 to 327 per year, while endothelial keratoplasty operations increased from 2 to 569 per year.

Geographical analysis showed wide variation across local authority areas in rates of keratoplasty around 1998-2004, especially for LK.

Conclusion

The total number of corneal graft operations performed in the UK has increased slowly over the past decade. The proportion of lamellar versus penetrating keratoplasty has increased, with LK performed at highest rates in specialist centres distributed across the UK.

INTRODUCTION

Corneal graft surgery has seen enormous changes since its birth over 100 years ago [START_REF] Zirm | Eine erfolgreiche totale Keratoplastil[END_REF] , including improvements in the processing and storage of corneal tissue in eye banks [START_REF] Doughman | Prolonged donor preservation in organculture: long-term clinical evaluation[END_REF][START_REF] Armitage | Supply of corneal tissue in the United Kingdom[END_REF] , more effective treatment of endothelial rejection, and the introduction of lamellar surgical techniques [START_REF] Archila | Deep lamellar keratoplasty dissection of host tissue with intrastromal air injection[END_REF][START_REF] Mcdonnell | The lamellar corneal graft for optical indications[END_REF][START_REF] Melles | A quick surgical technique for deep anterior lamellar keratoplasty using visco-dissection[END_REF][START_REF] Coombes | Deep lamellar keratoplasty with lyophilised tissue in the management of keratoconus[END_REF] . The prevalence of corneal disease may also have altered over time, for example changes in the prevalence of pseudophakic bullous keratopathy requiring keratoplasty [START_REF] Al-Yousuf | Penetrating keratoplasty: indications over a 10 year period[END_REF][START_REF] Sharif | Changing indications for keratoplasty, 1971-1990[END_REF][START_REF] Vail | Corneal transplantation in the United Kingdom and Republic of Ireland[END_REF][START_REF] Morris | Changing indications for keratoplasty[END_REF] following the introduction and refinement of phacoemulsification cataract surgery [START_REF] Keenan | Time trends and geographical variation in cataract surgery rates in England: study of surgical workload[END_REF] . Finally, indications for surgery have shifted in recent years; for example, penetrating keratoplasty (PK) has commonly been performed for keratoconus [START_REF] Al-Yousuf | Penetrating keratoplasty: indications over a 10 year period[END_REF][START_REF] Sharif | Changing indications for keratoplasty, 1971-1990[END_REF][START_REF] Vail | Corneal transplantation in the United Kingdom and Republic of Ireland[END_REF][START_REF] Morris | Changing indications for keratoplasty[END_REF] , but alternative therapeutic options have emerged, including deep anterior lamellar keratoplasty (DALK) [START_REF] Archila | Deep lamellar keratoplasty dissection of host tissue with intrastromal air injection[END_REF][START_REF] Mcdonnell | The lamellar corneal graft for optical indications[END_REF][START_REF] Melles | A quick surgical technique for deep anterior lamellar keratoplasty using visco-dissection[END_REF][START_REF] Coombes | Deep lamellar keratoplasty with lyophilised tissue in the management of keratoconus[END_REF] , intracorneal rings [START_REF] Colin | Correcting keratoconus with intracorneal rings[END_REF] and the advent of collagen cross-linking [START_REF] Wollensak | Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus[END_REF] .

The number of corneal graft operations performed in a country may be limited by finite supplies of corneal tissue. Accurate data on past and current practices in keratoplasty are therefore essential to predict future requirements. North America and Continental Europe have demonstrated interesting trends in the number of patients undergoing PK [START_REF] Ghosheh | Trends in penetrating keratoplasty in the United States 1980-2005[END_REF][START_REF] Darlington | Trends of penetrating keratoplasty in the United States from 1980 to 2004[END_REF][START_REF] Legeais | Nineteen years of penetrating keratoplasty in the Hotel-Dieu Hospital in Paris[END_REF][START_REF] Cursiefen | Changing indications for penetrating keratoplasty: histopathology of 1,250 corneal buttons[END_REF] , but the last detailed studies of corneal transplantation in the United Kingdom (UK) were published in 1993 [START_REF] Sharif | Changing indications for keratoplasty, 1971-1990[END_REF][START_REF] Vail | Corneal transplantation in the United Kingdom and Republic of Ireland[END_REF] . Similarly, a recent increase in lamellar keratoplasty (LK) versus PK is well known anecdotally, but robust data on the relative use of these approaches throughout the UK are not currently available in the published literature.

METHODS

Annual admission rates for corneal graft surgery in England were calculated from the Hospital In-Patient Enquiry (HIPE) and Hospital Episode Statistics (HES) for the years 1971 to 2006, distinguishing PK and LK. These datasets have been described previously [START_REF] Keenan | Time trends and geographical variation in cataract surgery rates in England: study of surgical workload[END_REF] . From 1998 to 2004, rates for PK and LK were also calculated distinguishing episodes of care and individuals treated; individual patients who underwent corneal graft surgery were counted once only in each year, even if they had more than one episode of care on which corneal graft surgery was recorded. In the analysis of trends over time, English national population denominators for each calendar year were obtained from the Office for National Statistics. To take account of changes over the years in the age structure of the population, surgical rates were standardised for age and sex, using the indirect method of standardisation and taking age-and sex-specific rates in five year age groups for the total period as the standard population.

In addition, annual numbers of eyes undergoing corneal graft surgery in the UK were calculated from NHS Blood and Transplant (NHSBT) data for the period April 1999 to March 2009, distinguishing PK, DALK, and endothelial keratoplasty (EK). This dataset is made up of information collected by NHSBT through the Transplant Record Form (TRF) for patients receiving donor corneal material in the UK from the Corneal Transplant Service (CTS). The TRF was introduced in April 1999, such that data are now available for 10 years (summarised by the NHS financial year, 1999/00 to 2008/9). This dataset includes information on patients receiving corneal grafts supplied by the two CTS eye banks, i.e. the Manchester Eye Bank and the Bristol Eye Bank, but over the study period did not capture information from the minority of patients (around 10%) receiving grafts from other eye banks, including the Moorfields Eye Bank and the East Grinstead Eye Bank. Accuracy of the NHSBT dataset is dependent on completion and return of TRF by every centre performing corneal graft surgery, such that figures may be more reliable for earlier years with longer interval for collection of outstanding forms; however, the NHSBT Ocular Tissue Transplant Audit has demonstrated a return rate of 97% over the study period.

HES were analysed to produce geographical profiles of people admitted to hospital in England for both PK and LK, by local authority (LA) of patients' residence, between 1998/9 and 2004/5. The data were used to construct maps showing the person-based admission rate per 100 000 resident population for each LA, expressed as an average annual rate. As before, rates were calculated using the indirect method of age standardisation, taking age-and sex-specific rates in the English population, in five year age groups, and applying them to the age-and sex-specific strata in each local authority.

The operative codes used to identify corneal graft surgery from HIPE and HES

RESULTS

English national admission rates for PK are shown in Figure 1. Annual rates for surgery were 0.7 (95% confidence intervals 0.6 to 0.8) episodes per 100 000 population in 1971. They increased slowly to 1.1 (1.0 to 1.2) in 1985. By the time that recording of HES started in 1989, the rate had already begun to increase sharply: it continued to increase rapidly from 2.5 (2.4 to 2.6) in 1989 to 3.9 (3.7 to 4.1) in 1992.

Over the next decade, the rate of surgery decreased slowly to 3.1 (2.9 to 3.2) in 2001, followed by a plateau at around 3.0 (2.9 to 3. Using HIPE and HES data, admission rates for PK and LK were analysed by age and sex over three time periods, and are presented in Figure 4 (PK) and Figure 5 (LK).

During the first period (1971-1985), rates of men undergoing PK demonstrated a bimodal distribution; this distribution was less evident in women. Above the 40-44 year group, rates generally increased with age. Rates were higher for men than women in almost all age groups. During the second period (1989-1997), rates of PK were generally much higher, but particularly in the older age groups. Again, a bimodal distribution was present (particularly for men) and rates were generally higher in men than in women. During the third period (1998-2004), rates of PK were generally fairly similar to rates in 1989-1997. Surgical rates decreased modestly in every age category from 45-79 years in men, but showed a smaller reduction in most age groups for women. Admission rates over the same time periods for patients undergoing LK are shown in Figure 5. In 1971-1985, rates of men undergoing LK showed one peak in the 35-39 year group, and a second broad peak in the age groups between 50 to 79 years. Rates of women undergoing LK were higher than for men for the age groups between 55 and 84 years. In 1989-1997, rates of LK were higher than in 1971-1985 for most age groups in men, but showed much smaller increases in women. In 1998-2004, surgical rates were higher still than in 1989-1997 for almost every age group. In contrast to the distribution for PK, rates increased much less with age.

Figure 6A shows a geographical profile of the annual rate of PK by LA, analysed by patients' place of residence, constructed using HES data. LAs showed a wide variation in rates of PK, ranging from 0.6 (0.1 to 1.7) to 6.4 (4.9 to 8.3) people per 100 000 population in 1998-2004. Clusters of LA areas covering populations with high surgical rates are seen around several major conurbations distributed around the UK. Similarly, Figure 6B shows a geographical profile of the annual rate of LK by LA of residence. LAs showed a very wide variation in rates of LK, ranging from 0.1 (0.0 to 0.3) to 11.2 (9.5 to 13.1).

DISCUSSION

The total number of corneal graft operations in England increased dramatically from around 50-60 per year in the early 1980's to around 1400-2000 per year in the early 1990's. This enormous increase in surgical activity was permitted by improvements in the processing, storage and distribution of corneal tissue through the addition of new CTS eye banks in Bristol (1986) and Manchester (1988) to existing eye banks in East Grinstead (1959) and Moorfields (1965), and the coordination of this eye bank network by the (then) United Kingdom Transplant Service (UKTS) [START_REF] Armitage | Supply of corneal tissue in the United Kingdom[END_REF] .

For most of the latter half of the twentieth century, PK was the corneal procedure of choice for visual rehabilitation, with LK relegated to primarily tectonic indications [START_REF] Terry | The evolution of lamellar grafting techniques over twenty-five years[END_REF] .

The effectiveness of PK was achieved by the development of newer sutures and microsurgical techniques, as well as an improved understanding of corneal endothelial physiology and the introduction of corticosteroids [START_REF] Terry | The evolution of lamellar grafting techniques over twenty-five years[END_REF] .

Our data show that national rates of patients undergoing PK in England increased dramatically from the late 1980s to reach a peak in the early 1990s, particularly in older age groups for both men and women. This expansion was permitted by the transformation in the methods of corneal tissue supply in the UK, as described above [START_REF] Armitage | Supply of corneal tissue in the United Kingdom[END_REF] .

In addition, this period saw surgical advances and refinements in technique which improved the safety of PK and reduced post-operative complications [START_REF] Price | Adult keratoplasty: has the prognosis improved in the last 25 years?[END_REF] . Shorter hospital stays also meant increased through-put and therefore greater surgical capacity. Demand for PK may also have grown from the increased incidence of pseudophakic bullous keratopathy following the massive expansion in cataract surgery seen in England during the 1980's [START_REF] Sharif | Changing indications for keratoplasty, 1971-1990[END_REF][START_REF] Vail | Corneal transplantation in the United Kingdom and Republic of Ireland[END_REF][START_REF] Morris | Changing indications for keratoplasty[END_REF][START_REF] Keenan | Time trends and geographical variation in cataract surgery rates in England: study of surgical workload[END_REF] .

Rates of PK in England declined very slowly from the early 1990's, particularly in older age groups for men. Possible explanations include a decrease in the prevalence of pseudophakic bullous keratopathy caused by improvements in phacoemulsification cataract surgery [START_REF] Al-Yousuf | Penetrating keratoplasty: indications over a 10 year period[END_REF] . In addition, advances in contact lens technology may have raised the threshold for surgery in keratoconus, and further therapeutic options have also emerged [START_REF] Colin | Correcting keratoconus with intracorneal rings[END_REF][START_REF] Wollensak | Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus[END_REF] . Finally, the increase in LK may partly explain the decrease in PK, as some surgeons have switched from penetrating to lamellar techniques for some patients [START_REF] Archila | Deep lamellar keratoplasty dissection of host tissue with intrastromal air injection[END_REF][START_REF] Mcdonnell | The lamellar corneal graft for optical indications[END_REF][START_REF] Melles | A quick surgical technique for deep anterior lamellar keratoplasty using visco-dissection[END_REF][START_REF] Coombes | Deep lamellar keratoplasty with lyophilised tissue in the management of keratoconus[END_REF][START_REF] Terry | The evolution of lamellar grafting techniques over twenty-five years[END_REF][START_REF] Price | Adult keratoplasty: has the prognosis improved in the last 25 years?[END_REF] .

National rates of patients undergoing LK in England increased dramatically during the late 1990's to reach a peak in the early 2000's, particularly in younger age groups.

NHSBT data demonstrate that DALK was chiefly responsible for this take-off.

Advances in lamellar techniques were permitted by improvements in surgical instrumentation in combination with refinements in technique [START_REF] Archila | Deep lamellar keratoplasty dissection of host tissue with intrastromal air injection[END_REF][START_REF] Mcdonnell | The lamellar corneal graft for optical indications[END_REF][START_REF] Melles | A quick surgical technique for deep anterior lamellar keratoplasty using visco-dissection[END_REF][START_REF] Coombes | Deep lamellar keratoplasty with lyophilised tissue in the management of keratoconus[END_REF][START_REF] Terry | The evolution of lamellar grafting techniques over twenty-five years[END_REF][START_REF] Price | Adult keratoplasty: has the prognosis improved in the last 25 years?[END_REF] . Proponents of DALK stressed the benefits of a non-penetrating operation, and cited the advantages as follows: prevention of endothelial cell loss leading to graft failure, avoidance of endothelial rejection, reduced requirement for topical steroid treatment, faster visual rehabilitation, and improved long-term graft stability [START_REF] Terry | The evolution of lamellar grafting techniques over twenty-five years[END_REF][START_REF] Price | Adult keratoplasty: has the prognosis improved in the last 25 years?[END_REF] . Corneal surgeons may have temporarily altered their practice following the publication of studies comparing visual outcomes of PK and DALK, where interface opacification was thought to limit the visual outcome in DALK. Funnell et al. published in 2006 their finding that eyes undergoing DALK were significantly less likely to attain Snellen best corrected visual acuity of 6/6 than those undergoing PK, in patients with keratoconus [START_REF] Funnell | Comparative cohort study of the outcomes of deep lamellar keratoplasty and penetrating keratoplasty for keratoconus[END_REF] , and this observation has recently been supported by NHSBT data [START_REF] Jones | Penetrating and deep anterior lamellar keratoplasty for keratoconus: a comparison of graft outcomes in the United Kingdom[END_REF] . However, DALK in the study by Funnell et al. was performed using Melles' technique [START_REF] Melles | A quick surgical technique for deep anterior lamellar keratoplasty using visco-dissection[END_REF][START_REF] Funnell | Comparative cohort study of the outcomes of deep lamellar keratoplasty and penetrating keratoplasty for keratoconus[END_REF] , and proponents of DALK point to better visual outcomes using improved methods including the 'big bubble' technique [START_REF] Anwar | Deep lamellar keratoplasty: surgical techniques for anterior lamellar keratoplasty with and without baring of Descemet's membrane[END_REF] . Further studies may help determine relative visual outcomes in PK versus DALK as best practised.

However, HES data show that rates of patients undergoing LK in

NHSBT data show that the annual number of EK operations in the UK has increased dramatically over the past decade. The advantages of EK have been described as follows: faster visual rehabilitation, reduced astigmatism, less suture-related infection and graft vascularisation, reduced likelihood of rejection, and improved globe integrity [START_REF] Goins | Surgical alternatives to penetrating keratoplasty II: endothelial keratoplasty[END_REF] . However, potential disadvantages include endothelial cell loss caused by graft folding, complications such as graft dislocation requiring revision procedures, and limited final visual acuity in some patients through interface opacification. In addition, EK is considered technically more difficult than PK and may require conversion to PK in some cases. However, the National Institute for Health and Clinical Excellence reported in 2009 that current evidence on safety and efficacy was adequate to support the use of EK, based on the combined results of over 6000 operations [START_REF]Corneal endothelial transplantation[END_REF] .

The distribution of keratoplasty (in 1998 to 2004) demonstrates enormous variation across England, particularly for LK. Some geographical areas (such as London) have relatively high rates of both PK and LK, while other areas have relatively high rates of PK but low rates of LK. This suggests that corneal surgery is practised most in specialist centres distributed across England, some of which perform predominantly PK, while others perform both PK and LK. This has important implications for patient choice, access to surgery, and surgical training.

Trends in keratoplasty are unique in ophthalmology, in that they must be considered in the context of a finite supply of corneal tissue for transplantation. The total number of corneal graft operations performed in the UK under NHSBT has tended to increase slowly from 1999 to 2009, while the total number performed in England under HES has remained fairly constant. However, Britain's expanding population means that these trends correspond to a very small increase in NHSBT surgical rates in the UK, and to a small decline in HES surgical rates in England. Given that highest rates of PK are found in the oldest age groups both men and women, the current demographic shift towards an older population is likely to exert significant pressure on supplies of corneal tissue in the near future.

While every effort should be made to increase the quantity of corneal tissue donated in the UK, it is also very important to maximise the benefit from each potential graft.

In this context, lamellar surgery has the advantage of increasing the number of possible keratoplasty operations [START_REF] Muraine | Impact of new lamellar techniques of keratoplasty on eye bank activity[END_REF] . As confidence with lamellar techniques continues to grow, donated corneas with an endothelial cell count insufficient for PK might be used for DALK, while corneas with stromal scarring might still be suitable for EK. Indeed, careful cooperation between eye banks, surgeons and patients might regularly permit the situation where one donated eye could provide sufficient tissue for two grafts: one anterior lamellar graft and one EK. In the meantime, further studies examining surgical and visual outcomes for PK versus LK, together with graft survival data, should inform the debate on the appropriate balance of penetrating and lamellar approaches appropriate for each corneal condition, patient and surgeon.

TITLES AND LEGENDS TO FIGURES

  datasets were: 145.1 for LK and 145.2 for PK in the Office of Population, Censuses and Surveys Classification of Surgical Operations and Procedures, 2 nd revision (OPCS2), 145.1 for LK and 145.2 for PK in OPCS3, and C46.2 for LK and C46.3 for PK in OPCS4. Numerator and denominator data for HIPE and HES results are available from the authors on request.

  2) up until 2006. English national admission rates for LK are shown in Figure 2. Annual rates were 0.2 (0.16 to 0.24) in the early 1970's, and declined to 0.1 (0.08 to 0.14) in the early 1980's. By 1989, the rate of surgery had begun to increase sharply: it continued to increase rapidly from 0.3 (0.20 to 0.30) in 1989 to 1.0 (0.89 to 1.07) in 2003. Over the following three years, surgical rates have shown a modest decline to 0.9 (0.77 to 0.93) in 2006. Annual numbers of eyes undergoing PK in the UK, obtained from NHSBT data, are shown in Figure 3. The number of PK operations remained fairly constant at around 2000 per year during the period 1999/00 to 2005/6. PK accounted for 91% of all corneal grafts in 1999/00, but the proportion declined gradually to 80% in 2005/6, as the total number of corneal grafts performed increased slowly over this period. The number of PK operations then decreased over the following three years to 1473 (60%) in 2008/9. Annual numbers of eyes undergoing DALK are also shown in Figure 3. The number of operations increased in roughly linear fashion from 91 (4%) in 1999/0 to 304 (13%) in 2006/7. A modest decline to 288 (12%) in 2007/8 was followed by a further increase to the highest level recorded of 327 (13%) in 2008/9. Finally, annual numbers of eyes undergoing EK are shown in Figure 3. The number of operations increased roughly exponentially from 2 (0.1%) in 1999/0 to 447 (19%) in 2007/8, and increased further to 569 (23%) in 2008/9.

  England reached a plateau from 2001, and have decreased from 2003. NHSBT data reveal a small decline in the annual number of DALK operations in the UK for the first time from 2006/7 to 2007/8, but this trend is reversed in 2008/9 to a new peak of 327 operations.

Figure 1 .Figure 2 .Figure 3 . 9 Figure 4 .Figure 5 .Figure 6 .

 1239456 Figure 1. Hospital Episode Statistics (HES) admission rates for penetrating

ACKNOWLEDGEMENTS

Geographical atlases of surgical rates were produced using data provided through EDINA UKBORDERS with the support of the Economic and Social Research Council (ESRC) and the Joint Information Systemic Committee (JISC), together with boundary material which is copyright of the Crown.

ETHICAL APPROVAL

The datasets are anonymised. Approval to analyse them in a programme of research undertaken by the Unit of Health-Care Epidemiology, Oxford University, has been obtained through the NHS Central Office for Research Ethics Committees (reference 04/Q2006/176).

COMPETING INTERESTS

None to declare

FUNDING

The Unit of Health-Care Epidemiology is funded to undertake research on the regional and national hospital databases by the English NHS National Coordinating Centre for Research Capacity Development. NHS Blood and Transplant is funded as a Special Health Authority whose responsibilities include acquiring information about donors and recipients of organs and tissues available for transplantation, and commissioning and conducting research and development.

LICENCE FOR PUBLICATION

The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if accepted) to be published in BJO editions and any other BMJPGL products to exploit all subsidiary rights, as set out in our licence (http://group.bmj.com/products/journals/instructions-for-authors/licence-forms).


Nadeem Ali
email: nadeem.ali@nhs.net

M A Mrcophth

Brian C Little

M A Do

Consultant Ophthalmologist Frcs Frcophth

Causes of cataract surgery malpractice claims in England 1995-2008

Keywords: claim, malpractice, litigation, cataract, ophthalmology Word count: 1915

Aims: To analyse the causes of malpractice claims related specifically to cataract surgery in the National Health Service in England from 1995-2008.

Methods:

All the malpractice claims related to cataract surgery from 1995-2008 from the National Health Service Litigation Authority were analysed. Claims were classified according to causative problem. Total numbers of claims, total value of damages, mean level damages and paid:closed ratio (a measure of the likelihood of a claim resulting in payment of damages) were determined for each cause.

Results: Over the 14 year period there were 324 cataract surgery claims with total damages of £1.97 million and mean damages for a paid claim of £19,900. Negligent surgery (including posterior capsule tear and dropped nucleus) was the most frequent cause for claims, while reduced vision accounted for the highest total and mean damages. Claims relating to biometry errors/ wrong intra-ocular lens power were the second most frequent cause of claims and result in payment of damages in 62% of closed cases. The claims with the highest paid:closed ratio were inadequate anaesthetic (75%) and complications of anaesthetic injections including globe perforation (67%).

Conclusions:

Claims from cataract surgery in the NHS are extremely infrequent. Consent, though essential, may not prevent a claim arising or resulting in damages. Refractive accuracy has significant medicolegal impact. Endophthalmitis can lead to successful claims if there is delay in diagnosis. Claims relating to inadequate anaesthesia or anaesthetic injection complications are particularly hard to defend.

BACKGROUND

Cataract surgery is the commonest operation undertaken in England with around 300,000 operations performed every year in the National Health Service (NHS) [START_REF]Focus on: Cataracts[END_REF][START_REF] Clarke | Hospital Episode Statistics and trends in ophthalmic surgery 1998-2004[END_REF] . Although the risk of an adverse event is low compared with many other operations, cataract surgery has a significant medicolegal impact due to its high volume [START_REF] Brick | Risk management lessons from a review of 168 cataract surgery claims[END_REF] . Both in USA and UK, cataract surgery has been found to contribute the largest share of malpractice claims out of the ophthalmic subspecialties [START_REF] Bettman | Seven hundred medicolegal cases in ophthalmology[END_REF][START_REF] Krausher | Medical malpractice litigation in ophthalmology: the New Jersey Experience[END_REF][6][START_REF] Tomkins | Over 120 years of defending ophthalmologists[END_REF] . In a recent study comparing ophthalmic subspecialty negligence claims in the NHS, we found that cataract surgery was responsible for the highest number of claims and the highest total damages in ophthalmology [START_REF] Ali | A decade of clinical negligence in ophthalmology[END_REF] .

It is therefore surprising that there has been little attention in the literature directed at the causes of litigation in modern cataract surgery. Such analysis might provide useful information to improve safety and reduce the burden of claims. The reports prior to 1990 are concerned with the pre-phacoemulsification era and do not relate to the risk profile of current surgical practice [START_REF] Bettman | Seven hundred medicolegal cases in ophthalmology[END_REF][START_REF] Krausher | Medical malpractice litigation in ophthalmology: the New Jersey Experience[END_REF] . For the period following the widespread introduction of phacoemulsification in the mid-1990s, we were able to identify two studies which focus on causes of cataract claims. The first examined 168 claims from 1987 to 1997 in USA [START_REF] Brick | Risk management lessons from a review of 168 cataract surgery claims[END_REF] . The second study analysed 96 claims from 1990 to 1999 arising from private practice in the UK 9 . However, the independent sector differs in many regards from the context of cataract surgery in the NHS: the number of operations is far fewer; surgery is performed only by consultants; and patient demographics and expectations are different. Furthermore it has been identified that, outside of USA, there is a lack of specific guidance on the emerging issues of ophthalmic malpractice and medical litigation at a national level [START_REF] Mavroforou | Physicians' liability in ophthalmology practice[END_REF] . There is therefore a need for a systematic evaluation of the causes of negligence claims related to mainstream cataract surgery in the setting of the NHS.

Cataract claims Ali & Little (2010) 4

Since 1995, medical malpractice claims in the NHS in England have been handled by a central body, the NHS litigation authority (NHSLA). The NHSLA has maintained a comprehensive database of claims since its inception. Apart from the first year, 1995-96 (when ascertainment was estimated to be 90%), the capture of claims by the database is considered to be complete, due to the procedural requirement of claims to be referred to the NHSLA. For each claim, the database includes a brief case description with details of damages where awarded. Using raw data obtained from the NHSLA database, this study aims to analyse the causes of malpractice claims in cataract surgery in England from 1995-2008.

METHODS

An online data-request form was submitted to the NHSLA requesting data on all claims arising from the specialty of ophthalmology from 1995 to 2008. We then analysed, claim by claim, the tabulated raw data provided and classified claims according to standard ophthalmic subspecialty divisions. All the claims for cataract surgery were reviewed and grouped according to causative problem. The number of ongoing claims ("open"), completed claims ("closed"), and claims with payment of damages ("paid") were determined. The total and mean level of damages were calculated for each category of cause. For causes where there were at least 3 claims, the paid:closed ratio was also calculated (which indicates the likelihood of a claim resulting in payment of damages).

RESULTS

1132 claims for the whole of ophthalmology in the period 1995-2008 were studied. Of these, 324 (29%) were related to cataract surgery, 225 (69%) of which closed. For cataract surgery claims, the paid:closed ratio was 44%, with total damages of £1.97 million and mean damages for a paid claim of £19,900.

Table 1 shows the breakdown of claims by causes, with related causes grouped into areas. For convenience, Table 2 shows the top five ranking problems for each of the parameters determined (total claims, total damages, mean damages, paid:closed ratio). information regarding geographical spread or individual hotspot units can be discerned. In addition, the data are confined to England and no claims from private practice or general practice (eg delayed referrals from primary care) are included. From a risk management perspective, it is also important to recognise that negligence claims represent just the tip of the risk iceberg. Near-misses, undetected adverse events, cases in which patients do not take matters further, and resolution of complaints by local or national nonlegal bodies represent a large pool of clinical incidents, most of which never reach the NHSLA. Further work would be needed to see if the risk profile suggested by claims matches that of these other sources of data.

Table1: Breakdown of claims by causes

One of the striking findings for most readers is likely to be the low total number of claims. There were only 324 claims over a fourteen year period, equivalent to 23 per year. Given that hundreds of thousands of cataract operations are performed in the NHS per year, only a tiny fraction will lead to a claim. This is probably due to the inherent low risk of the surgery and the fact that there are many alternative routes available to complainants (mentioned above) that prevent most events ever converting into claims.

We found that reduced vision after surgery and negligent surgery (including posterior capsule tears and dropped nuclei) together make up over one third of the claims and 43% of the damages. These claims result in damages being paid in 32% of closed cases. This is of interest as it is part of routine consent for cataract surgery to warn of the risk of the standard intra-operative complications and post-operative reduced vision. Nevertheless, this does not prevent claims arising, nor from being successful in many cases. This highlights the fact that, just because a complication is known to occur on a regular basis and is consented for, does not imply that there is no fault attributable in the individual case. It also highlights the need for surgeons to take every precaution available to reduce the chance of the predictable complications of cataract surgery. In addition, it is necessary to discuss pre-operatively with patients potentially unavoidable complications which may occur without surgery being negligent (eg dropped nucleus in a posterior polar cataract with pre-existing posterior capsule defect).

Biometry or intra-ocular lens (IOL) power errors are also a major cause of claims and, more often than not, lead to payment of damages (paid:closed ratio of 62%). This is despite the fact that visual outcomes may be excellent [START_REF] Brick | Risk management lessons from a review of 168 cataract surgery claims[END_REF] . This underlines the critical importance of accurate biometry and the need for robust systems for ensuring the biometry data in the notes match the patient, the power of the IOL inserted matches that documented in the notes, and that any pre-operative anomalies or concerns are flagged up and acted upon. This may be facilitated by using a tailored version of the recently introduced WHO Surgical Safety Checklist. As patients' expectations of the refractive outcomes of cataract surgery rise, this area of litigation may well increase.

The claims with the highest paid:closed ratio represent the ones that are hardest to defend. It would have been difficult to predict that inadequate anaesthetic would be the highest ranking on this measure. The psychological distress caused to a patient who suffered pain while awake during an operation clearly has a strong resonance in a sympathetic court of law. This is a pertinent finding as there is a trend towards lighter forms of ocular anaesthesia, such as topical only. However, perhaps we should welcome this trend since the second most likely cause to result in damages is globe perforation from anaesthetic injection, a well-described medicolegal scenario [START_REF] Boniuk | Perforation of the globe during retrobulbar injection: medicolegal aspects of four cases[END_REF] .

Endophthalmitis has an incidence of between 0.05% and 0.25% [START_REF] Study Group | Prophylaxis of postoperative endophthalmitis following cataract surgery: results of the ESCRS multicenter study and identification of risk factors[END_REF] , yet it accounted for 4% of claims. Part of this may reflect the devastating nature of the condition and the affected patient's feeling of the need for compensation. There is also heightened public awareness about the risk of hospital-acquired infections.

But it is a complication that is universally consented for and is rarely attributable to a specific fault at the level of the surgeon or the Trust. In several of the claims, it was explicitly stated that it was the delay in diagnosis of endophthalmitis which was the prime cause of the claim. This might be reduced by better education of front-line staff, ophthalmic or non-ophthalmic, to whom these cases first present.

There is now a universal consent form for cataract surgery, based on the Royal College of Ophthalmologists guidelines, which is freely downloadable 13 . It includes most of the complications highlighted by this study. However as discussed above, consent, though essential, does not necessarily prevent a claim. The factors that motivate patients to sue centre more around behaviour than around clinical competence. There are predisposing factors to litigation (eg rudeness, delays, inattentiveness, miscommunication and apathy) as well as precipitating factors (eg adverse outcomes, iatrogenic injuries, failure to provide adequate care, mistakes and systems errors). In practice it appears that precipitating factors are unlikely in themselves to lead to litigation in the absence of predisposing factors [START_REF] Bunting Rf | Practical risk management principles for physicians[END_REF] . It has also been demonstrated that 70% of litigation is related to poor communication after an adverse outcome, where patients feel that they have been deserted, devalued, poorly informed or have been misunderstood [START_REF] Beckman | The doctor-patient relationship and malpractice. Lessons from plaintiff depositions[END_REF] . It therefore behoves us to make friends with our mistakes. After any adverse event, what most patients require is a sympathetic apology that it has happened (which has no legal standing as an admission of liability) and a clear explanation. People are reluctant to sue someone that they like [START_REF] Gorney | The role of communication in the physician's office[END_REF] .

DISCUSSION

  This is the most comprehensive factually-based national study to date that directly compares the causes and outcomes of the medicolegal activity associated with modern cataract surgery. It is also the largest published series of cataract claims in the world, and one of very few such studies since the introduction of phacoemulsification. It serves to focus our attention on the areas of our practice where there is room for improvement and provides an evidence base for the development of ophthalmic medicolegal guidance.Nevertheless the study has some drawbacks. The data supplied by the NHSLA are in summary form and often details about the events surrounding the claim are limited. It is therefore not always possible to assign the claim to a causative problem (the 9 indeterminate claims.) The claims are anonymised so no Cataract claimsAli & Little (2010)

Table 2 :

 2 Top five ranking causes for each parameter

	Rank	Total claims	Total damages	Mean damages	Paid:closed ratio
	1	negligent surgery	reduced vision	reduced vision	inadequate anaesthetic

Acknowledgements

We are grateful to the NHSLA for providing the raw data.

Funding

Nil to declare

Competing interests

None declared

Licence for Publication

The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd to permit this article (if accepted) to be published in BJO and any other BMJPGL products and sublicences such use and exploit all subsidiary rights, as set out in our licence (http://group.bmj.com/products/journals/instructions-forauthors/licence-forms).


Claudia Thomas
email: clthomas@sgul.ac.uk

Chris Power

Á C Power

Shift work and risk factors for cardiovascular disease: a study at age 45 years in the 1958 British birth cohort

Keywords: Cardiovascular disease, Cohort studies, Employment, Shift work

    Shift work and risk factors for cardiovascular disease: a study at age 45 years in the 1958 British birth cohort

Introduction

Understanding the links between exposures in the workplace, such as shift-work, and cardiovascular disease (CVD) is essential to tackling socioeconomic inequalities in health [START_REF] Macdonald | Occupation as socioeconomic status or environmental exposure? A survey of practice among population-based cardiovascular studies in the United States[END_REF]. Not only being in work but experiencing good working conditions are vital for health and well-being [START_REF] Black | Working for a healthier tomorrow[END_REF][START_REF] Coats | Healthy work: productive workplaces: why the UK needs more good jobs[END_REF].

More than 3.5 million people are employed as shiftworkers in the UK [START_REF]Shift work and fatigue[END_REF]. Although most research on the health consequences of shift-work focuses on night or rotating shift-work, by definition shift-work includes employment outside of standard working hours such as evening and weekend work [START_REF] Monk | Making shift work tolerable[END_REF]. Approximately 20% of industrialised populations are required to work outside the standard 8 a.m. to 5 p.m. working day and this percentage is forecast to increase as demand grows for the provision of goods and services around the clock [START_REF] Rajaratnam | Health in a 24-h society[END_REF]. Night-work is estimated to increase the risk of coronary heart disease (CHD) by 40% [START_REF] Bøggild | Shiftwork, risk factors and cardiovascular disease[END_REF]. Adverse changes have also been reported for a range of CVD risk factors although findings are inconsistent due to methodological differences [START_REF] Lorenzo | Effect of shift work on body mass index: results of a study performed in 319 glucose-tolerant men working in a Southern Italian industry[END_REF][START_REF] Karlsson | Is there an association between shift work and having a metabolic syndrome? Results from a population based study of 27, 485 people[END_REF][START_REF] Lasfargues | Relations among night work, dietary habits, biological measure, and health status[END_REF][START_REF] Morikawa | Effect of shift work on body mass index and metabolic parameters[END_REF][START_REF] Niedhammer | Prevalence of overweight and weight gain in relation to night work in a nurses' cohort[END_REF][START_REF] Parkes | Shift work and age as interactive predictors of body mass index among offshore workers[END_REF][START_REF] Van Amelsvoort | Duration of shiftwork related to body mass index and waist to hip ratio[END_REF][START_REF] Nagaya | Markers of insulin resistance in day and shift workers aged 30-59 years[END_REF][START_REF] Morikawa | Relationship between shift work and onset of hypertension in a cohort of manual workers[END_REF][START_REF] Fialho | Effects of 24-h shift work in the emergency room on ambulatory blood pressure monitoring values of medical residents[END_REF][START_REF] Romon | Increased triglyceride levels in shift workers[END_REF][START_REF] Mikuni | Glucose intolerance in an employed population[END_REF].

It is unclear why shift-work is associated with increased CVD risk. Several pathways have been suggested including: disturbed circadian rhythms resulting in sleep deprivation and desynchronisation of metabolic processes; neuroendocrine effects of stress arising from the nature of night-work or through social and domestic problems arising from working anti-social hours; and behavioural changes (e.g. diet and smoking) related to stress and/or a consequence of working conditions [START_REF] Knutsson | Shiftwork and cardiovascular disease: a review of disease mechanisms[END_REF]. The specific pathways involved may depend on the type of shift-work undertaken. For example, night-work may be more strongly related to circadian disruption whereas evening or weekend work may be more closely related to social disruption [START_REF] Knutsson | Shiftwork and cardiovascular disease: a review of disease mechanisms[END_REF]. To date supporting evidence is lacking on the proposed pathways, although several studies have found poorer health behaviours among night-workers compared to dayworkers [START_REF] Lasfargues | Relations among night work, dietary habits, biological measure, and health status[END_REF][START_REF] Van Amelsvoort | Smoking among shift workers: more than a confounding factor[END_REF][START_REF] Kivimaki | Does shift work lead to poorer health habits? A comparison between women who had always done shift work with those who had never done shift work[END_REF]. We aim to improve understanding of the relationship between shift-work and biological risk markers for CVD in employed British adults. The objectives are to establish whether (1) different types (night, early mornings, evening, weekend) and total burden of shift-work are associated with risk factors for CVD at age 45 years; (2) associations are explained by socio-economic circumstances, occupational factors and health behaviours.

Methods

Study sample and design

Data are mainly from the 45 years and 42 years surveys of the 1958 British birth cohort. The cohort consists of 18,558 individuals: born in one week in March 1958 in England, Scotland and Wales [START_REF] Fialho | Effects of 24-h shift work in the emergency room on ambulatory blood pressure monitoring values of medical residents[END_REF]638) with the addition of immigrants (n = 920) with the same birth dates up to age 16 years [START_REF] Power | Cohort profile: 1958 British birth cohort (National Child Development Study)[END_REF]. At 45 years, 11,971 cohort members who had not died or emigrated, were still in contact with the survey, and who were able to provide informed consent were invited to a clinical examination undertaken in their home by a trained nurse; 9,377 (78%) participated. Ethical approval for the 45 years follow-up was given by the South East Multi-Centre Research Ethics Committee. Information from earlier contacts with the cohort was used as described below for shift-work (at 42 years), potential confounding and mediating factors (42 years) and to allow for sample attrition (birth and 7 years). Analyses presented here are based on 7,839 cohort members participating in the clinical evaluation at 45 years and who were in paid employment at 42 years.

Measurement of CVD risk factors

All outcome measurements were taken by nurses using standardised protocols at 45 years. Blood pressure was measured three times using an Omron 705CP automated sphygmomanometer (Omron, Tokyo, Japan). Mean systolic (SBP) and diastolic blood pressure (DBP) were calculated from the measures obtained that the nurses reported to be reliable. Non-fasted venous blood samples were obtained. Glycosylated haemoglobin (HbA1c) was assayed by ion exchange high performance liquid chromatography on whole blood (Tosoh A1c2.2 Glycohemoglobin Analyser, HLC-723GHb, Tosoh Corp, Tokyo, Japan). Triglycerides, total and high density lipoprotein (HDL) cholesterol were measured by autoanalyser. Fibrinogen was measured by the Clauss assay in an MDA-180 automated coagulometer (Biomerieux, Basingstoke). Fibrinogen values [5.62 g/l (n = 9) were excluded due to the potential for distortion from assay imprecision and from acute-phase reactions [START_REF] Wood | Regression dilution methods for meta-analysis: assessing longterm variability in plasma fibrinogen among 27, 247 adults in 15 prospective studies[END_REF]. C-reactive protein (CRP) was measured on citrated plasma by high-sensitivity nephelometric analysis of latex particles coated with CRP-monoclonal antibodies. CRP values [10 mg/l (n = 154) indicating acute inflammation, e.g. due to infection, were excluded [START_REF] Pearson | Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association[END_REF]. Standing height was measured using a Leicester portable stadiometer and weight was measured to the nearest 0.1 kg. Self reported weight or height was recorded when accurate measurements or consent for measurement were not available. Body mass index (BMI) was calculated as kg/m 2 . Waist circumference (WC) was measured midway between the costal margin and iliac crest.

Measurement of shift-work

Participants reported the frequency of working at night (2200-0400), early mornings (0400-0700), evenings (1800-2200) and weekends (Saturday or Sunday) in their main job at 42 years as ''never'' ''less often than once a month'', ''at least once a month'', and ''at least once a week'' (meaning every weekend in the case of weekend work). ''Any shiftwork'' was defined as any regular employment (Conce/ week) outside the hours of 0700-1800 [START_REF] Monk | Making shift work tolerable[END_REF].

Covariates

Factors associated with CVD and shift-work were included in the analyses as confounders. These included the number of hours worked per week in the participant's main job, whether the participant was self-employed or an employee and socio-economic position (SEP) using the Registrar General's Social Class, and grouped as I&II, III nonmanual, III manual, IV&V.

Information on health behaviours at 42 years was included as mediators of associations between shift-work and risk factors for CVD. Smoking was coded in four categories from never or ex-smoker to current smoker of C20 cigarettes/day. Frequency of alcohol consumption was analysed using five categories from never or rarely to most days. For diet, participants reported consumption of chips, fried food, and fruit and vegetables, categorised as never, \1, 1-2 or C3 days/week. Frequency of leisure activity ranged from \2-3 times/month to 4-7 days/week. Full details on measurement of diet and physical activity have been reported previously [START_REF] Parsons | Changes in diet and physical activity in the 1990s in a large British sample (1958 birth cohort)[END_REF].

Data analysis

Associations between risk factors for CVD and shift-work exposure were analysed using multiple linear regression. The distributions for triglycerides and CRP were positively skewed therefore natural log transformations were used; geometric means and standard deviations are presented. Geometric means are also presented for HbA1c, but regression analyses use untransformed data with robust standard errors as the assumption of constant error variance could not be met with transformation [START_REF] White | A heteroskedasticity-consistent covariance matrix estimator and a direct test for heteroskedasticity[END_REF]. For regression models, all CVD risk factors were converted to standard deviation scores (mean = 0, SD = 1) in order to facilitate comparison across outcomes.

Total burden of shift work participation was analysed by summing the number of shift-work types worked C1/week (0-4). For analyses of different shift work types we conducted exploratory analyses for all four shift-work types separately. These exploratory analyses revealed similar associations with CVD risk factors for night and early morning work; likewise relationships were similar for evening and weekend work. Therefore, indices of regular (C1/week) night/early morning (0-2) and evening/weekend (0-2) work were calculated to isolate potential circadian effects of shift-work [START_REF] Knutsson | Shiftwork and cardiovascular disease: a review of disease mechanisms[END_REF]. Shift-work variables were modeled as categorical (coefficients represent the difference in mean levels of the outcome for number of regular shift-work types relative to the baseline category) and continuous variables (linear trends across shift work categories for each additional increase in shift-work type).

Men and women were analysed separately as there were gender differences in shift work participation and levels of CVD risk factors (Table 1). Models were adjusted for (1) confounding factors: SEP, hours worked/week, employee or self-employed (plus night/morning or evening/weekend index for evening/weekend and night/morning models, respectively); (2) health behaviours: smoking status, alcohol consumption, diet, physical activity and adiposity (CVD risk factors except BMI and WC); (3) confounding factors plus health behaviours (and adiposity as before).

We investigated the effects of factors that could influence measurement of outcomes on shift-work/CVD risk factor associations. We examined adjustments for diabetes medication for analyses of HbA1c, anti-hypertensive medication for blood pressure, and lipid regulating medication for lipids. We also examined adjustments for time of day, delay in the laboratory receiving the blood sample, month of nurse visit, recent food consumption, type of flooring, air temperature. Final models included adjustments for time of day (blood pressure and triglycerides), type 1 diabetes and treatment for type 2 diabetes (HbA1c).

The sample with complete data on CVD risk factor outcomes, shift-work, confounding and mediating factors ranged from 6,775 (BMI) to 5,486 (CRP). Previous work has demonstrated that attrition has resulted in moderate underrepresentation of specific groups in the 45 years survey, including those from families with no male head and those with childhood behavioural or cognitive problems [START_REF] Atherton | Loss and representativeness in a biomedical survey at age 45 years: 1958 British birth cohort[END_REF]. Analyses were repeated using inverse probability weighting to assess bias due to attrition, however, results were similar and unweighted results are presented. Analyses were undertaken using STATA version 10.1 (StataCorp, Texas).

Results

Men had less favourable levels of all risk factors for CVD compared to women except for CRP and were also more likely to undertake shift-work (Table 1). Evening work (1800-2200) was most common for both men and women (54 and 37%, respectively), while men were more likely to participate in all forms of shift-work. Approximately 50% of those working nights also worked early mornings, while 94 and 75% of night and morning workers, respectively, also worked evenings (Supplementary Table 1).

Most shift-work types were associated with risky health behaviours with a few notable exceptions (Table 2). There was no difference in the percentage of evening workers who smoked. Lack of exercise was associated only with weekend work, and frequency of fried food and chip consumption was not always consistently related to shift-work. Alcohol consumption was higher for evening and weekend, but not for night or morning work.

First for total burden of shift-work, Fig. 1 presents differences in CVD risk factors according to the number of types of regular shift-work. For men, there was a significant positive linear trend between number of shift-work types and BMI, WC, total cholesterol, triglycerides, HbA1c and CRP levels. Trends for fibrinogen and HDL were nonsignificant. For those with the heaviest shift-work burden, regularly working all four shift-work types, CVD risk factors were approximately 0.1-0.2 standard deviations (SD) higher than non shift-workers. For example, this equates to an increased BMI and WC of 0.8 kg/m 2 and 1.2 cm, respectively. For women, there was a positive linear trend for triglyceride levels only, but an inverse relationship for DBP. The associations for CVD risk factors were of a similar magnitude, ranging from 0.02 to 0.04 SD per unit increase in number of shift-work types (Table 3). After adjustment effect sizes were reduced, with the greatest attenuation following adjustment for SEP and other work-related factors for all outcomes, except for triglycerides. Adjustment for adult health behaviours had little impact on the associations seen for BMI and WC; the attenuation for lipids and CRP was due to adjustment for adiposity rather than health behaviours (data not shown). Next, for separate analyses of night/morning and evening/weekend work, associations were found primarily for the former and few for the latter (Fig. 2). Among men, adverse levels of all CVD risk factors except for blood pressure and total-cholesterol were observed for those working night/early mornings, whereas, BMI and totalcholesterol were significantly elevated in those who worked evenings/weekends. For women, only triglyceride levels were significantly elevated in association with night/early morning work, although effect sizes were similar to those seen in men for BMI, WC, HDL and HbA1c. There was some indication that both night/early morning and evening/ weekend work were associated with lower blood pressure in women; furthermore, women regularly working evenings and weekends had reduced CRP levels (associations that were robust to adjustment; data not shown). Table 4 shows that for night/early morning work, adjustments for socioeconomic and work-related factors partially explained associations with CVD risk factors except HDL. Adjustment for health behaviours had little impact on measures of adiposity (BMI, WC) but markedly attenuated associations with blood lipids, HbA1c and inflammatory factors. Only BMI, WC and CRP remained significantly elevated in association with night/morning work in men following adjustment. An association between evening/weekend work and BMI in men was no longer evident after allowing for night/morning shift-work (coeff = -0.002, 95%CI = -0.042, 0.037), whereas the association with total cholesterol was reduced by 50% following full adjustment.

Discussion

In this British population sample of 45-year-olds, adverse levels of several risk factors for CVD were observed in association with increasing levels of night and early morning work rather than evening or weekend work.

Relationships were explained by socio-economic, other occupational factors and health behaviours for most CVD risk factors examined. More than 50% of study participants reported that they worked non-standard hours at least once per week, mostly in the evenings or at weekends. Similar proportions regularly worked nights or early mornings (approximately 13%). Directly comparable data on the prevalence of shift-work is scarce, in general, however, our population resembles the working population in Britain in respect of the extent to which they worked non-standard hours [START_REF] Riedmann | Working time and work-life balance in European companies[END_REF][START_REF] Beese | Comparative survey on operating hours and working time[END_REF][START_REF] Mcormond | Changes in working trends over the past decade[END_REF].

The main strength of this study is that it uses a large population-based cohort with key advantages over occupational cohorts, namely, that the results are generalisable to the whole working population rather than narrowly defined occupations, and follow-up is not determined by employment status [START_REF] Macdonald | Respond to ''search for preventable causes of cardiovascular disease[END_REF]. Few population-based studies have published findings for exposures such as shift-work despite collecting data, while others have less occupational diversity and are therefore limited in generalisability [START_REF] Macdonald | Occupation as socioeconomic status or environmental exposure? A survey of practice among population-based cardiovascular studies in the United States[END_REF]. We also studied different types of shift-work, including evening and weekend work that to date have received little attention, and the availability of frequency data permitted the examination of dose-response relationships. The cohort Adjusted for time of day also benefits from a range of biological risk factors for CVD measured in mid-adulthood.

The main limitation was that, due to attrition, the sample with complete data was less than half of the original birth cohort, leading to an under-representation of participants from disadvantaged backgrounds [START_REF] Atherton | Loss and representativeness in a biomedical survey at age 45 years: 1958 British birth cohort[END_REF]. Because associations between work and health may be underestimated in a more advantaged population, analyses were repeated using inverse probability weighting, however, we found that bias was negligible. For practical reasons non-fasted blood samples were obtained, although recent evidence suggests that non-fasted triglyceride levels are independently associated with incident cardiovascular events and may therefore be a better predictor of cardiovascular risk than fasted triglyceride levels [START_REF] Bansal | Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women[END_REF][START_REF] Nordestgaard | Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women[END_REF]. Interpretation of results should take into consideration that individuals only needed to partially participate in the time intervals defining the shiftwork types, and therefore may not have worked the whole interval, e.g. an evening worker need not have worked all 4 h between 6 p.m. and 10 p.m.

We studied men and women separately because of their differing cardiovascular risk profiles, as well as patterns of exposure to shift-work. Formal tests of interaction did not detect gender differences in associations between shiftwork and CVD risk factors, which could be due to the smaller number of women participating in shift-work. Although the only significant finding for women who regularly undertook night-work was increased triglycerides, associations with adiposity and HDL were of a similar magnitude to those seen for men, suggesting that women may be similarly affected by night-work. Our findings are consistent with those from other population-based studies that have also reported increased adiposity and triglyceride levels in female night-workers [START_REF] Karlsson | Is there an association between shift work and having a metabolic syndrome? Results from a population based study of 27, 485 people[END_REF][START_REF] Lasfargues | Relations among night work, dietary habits, biological measure, and health status[END_REF]. We also found that women regularly working shift-work had lower DBP, thus raising the possibility of selection effects, such that women with hypertension do not undertake shift-work [START_REF] Knutsson | Methodological aspects of shift-work research[END_REF]. Selection effects may also explain the lack of association seen for blood pressure in men. Evidence for an association between night-work and blood pressure is generally weak [START_REF] Knutsson | Shiftwork and cardiovascular disease: a review of disease mechanisms[END_REF]. Effect sizes may be underestimated if selection out of shift-work is related to high blood pressure, which is plausible given the free health assessments offered to nightworkers under the European working hours directive [START_REF] Harrington | Health effects of shift work and extended hours of work[END_REF].

In accordance with previous studies, we found regular night-work to be associated with adverse levels of several CVD risk factors in men including adiposity, blood lipids and blood glucose [8-11, 13-15, 18, 19]. An important new finding in our study was the elevated levels of inflammatory factors, CRP and fibrinogen, in association with nightwork. We are aware of one small, cross-sectional study of factory workers where no difference in CRP levels between night and day workers was found [START_REF] Lavie | Elevated plasma homocysteine in older shiftworkers: a potential risk factor for cardiovascular morbidity[END_REF]. Whilst most associations were for night-work and less so for evening/ weekend work, the graded association between number of types of shift-work and several CVD risk factors suggests that evening/weekend work may contribute to the overall burden of shift-work. In the case of BMI, the evening/ weekend work association was due to the overlap between evening work and night work, and was attenuated once night-work had been taken into account. It has been previously suggested that if night workers are more at risk of CVD than workers of other atypical hours this would implicate the disturbance of metabolic rhythms in the development of CVD in night-workers [START_REF] Knutsson | Shiftwork and cardiovascular disease: a review of disease mechanisms[END_REF]. However, we found that most associations were explained by socioeconomic factors, workplace characteristics, and health behaviours. Associations for non-adiposity CVD risk factors were generally explained by concurrent adiposity and health behaviours, but the association between night-work and adiposity remained significant after adjustment. In this study and elsewhere [START_REF] Lasfargues | Relations among night work, dietary habits, biological measure, and health status[END_REF][START_REF] Van Amelsvoort | Smoking among shift workers: more than a confounding factor[END_REF][START_REF] Kivimaki | Does shift work lead to poorer health habits? A comparison between women who had always done shift work with those who had never done shift work[END_REF], night-workers were more likely to smoke and have a poorer diet compared to day workers, and yet health behaviours explained little of the associations with adiposity. However, health behaviours at one point in time only were taken into account and may not reflect longer term patterns. Since health behaviours and SEP are closely related, it is possible that some of the longer term influence of health behaviours was accounted for by adjustment for SEP, and in the case of CVD risk factors other than BMI and WC, by adjustment for adiposity. Hence, there is some potential for residual confounding. In addition, the number of years employed in shift-work may influence the extent to which current health behaviours affect disease risk. Alternatively, individuals who work at nights and early mornings may differ with respect to risk factors for CVD before they become shiftworkers.

In conclusion, the results from this study indicate that observed associations between night work and adverse profiles of CVD risk factors are related to socioeconomic, other occupational factors and health behaviours.

Fig. 1

 1 Fig. 1 Differences in CVD risk factor SD scores in association with number of types of regular shift work (nights, early mornings, evenings or weekends C1/week). * Trend P \ 0.05. Vertical bars represent 95% confidence intervals

Fig. 2

 2 Fig. 2 Differences in CVD risk factor SD scores in association with regular (C1/week) night/early morning work and evening/weekend work. * Trend P \ 0.05. Vertical bars represent 95% confidence intervals

Table 1

 1 Shift work patterns at 42 years and CVD risk factors at 45 years in 4,141 Male and 3,698 Female Members of the 1958 Cohort

		Men		Women
		Total N	n (%)	Total N	n (%)	P-value b
	Shift work, C1/week a
	Any shift work, 42 years	4,138	2,710 (65.5)	3,696	1,665 (45.0)	\0.001
	Night (2200-0400)		662 (16.0)		368 (10.0)	\0.001
	Morning (0400-0700)		776 (18.7)		300 (8.1)	\0.001
	Evening (1800-2200)		2,226 (53.8)		1,357 (36.7)	\0.001
	Weekend		1,358 (32.8)		864 (23.4)	\0.001
	Number shift types worked C1/week
	0 (no shift work)		1,428 (34.5)		2,031 (55.0)
	1 type		1,261 (30.5)		865 (23.4)
	2 types		782 (18.9)		474 (12.8)
	3 types		471 (11.4)		228 (6.2)
	4 types (all)		196 (4.7)		98 (2.7)	\0.001
	Night/mornings C1/week
	0 (no night or morning)		3,056 (73.9)		3,203 (86.7)
	1 (night or morning)		726 (17.5)		318 (8.6)
	2 (night and morning)		356 (8.6)		175 (4.3)	\0.001
	Evenings/weekends C1/week
	0 (no evening or weekend)		1,552 (37.5)		2,071 (56.0)
	1 (evening or weekend)		1,558 (38.4)		1,029 (27.8)
	2 (evening and weekend)		998 (24.1)		596 (16.1)	\0.001
			Mean (SD)		Mean (SD)
	BMI (kg/m 2 )	4,131	27.82 (4.22)	3,687	26.92 (5.47)	\0.001
	Waist circumference (cm)	4,114	98.38 (10.94)	3,666	85.26 (12.56)	\0.001
	Systolic blood pressure (mmHg)	4,116	132.91 (14.95)	3,659	120.32 (15.50)	\0.001
	Diastolic blood pressure (mmHg)	4,116	82.08 (10.39)	3,659	75.59 (10.24)	\0.001
	Triglycerides (mmol/l) c	3,510	2.08 (1.22)	3,074	1.34 (0.71)	\0.001
	Total cholesterol (mmol/l)	3,523	6.07 (1.13)	3,081	5.68 (0.99)	\0.001
	HDL-cholesterol (mmol/l)	3,510	1.44 (0.33)	3,079	1.70 (0.40)	\0.001
	HbA1c (%) c	3,565	5.27 (0.57)	3,120	5.15 (0.47)	\0.001
	C-reactive protein (mg/l) b, d	3,393	0.91 (0.95)	2,931	0.94 (1.13)	0.19
	Fibrinogen (g/l) e	3,444	2.86 (0.56)	3,016	3.00 (0.61)	\0.001

BMI body mass index; HbA1c glycosylated haemoglobin; HDL high density lipoprotein a Outside the hours of 0700 and 1800 or on weekends b P values from t test or v 2 test of sex difference as appropriate c Geometric mean (SD) d CRP excludes values [10 mg/l, n = 154 e Fib excludes values [5.62 g/l, n = 9

Table 2

 2 Relationships between shift-work, confounding and health behaviour mediating variables at 42 years

		Nights, %		Mornings, %		Evenings, %		Weekends, %
		\1/week	C1/week	\1/week	C1/week	\1/week	C1/week	\1/week	C1/week
	Self-employed	14.0	18.7***	14.7	14.3	9.5	20.8***	10.8	24.3***
	Works [48 h/week	20.1	40.2***	19.7	41.2***	10.6	39.1***	16.2	41.8***
	Manual social class	33.8	39.2***	32.0	50.6***	39.8	28.3***	33.5	37.3***
	Current smoker	22.1	26.4***	21.6	29.4***	22.8	22.6	21.7	25.3***
	Exercises B1/week	33.7	34.5	33.6	35.1	33.3	33.2	32.5	37.1***
	Fruit and vegetables \once/day	42.2	46.1*	42.0	47.0**	40.4	45.4***	41.1	46.6***
	Fried food at least 1/week	45.8	49.2*	46.0	47.9	43.2	49.9***	45.2	48.9**
	Chips at least 1/week	43.8	45.9	43.2	49.4***	45.2	42.6*	43.0	46.8**
	Drinks most days	20.8	21.2	21.2	18.7	18.4	23.8***	20.2	22.5*

*** P \ 0.001, ** P \ 0.01, * P \ 0.05 (from v 2 test)

Table 3

 3 Differences in CVD risk factor SD scores (95% CI) per unit increase in number of regular shift types with adjustments for confounders and health behaviours

		%	-36	-46	-32	-66	-37	-58		42	-29
		All	0.027 (0.003, 0.051)	0.013 (-0.008, 0.034)	0.023 (-0.008, 0.054)	0.010 (-0.014, 0.034)	0.017 (-0.011, 0.045)	0.013 (-0.011, 0.038)		-0.047 (-0.079, -0.015)	0.027 (-0.001, 0.055)
		%	7	4	-26	-38	-70	-65		24	-50
		Health behaviours b	0.045 (0.023, 0.067)	0.025 (0.006, 0.044)	0.025 (-0.003, 0.053)	0.018 (-0.006, 0.043)	0.008 (-0.018, 0.033)	0.011 (-0.011, 0.034)		-0.041 (-0.071, -0.012)	0.019 (-0.007, 0.045)
		%	-40	-54	-24	-38	7	-26		27	29
	Adjustments	Confounders a	0.025 (0.000, 0.049)	0.011 (-0.011, 0.032)	0.026 (-0.006, 0.057)	0.018 (-0.006, 0.043)	0.029 (-0.001, 0.059)	0.023 (-0.004, 0.051)		-0.042 (-0.076, -0.009)	0.049 (0.018, 0.080)
	Unadjusted		0.042 (0.020, 0.064)	0.024 (0.005, 0.043)	0.034 (0.006, 0.063)	0.029 (0.004, 0.054)	0.027 (0.000, 0.055)	0.031 (0.006, 0.056)		-0.033 (-0.064, -0.002)	0.038 (0.009, 0.067)
	N		4,048	4,048	3,453	3,495	3,441	3,329		3,153	3,020
	Outcome	Men	BMI	WC	Total chol	HbA1c c	Triglyceride d	CRP	Women	DBP d	Triglyceride d

a Social class, total hours worked/week, employee or self employed b Physical activity, diet, smoking and alcohol (plus BMI and WC in non-adiposity models) c Adjusted for diabetes treatment d

Table 4

 4 Differences in CVD risk factor SD scores (95% CI) per unit increase in night/morning work and evening/weekend work with adjustments for confounders and health behaviours

		%		-30	-15	-59	-56	-91	-43	-84		-54			100	-47
		All		0.060 (0.015, 0.105)	0.051 (0.011, 0.090)	-0.024 (-0.072, 0.025)	0.025 (-0.027, 0.077)	0.005 (-0.042, 0.053)	0.052 (0.007, 0.098)	0.010 (-0.042, 0.062)		0.039 (-0.022, 0.100)			0.000 (-0.039, 0.040)	0.031 (-0.020, 0.083)
		%		3	5	-110	-75	-54	-52	-77		-49			10	-24
		Health behaviours b		0.089 (0.048, 0.129)	0.063 (0.027, 0.098)	0.006 (-0.038, 0.050)	0.014 (-0.033, 0.061)	0.026 (-0.019, 0.070)	0.044 (0.003, 0.085)	0.014 (-0.033, 0.061)		0.043 (-0.012, 0.098)			0.044 (0.011, 0.078)	0.045 (0.002, 0.088)
		%		-33	-23	29	-11	-56	-16	-40		-26			-105	-37
	Adjustments	Confounders a		0.058 (0.012, 0.103)	0.046 (0.006, 0.085)	-0.076 (-0.130, -0.023)	0.051 (-0.005, 0.107)	0.025 (-0.023, 0.074)	0.076 (0.025, 0.126)	0.037 (-0.018, 0.092)		0.062 (-0.006, 0.130)			-0.002 (-0.042, 0.037)	0.037 (-0.016, 0.089)
	Unadjusted			0.086 (0.045, 0.126)	0.060 (0.025, 0.096)	-0.059 (-0.107, -0.011)	0.057 (0.007, 0.107)	0.057 (0.011, 0.103)	0.091 (0.045, 0.136)	0.062 (0.013, 0.111)		0.084 (0.023, 0.146)			0.040 (0.007, 0.073)	0.059 (0.015, 0.102)
	Outcome N	Night/morning work	Men	BMI 4,048	WC 4,048	HDL 3,441	Triglyceride d 3,441	HbA1c c 3,495	CRP 3,329	Fibrinogen 3,377	Women	Triglyceride d 3,020	Evening/weekend work	Men	BMI 4,048	Total chol 3,453

a Social class, total hours worked/week, employee or self employed, evening/weekend work index b Physical activity, diet, smoking and alcohol (plus BMI and WC in non-adiposity models) c Adjusted for diabetes treatment d Adjusted for time of day

C. Thomas, C. Power

Acknowledgments This work was supported by the Medical Research Council [grant number G0000934 to CP] and the Economic Social Research Council [grant number RES-163-27-1011 to CT]. This work was undertaken at GOSH/UCL Institute of Child Health which received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. The Centre for Paediatric Epidemiology and Biostatistics also benefits from funding support from the Medical Research Council in its capacity as the MRC Centre of Epidemiology for Child Health. This work was presented at the Society for Social Medicine Annual Meeting, Southampton, UK, September 2008.