Anthony Spiteri

PhD Rajesh Aggarwal

MRCS Tom Kersey

Larry Benjamin

MD Ara Darzi

FRCS Philip Bloom

Mrcophth Larry

FRCOphth Benjamin Frcsed

Mr Anthony Spiteri

Phacoemulsification Skills Training and Assessment

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Cataract extraction by phacoemulsification was pioneered by Charles David Kelman [START_REF] Kelman | Phaco-emulsification and aspiration. A new technique of cataract removal[END_REF] in New York City in 1967. Over the next 25 years it replaced the traditional inpatient cataract surgery with a much less intrusive and more curative procedure that could be performed on an outpatient basis. According to Hospital Episode Statistics over 280,000 phacoemulsifications were carried out in the financial year 2005-2006 in the UK alone. 2 It has become by far the key index operation for Ophthalmologists, with the Royal College guidelines expecting trainees to complete 350 phacoemulsification cataract procedures by the end of Ophthalmic Specialist Training year 7 3 .

Challenges in phacoemulsification training

The quality of ophthalmic surgical training is increasingly challenged by an untimely convergence of several factors. The public's unprecedented high expectations and demands for safety are fuelled by readily accessible information on hospital performances such as the Electronic Cataract National Dataset 4 . In addition, consultantled care provided by Independent Treatment Centres (ITCs) and the further reduction of working hours (to 48 hours a week by 2009), imposed by the European Working Time Directive, are leading to concerning reports 5 ' 6 about the reduced overall training opportunities.

The training of novice phacoemulsification surgeons, as with all postgraduate medical training, has altered substantially in the last decade [START_REF] Gibson | The first cut is the deepest: basic surgical training in ophthalmology[END_REF] . Although the Halstedian apprentice model of teaching has served ophthalmology education for over 100 years, it fails to ensure that experience is gained in all the essential areas and is therefore inappropriate as well as stressful. The limitations [START_REF] Smith | Teaching phacoemulsification in US Ophthalmology residencies: can the quality be maintained?[END_REF] of this approach are hard to ignore, and even more difficult to amend.

Increasingly, the demonstration of competency is gathering general consensus as the preferred method to drive ophthalmic trainees along the surgical learning curve.

Benjamin [START_REF] Benjamin | Selection, teaching and training in Ophthalmology[END_REF] reports that team working, leadership, insight, dexterity, decision making, prioritizing and empathy are all important and should be assessed.

Moreover, the almost 10-year-old accepted standard for complication rates as determined by the 1997-8 National Cataract Surgery Survey (NCSS) is out-of-date. This reflects the great advances in the practice and provision of modern phacoemulsification surgery achieved since then [START_REF] Zaidi | Raising the benchmark for the 21 st century -the 1000 cataract operations audit and survey: outcomes, Consultant supervised training and sourcing NHS choice[END_REF] . It also suggests that although training opportunities are being compromised, the required expected standards are higher.

The challenge for the current generation of ophthalmologists is to increase the quality of training and indeed maintain standards. It is necessary to utilise training methods outside the operating theatre (wet labs, simulation) while simultaneously demonstrating competence during formal assessments.

Phacoemulsification TRAINING outside the operating theatre

Wet labs use cadaveric human or animal models, or synthetic eyes (designed specifically for performing phacoemulsification) to rehearse the steps of cataract extraction.

Laboratory practice allows surgeons to acquire skills in a controlled environment, free of the pressures of operating on real patients according to Piaget's and Vygotsky's pedagogical philosophy of "learning by doing". This has been proven to be effective in training general surgeons. 11 ' 12 The mandatory introduction of micro-surgical skills courses in the UK was an attempt to teach basic micro-surgical skills within a structured curriculum. This is not an entirely new concept in ophthalmology. Kirby [START_REF] Kirby | A course in surgical technique for residents in ophthalmology[END_REF] reported a resident course in basic ophthalmic surgery techniques that had been in use since 1966. The success of this form of training is now evident from the large number of micro-surgical skills courses available worldwide.

Courses last 2-3 days and consist of didactic lectures with some hands-on wet lab simulator practice. Skills practice varies from performing single tasks like knot tying to learning of complex procedures such as lid and corneal wound repair, capsulorrhexis and phacoemulsification.

However these methods have been criticized for being unrealistic [START_REF] Spitz | Decline in surgical training[END_REF] with inaccurate simulation of tissue consistency and anatomy [START_REF] Smith | Teaching phacoemulsification in US ophthalmology residencies: can the quality be maintained?[END_REF] and also lacking any form of objective assessment. These problems can be addressed through the development of computer simulators after similar technology had been used to train airline pilots for a number of years providing realistic simulation with an accurate assessment of performance. It has already been emulated successfully in other branches of surgery [START_REF] Aggarwal | Proving the effectiveness of virtual reality simulation for training in laparoscopic surgery[END_REF] ' 17 ' 18 ' [START_REF] Aggarwal | Virtual reality simulation training can improve inexperienced surgeons' endovascular skills[END_REF] . The possibility of an analogous situation in ophthalmology is becoming a reality.

Virtual reality systems in phacoemulsification

The term virtual reality refers to a "computer-generated representation of an environment that allows sensory interaction, thus giving the impression of actually being present" [START_REF] Coleman | Virtual reality and laparoscopic surgery[END_REF] .

Over the past two decades researchers have developed many ophthalmic virtual reality surgery simulators.

The training systems published in the literature come from the USA, Japan, France, Sweden, Austria and Germany. One of the first projects to embrace this technology for ophthalmic surgical education was the Ophthalmic Retrobulbar Injection Simulator (ORIS) [START_REF] Merril | The Ophthalmic Retrobulbar Injection Simulator (ORIS): An application of Virtual Reality to Medical Education[END_REF] while Sinclair et al [START_REF] Sinclair | Computer-simulated eye surgery. A novel teaching method for residents and practitioners[END_REF] were the first to develop haptic (tactile) feedback in an eye surgical simulator using 4 instruments (scalpel, forceps, scissors and phacoemulsifier). Webster et al utilized haptic feedback for simulating Gimbel and Neuhann's continuous curvilinear capsulorrhexis technique. [START_REF] Webster | A haptic surgical simulator for the continuous curvilinear capsulorehxis procedure during cataract surgery[END_REF] They recently further described simulations of this technique using the EYESI. [START_REF] Webster | Simulating the continuous curvilinear capsulorehxis procedure during cataract surgery on the EYESI system[END_REF] ' [START_REF] Webster | A Didactic Training Simulation System for the Continuous Curvilinear Capsulorhexis Cataract Procedure on the EYESI TM System[END_REF] Phacoemulsification surgery prototypes started appearing over the past five years, one of the earliest being developed in Sweden by Laurell et al. [START_REF] Laurell | Computer-simulated phacoemulsification[END_REF] Another novel method of teaching cataract surgery was developed by Prinz et al. The "Ophthalmic Operation Vienna" uses surgical videos accompanied by 3D animated sequences of all surgical steps for cataract and glaucoma surgery. [START_REF] Prinz | Advantage of three dimensional animated teaching over traditional surgical videos for teaching ophthalmic surgery: a randomized study[END_REF] Moreover, Henderson et al described the Virtual Mentor [START_REF] Henderson | Virtual training tool[END_REF] to teach cognitive aspects of cataract surgery isolated from the physical tasks. The use of endoscopy has also been proposed as a tool to augment threedimensional understanding of ocular structures and thereby assist in teaching cataract surgery to residents [START_REF] Henderson | Using endoscopy to teach cataract surgery[END_REF] . Posterior segment simulators range from retinal photocoagulation [START_REF] Rouland | SOPHOCLE (Ophthalmologic Simulator of Laser PHOtocoagulation):contribution to virtual reality[END_REF] to vitreoretinal surgery. [START_REF] Hikichi | Vitreous surgery simulator[END_REF] ' 32 ' 33 ' [START_REF] Rossi | Virtual vitreoretinal surgical simulator as a training tool[END_REF] At present, the only commercially available ophthalmic virtual reality surgical training system on the market is the EYESI produced by VR magic, Mannheim, Germany (Fig 1).

EYESI was originally designed as a vitreoretinal surgery simulator. [START_REF] Khalifa | Virtual Reality in Ophthalmology training[END_REF] It has since evolved to include a breadth of ophthalmic surgical procedures including capsulorrhexis simulation and phacoemulsification modules. The simulator consists of a mannequin head prop with a separate vitreoretinal and cataract surgical interface. Movements of the instruments are relayed in real time onto a computer monitor as well as onto a stereo microscope complete with foot pedals.

Using this simulator, trainees can practice standardized phacoemulsification techniques and abstract tasks repeatedly with instant objective feedback of performance. With graded exercises at different skill levels, they can be used as the basis for a structured training programme.

Learning curves on phacoemulsification trainers.

A learning curve is defined as a line graph displaying opportunities across the x-axis, and a measure of student performance along the y-axis. To our knowledge, there is no published data on the learning curve of ophthalmic surgical trainees during wet lab training or microsurgical skills courses. This is probably owing to the fact that validated eye surgical skills assessment tools are only recently emerging. Prior to this, assessment on the rate of proficiency acquisition using these methods was not accurately possible.

Assessment using virtual reality systems is more readily available using the accompanying manufacture-provided default performance thresholds (though these too need yet to be validated).

Transfer of skills from phacoemulsification trainer to human patient

There are virtual reality to operating room (so-called "VR to OR") trials published in laparoscopy (17, 18), bronchoscopy (19) and endovascular (20) surgery. The legitimacy of ophthalmologic surgery simulators through trials however beckons. These studies are essential to show transfer of simulated skills to real operations before simulators can be incorporated into the ophthalmology training curriculum.

The studies that have so far established validity relate to vitreoretinal procedures. Peugnet et al [START_REF] Peugnet | Virtual reality versus conventional training in retinal photocoagulation: a first clinical assessment[END_REF]

ASSESSMENT of technical skills in phacoemulsification surgery

Adequate assessment is necessary to demonstrate competence. For any method of skill assessment to be used with confidence it must be objective, reliable, valid and feasible.

Reliability of an evaluation instrument relates to its ability to provide consistent results with minimal errors of measurement. Test/Retest reliability and Inter/Intra observer reliability are the most commonly used methods. [START_REF] Murphy | Psychological testing : principles and applications[END_REF] Validity is defined as the extent to which an assessment instrument measures what it was designed to measure. An assessment should be able to demonstrate several forms of validity from the most basic face validity to content and construct or contrast (discriminative) validity to the most powerful predictive validity. Feasibility or practicality refers to the length and number of assessments, the number of personnel and the required time, space and costs.

Traditionally, however, assessment methods have been subjective making them inherently susceptible to weaknesses. The opinion of the assessing trainer, for example, may be critically important. Friedlich et al [START_REF] Friedlich | Structured assessment of minor surgical skills (SAMAA) for family medicine residents[END_REF] demonstrated that a new exam for family medicine had low reliability when family physicians serve as examiners but moderate reliability when surgeons where the evaluators. Furthermore, the keeping of a personal surgical logbook is a reflection of one's experience as opposed to one's expertise.

Complication rates, not only accumulation of numbers, need to be addressed when evaluating the competence of a surgeon.

Emerging tools in ophthalmic surgical skill assessment.

In an attempt to design better ways of training ophthalmic surgeons, a number of different objective assessment tools have been described. Objective Assessment of Skills in Intraocular Surgery (OASIS) 41 (Table 1) is an entirely objective tool and thus has no inter-rater variability. It is a feasible one page evaluation form with pre-, intra-and postoperative results components to phacoemulsification. The more subjective Global Rating Assessment of Skills in Intraocular Surgery (GRASIS) was developed later to be complementary to OASIS. GRASIS is a subjective, also one-page, evaluation form based on a 5-point Likert Scale with middle and extreme points anchored by explicit descriptors [START_REF] Cremers | Global Rating Assessment of Skills in Intraocular surgery[END_REF] . A similar method is used in assessing ophthalmic plastic surgical skills (OPSSAT) [START_REF] Gauba | Ophthalmic Plastic Surgical Skills Assessment Tool[END_REF] .

Another method of assessment, originally developed to improve human performance and safety in high-risk industry, is the Human Reliability Analysis (HRACS). The underlying principle is error analysis and has been used successfully in assessing laparoscopic cholecystectomies. Its use was modified for use in ophthalmology and has had face and content validity established [START_REF] Gauba | Human reliability analysis in cataract surgery[END_REF] .

Video-based assessment in phacoemulsification surgery

In order to reduce assessor bias, video-based assessments have been shown to reduce subjectivity in a manner similar to the Objective Structured Clinical Examination (OSCE) used in assessing the clinical skills of history taking, physical examination and patientdoctor communication [START_REF] Van Der Vleuten | Assessment of clinical skills with standardized patients: state of the art[END_REF] . Martin et al [START_REF] Martin | Objective structured assessment of technical skills (OSATS) for surgical residents[END_REF] developed a similar approach to the assessment of operative skill, the Objective Structured Assessment of Technical Skill (OSATS) in general surgery. They used a 2-hour 6-station measurement of surgical performance of surgical trainees during simulated tasks e.g. excision of skin lesion, abdominal wall closure and bowel anastomoses. The OSATS tool demonstrated high reliability and construct validity. This study also concluded that bench model simulation gives equivalent results to use of live animals for this test format suggesting that we can effectively measure residents' technical ability outside the operating room using bench model simulations.

Saleh, Gauva et al [START_REF] Saleh | Objective Structured Assessment of Cataract Surgical Skill[END_REF] adapted OSATS for Cataract Surgery (OSACSS). OSACSS has a six-item global rating system and a fourteen-item task-specific component consisting of a checklist particular to cataract surgery. Each of the components is rated on a 5-point Likert scale. Thirty-eight surgical videotapes from 38 surgeons of four different levels of experience were evaluated. This study demonstrated construct validity of the OSACCS system with the total scores as well as the global and task-specific scores.

Binenbaum, Volpe et al [START_REF] Fisher | Development and Face and Content Validity of and Eye Surgical Skills Assessment Test for Ophthalmology Residents[END_REF] ' [START_REF] Taylor | Microsurgical Lab testing is a reliable method for assessing ophthalmology residents' surgical skills[END_REF] developed the Eye Surgical Skills Assessment Test (ESSAT). This is a 3-station wet lab setting including skin suturing, muscle recession and phacoemulsification / wound construction and suturing technique. Similar to OSACCS, the assessment methods include a station-specific checklist and a global rating scale performance for experts to complete while reviewing the resident's videotaped performance.

The disadvantages with all of the above rating scales are that they are complex and timeconsuming. Furthermore, the scales are open to human error and not entirely without subjectivity. To achieve instant objective feedback of a surgeon's technical skills dexterity analysis and virtual reality may be more useful.

Dexterity analysis in ophthalmic surgery

The Imperial College Surgical Assessment Device (ICSAD) (fig. 2) is an objective assessment of corneal suturing by using economy of movement measures. It is a system that has recently been validated to discern between trainees of different surgical experience in laparoscopic procedures, both for simple tasks [START_REF] Torkington | Skill transfer from virtual reality to a real laparosopic task[END_REF] and for real procedures such as laparoscopic cholecystectomy [START_REF] Smith | Motion analysis[END_REF] .

The ICSAD has sensors placed on the back of a surgeon's hands [START_REF] Taffinder | Can a computer measure surgical precision? Reliability, validity and feasibility of the ICSAD[END_REF] . A commercially available device (Isotrack II; Polhemus, Vermont, USA) emits electromagnetic waves to track the position of the sensors in the x, y and z axes 20 times per second. This device is able to run from a standard laptop computer and data are analysed in terms of time taken, distance travelled and total number of movements for each hand.

Saleh et al 53 evaluated motion tracking using the ICSAD to assess its role as a more objective assessment of ophthalmic surgical skill. The performance of 3 groups of differing levels of surgical skill was analysed while performing corneal sutures. Highly statistically significant differences were found between the 3 grades of surgeon experience for time taken (p<.001), number of hand movements (p<.001), and path length of the hand movements (p<.002) to complete the given task.

Virtual reality simulators as assessment devices

Assessment of any task performed on a simulator or otherwise, together with meaningful feedback, is a vital part of the learning process. [START_REF] Carter | Consensus guidelines for validation of virtual reality surgical simulators[END_REF] The use of the EYESI as an assessment device was first demonstrated by Rossi et al [START_REF] Rossi | Virtual vitreoretinal surgical simulator as a training tool[END_REF] using the vitreoretinal module. They showed a significant difference between students, residents and experienced surgeons in average completion time and number of surgical mistakes when performing the membrane-peeling module. Park et al [START_REF] Park | The EYESI 2.2 Ophthalmosurgical Simulator: Is it a Good Teaching Tool?[END_REF] later demonstrated that more experienced intraocular surgeons scored higher than more junior residents when performing 5 basic psychomotor tasks on the EYESI. When evaluated by group, higher course scores correlated with years of prior intraocular surgical experience.

The more experienced intraocular surgeons reported that they felt the simulator to be an excellent supplemental teaching tool for intraocular surgery.

Comparison of assessment tools

Currently there is no consensus regarding the optimal assessment tool for phacoemulsification procedures, and perhaps video-based, virtual reality and dexterity systems should be used in conjunction. Other tools, such as eye-tracking devices, may also be used to highlight important areas of the operation.

Conclusion

Prior to incorporating virtual simulation into current training programmes there is a need to develop validated curricula for basic, intermediate and advanced levels of training.

Learning curves then need to be determined which will allow the correct frequency of training to be calculated and whether tutors need to be present at all times. Competency levels should be defined using at least a national approach, enabling standardization of training programmes. The organization of these programmes must also be addressed. It is not necessary for every hospital to have a virtual reality simulation laboratory; training can be provided at regional skills centres. Unlike the current one-off microsurgical skills courses, with the establishment of regional centres, it should prove possible to develop training programmes over periods of months and years. [START_REF] Aggarwal | Laparoscopic skills training and assessment[END_REF] Such tools can then be utilized to address the increasingly limited opportunities for technical training and assessment that are offered to doctors, not only during training but throughout their careers (re-training and re-validation). Furthermore, for the first time, a proficiency based curriculum can make the actual level of skill rather than a predetermined period of time the primary factor in physicians' progression up the training ladder. This risk-free training in technical skills will also ensure that patients are cared for by doctors with expertise in the procedures they perform. Financially, improved surgical training outside the theatre translates into greater cost-effectiveness in terms of anaesthesia and operating room time. Furthermore costs will be reduced from managing patient morbidity following surgical complications.

Simulations, however, are not intended as a stand-alone teaching medium. They are more likely to be successful if systematically integrated with enriched curricular and educational environments. Previous attempts in other surgical specialties to rely solely on virtual-reality have been unsuccessful [START_REF] Gerson | A prospective randomized trial comparing a virtual reality simulator to bedside teaching for training in sigmoidoscopy[END_REF] and such a notion in ophthalmology training is likewise not recommended. Without doubt, virtual reality is more likely to be successful if systematically integrated into a carefully constructed education and training program that objectively evaluates technical skills proximate to the learning experience [START_REF] Hanna | Task performance in endoscopic surgery is influenced by location of the image display[END_REF] . Training could comprise starting with wet-labs and simulators to gain awareness followed by structured or modular training in theatre with scored assessments and ICSAD type systems to show improvements in efficiency would comprise a good package. This will lead to improved clinical reasoning and professionalism which will inevitably translate into enhanced patient care.

  tested a retinal photocoagulation simulator. Their results showed that residents training on the simulator required only 25.4 days of training compared with 42.25 days in the group that received conventional training. EYESI's vitreoretinal module was studied by Jonas and colleagues 37 who found that the group that trained on the simulator performed better than the non-trained group when evaluated in a wet lab setting performing vitrectomy on pig eyes. One of the first phacoemulsification simulator trials was carried out by Folgar et al 38 who compared objective surgical outcomes in cataract surgeries performed by residents who have trained with the EYESI versus those who have trained utilizing traditional didactic and wet-lab methods. They suggest that ophthalmology residents who train with the EYESI simulator system may decrease surgical time, ultrasound time and energy dissipation, and rely less on attending interventions compared to residents who begin training directly with patients The promising trial results are an indication that virtual reality simulation might be what training programmes desperately need in these challenging times. However it is necessary to obtain objective measurements of real performance to confirm this.

  The importance of virtual reality simulators in assessing the training of ophthalmic surgeons is acknowledged in the new Work Based Assessments (WBAs) for Ophthalmic Specialist Training (OST) released by the Royal College of Ophthalmologists in June 2007. The practical skills WBAs such as the Direct Observation of Procedural Skills (DOPS) and the Objectively Structured Assessment of Technical Skills (OSATS) both include simulator, together with wet lab and patient, as an optional method of having the procedure performance assessed.

Fig 1 -

 1 Fig 1-A: The EYESI virtual reality ophthalmosurgical simulator B: Display screen C: Training history graph.

Fig 2 -

 2 Fig 2-Imperial College surgical assessment device (ICSAD) A: Sensors and motion box B: Data analysis graphs

Fig 1 -

 1 Fig 1-A: The EYESI virtual reality ophthalmosurgical simulator B: Display screen C: Training history graph.

Fig 2

 2 Fig 2 Imperial College surgical assessment device (ICSAD) -A: Sensors and motion box B: Data analysis graphs

Table 1 -

 1 Comparison of OASIS and GRASIS.


Ameenat Lola Solebo

Isabelle Russell-Eggitt

Ken K Nischal

Anthony T Moore

Phillippa Cumberland

Jugnoo S Rahi
email: j.rahi@ich.ucl.ac.uk

Cataract surgery and primary intraocular lens implantation in children ≤2 years old in the United Kingdom and Ireland: findings of national surveys

Keywords: Cataract Infant Operations Lens Implantation, Intraocular Methodology, Survey

Background

We have investigated the current patterns of practice relating to primary intraocular lens (IOL) implantation in children ≤2 years old in the UK and Ireland

Methods

National postal questionnaire surveys of consultant ophthalmologists in the UK & Ireland.

Results

76% of 928 surveyed ophthalmologists replied. 47 (7%) of the respondents operated on children aged under ≤2 with cataract. 41 (87%) of respondents performed primary IOL implantation, but 25% would not implant an IOL in a child under 1 year old. 88% of surgeons used limbal wounds, 80% manual capsulotomies, 98% posterior capsulotomies, and 100% hydrophobic acrylic lenses. The SRK/T formula was most commonly used (70%). Exclusion criteria for primary IOL implantation varied considerably and included microphthalmos (64% of respondents), anterior and posterior segment anomalies (53%, 58%), and glaucoma (19%).

Discussion

Primary IOL implantation in children ≤2 has been widely adopted in the UK & Ireland.

There is concordance of practice with regards to surgical technique and choice of IOL model. However, variation exists in eligibility criteria for primary IOLs: this may reflect a lack of consensus on which children are most likely to benefit. Thus there is a need for systematic studies of the outcomes of primary IOL implantation in younger children.

BACKGROUND

Primary intraocular (IOL) implantation has become accepted practice for older children with cataract. 1;2 Whilst primary IOL implantation is being increasingly undertaken in children in the first 2 years of life, 3;4 the long term benefits and the factors associated with positive and negative outcomes are unclear. 1;2;5-9 The British Isles Congenital Cataract Interest Group (BCCIG), a research network comprising British and Irish ophthalmic consultants, was established in 1995 in order to study the incidence, detection, causes, management and outcomes of congenital and infantile cataract. [START_REF] Rahi | Congenital and infantile cataract in the United Kingdom: underlying or associated factors. British Congenital Cataract Interest Group[END_REF][START_REF] Rahi | Ascertainment of children with congenital cataract through the National Congenital Anomaly System in England and Wales[END_REF][START_REF] Chak | Long-term visual acuity and its predictors after surgery for congenital cataract: findings of the British congenital cataract study[END_REF][START_REF] Chak | The health-related quality of life of children with congenital cataract: findings of the British Congenital Cataract Study[END_REF][START_REF] Chak | Incidence of and factors associated with glaucoma after surgery for congenital cataract: findings from the British Congenital Cataract Study[END_REF] A national epidemiological study to investigate outcomes following primary IOL implantation in children ≤2 years old with congenital and infantile cataract is now being undertaken through the BCCIG. As a foundation for this research, we have investigated the surgical management of cataract in younger children in the UK and Ireland, with a focus on primary IOL implantation.

METHODS

In October 2008, 960 consultants comprising all members of the BCCIG, all consultant members of the Royal College of Ophthalmologists and Irish consultant ophthalmologists with a known interest in congenital cataract, were contacted using postal questionnaires accompanied by hand addressed cover letters and postage paid reply envelopes. Members of the BCCIG who did not respond to the mailing were sent reminders.

We sought to discover the number of children ≤2 years old with congenital or infantile cataract managed over the previous year, the number undergoing surgery with and without primary IOL implantation and the details of surgical management. Respondents were asked to estimate the number of children managed over the preceding year. Exclusion criteria for primary implantation in children ≤2 were requested, as was preferred IOL model and IOL power calculation formulae together with details of surgical technique including lens aspiration and vitrectomy approaches and capsulotomy practices. The post operative measurement of axial length was also investigated.

Statistical analysis

Free text answers on exclusion criteria were coded. Descriptive analysis of the responses was undertaken.

RESULTS

32 of the 960 distributed questionnaires were returned as undeliverable. 709 (76%) of the remaining 928 contacted consultants replied to the survey. Replies were received between October 2008 and January 2009. 47 (7%) of the 709 respondents stated that they operated on children ≤2 years old, estimating that over the preceding year they had operated on a total of 301 children. 6 (13%) of the 47 surgeons did not perform primary IOL implantation in any child ≤2. The 41 surgeons who did perform primary IOL implantation estimated that in the preceding year they had operated on 268 children (116 with unilateral, 152 with bilateral cataract), undertaking primary IOL implantation in 65% (table 1).

How many children ≤2 years old have you operated on over the last year? (47 surgeons)

Unilateral cataract

Bilateral

Exclusion criteria

Exclusion criteria for primary IOL implantation in children ≤2 were provided by 36 of the 41 respondents. 6 (17%) surgeons did not mention any ocular anomaly amongst their stated exclusion criteria. 23 (64%) described specific anomalies which would prevent them from implanting an IOL. Of these, 16 cited short axial length or microphthalmos, with 5 specifying different lengths below which they would not implant (16, 18 and 20mm). Anterior and posterior segment anomalies were exclusion criterion for 12 and 14 respondents respectively. 7 (19%) respondents considered the presence of any co-existent ocular anomaly to be sufficient cause for exclusion. Thus, microphthalmos is an exclusion criteria for 64% (23/36) of respondents, anterior segment anomaly 53% and posterior segment anomaly 58%. 9 (25%) cited microcornea, with surgeons again specifying differing corneal diameters, either below 9mm (3 respondents) or 10mm (3 respondents). 7 (19%) cited persistent hyperplastic primary vitreous (PHPV, or persistent fetal vasculature), with 5 of the 7 specifying 'significant' PHPV. Other stated exclusion criteria included abnormal capsular support (10/36 or 28%, with 4 respondents specifying ectopia lentis), glaucoma (7/36, 19%) and uveitis (3/36, 8%). The age of the child was cited by 6/36 (17%) of the 36 respondents. Different minimum age limits were used: 12 months, 6 months and 1 month old minimal ages by 3, 2 and 1 respondent respectively. Thus, 25% (9/36) of respondents would not perform primary IOL implantation in any child under 1 year old. 7 (19%) consultant ophthalmologists commented on parental preference as an exclusion criterion for primary IOL implantation.

Details of routine surgical management

As shown in table 2, all respondents used a hydrophobic acrylic IOL, with 90% using an Acrysof model. 70% reported using the SRK/T formula for IOL power calculation, with 37% using it in combination with the Hoffer Q formula. 6 respondents specified that they used either formula, dependent on the axial length of the child. With regards to routine surgical technique, 80% of surgeons used limbal wounds for surgery; manual capsulotomy techniques were used by 88%; posterior capsulotomies were created by all but 1 surgeon.

Of those using posterior capsulotomies, 78% also performed anterior vitrectomy with 16% stating that their surgical approach (anterior versus posterior) depended on the axial length or age of the child. The majority of respondents (71%) do not routinely post-operatively measure the axial lengths of pseudophakic children.

Number of respondents

DISCUSSION

Cataract surgery in children ≤2 is undertaken by a small group of sub-specialists in the UK and Ireland. Whilst the technical demands of surgery are considerable, our finding that fewer than 1 in 20 responding consultants undertake cataract surgery in these children may be an indication of the level of post operative ophthalmic, orthoptic, optometric and supportive nursing care necessary to achieve a good outcome. Primary intraocular lens implantation in children ≤2 has been adopted by the majority of the responding surgeons who manage children with cataract. There exists concordance of surgical approach, with most surgeons choosing an AcrySof hydrophobic acrylic IOL, manual curvilinear anterior capsulorhexis, limbal wound access and posterior capsulotomy with anterior vitrectomy.

However, our finding that variability exists with regards to exclusion criteria suggests that there is disparity of opinion on which children will benefit following primary IOL implantation, and which children are at least risk of complications and poor outcome.

Whilst this disparity may be due to differing personal preferences within a relatively new and evolving field, it may also be a reflection of absences within the evidence base on the practice of primary IOL implantation in children ≤2.

The high (76%) response rate to this postal survey is, we believe, an indication of the current relevance of this issue to all ophthalmologists. This figure is high in comparison to other published work, 4;15;16 and strengthens the generalisability of our findings. We recognise that the use of free text responses may have precluded comprehensive responses in relation to exclusion criteria for primary IOL implantation. We also believe that the estimated total of 301 children undergoing cataract surgery over the preceding year, as reported in this survey, may be an overestimate: previous work undertaken through the BCCIG has shown that between 1995 and 1996, 168 children under 2 were diagnosed with congenital or infantile cataract in the UK, with surgery undertaken in 165, Previously published literature exists on international practice styles and preferences in paediatric cataract surgery and IOL implantation, [START_REF] Wilson | Pediatric cataract surgery and intraocular lens implantation: practice styles and preferences of the 2001 ASCRS and AAPOS memberships[END_REF] and also preferences of surgical specifics such as IOL model [START_REF] Wilson | Choice of intraocular lens for pediatric cataract surgery: survey of AAPOS members[END_REF] and capsulotomy method. [START_REF] Bartholomew | Pediatric anterior capsulotomy preferences of cataract surgeons worldwide: comparison of 1993, 2001, and 2003 surveys[END_REF] In 2003, Wilson et al [START_REF] Wilson | Pediatric cataract surgery and intraocular lens implantation: practice styles and preferences of the 2001 ASCRS and AAPOS memberships[END_REF] surveyed members of the American cataract and paediatric sub-speciality societies and reported that up to 89% of respondents would implant IOLs in a child ≤2 with unilateral cataract, and 78% in a child ≤2 with bilateral cataract. Hydrophobic acrylic IOLs were used by 71% of paediatric surgeons. There was disagreement on whether microphthalmos, anterior segment anomalies, or persistent fetal vasculature were contraindications to IOL placement in children. Whilst these findings are of interest, only 2% of the respondents to that survey were UK consultants. As such, the findings are not necessarily readily extrapolated to practices in the UK and Ireland.

Better understanding of visual development and amblyopia, 17;18 and the introduction of mechanical lensectomy, mechanical vitrectomy, capsulotomy techniques, ophthalmic viscous devices and other novel technologies 1;2 have led to improvements in visual outcomes for children with cataract. 2;19 Primary IOL implantation has become the treatment of choice in older children, with medium to longer-term outcome data becoming available, 2;3;20 and there is good biocompatibility evidence for IOL material implantation in young eyes. [START_REF] Wilson | Intraocular lenses for pediatric implantation: biomaterials, designs, and sizing[END_REF] Short term visual rehabilitation following IOL implantation in early childhood is at least comparable to that with contact lens correction of surgical aphakia 5;7;22;23 but there is uncertainty about both the long-term benefits and the risks of primary IOL implantation in children aged under 2 years, with regards to the predictability of refractive outcomes with different power equations, post operative complication rates and the need for further surgery. 7;23-25 The Infant Aphakia Treatment Study, currently underway in North America, is investigating outcomes in a defined cohort of infants under 6 months old with unilateral cataract [START_REF] Wilson | ASCRS white paper. Hydrophobic acrylic intraocular lenses in children[END_REF] following standardised cataract surgery with and without primary IOL implantation. Their findings will be welcomed by paediatric ophthalmic surgeons. Nevertheless, further research is necessary on outcomes within a more diverse group of patients, in particular older infants and those with bilateral cataract or other ocular disease, as well as outcomes in settings outside the US where management practices and health care systems differ.

Whilst our findings reflect the increasing adoption of IOLs for children ≤2, 13% of consultants reported that they would not use primary IOLs in any child ≤2 yrs old, a quarter would not use IOLs in a child under 1 year old, and there exists notable variance in the cited exclusion criteria. A national epidemiological study into primary IOL implantation in children ≤2, now underway through the BCCIG, should address important unanswered questions on the outcomes and predictors of outcomes of primary IOL implantation in a nationally representative cohort of children ≤2 years old.

how many children ≤2 years old have you performed primary IOL implantation over the last year?

			cataract	Total
	Median	2	2.5	5
	Range (min to max)	0-10	0-15	0-25
	Total	133	168	301
	In (41 surgeons)
		Unilateral cataract	Bilateral cataract	Total
	Median	2	1	2
	Range	0-8	0-14	0-19
	Total	87	86	173
	As a proportion of children	75%	57%	65%
	undergoing surgery	(87/116)	(86/152)	(173/268)

Table 1 .

 1 Surgical management of children ≤2 with cataract: number of children undergoing surgery as estimated by respondents

(n=41) IOL model

	MA60	14
	MA30	13
	SA60	8
	SN60AF	4
	SN60 IQ	3
	AMO	4
	Sensar	3
	Tecnis	1
	HoyaVA	1
	IOL power calculation formulae
	SRK/T	28
	Hoffer Q	21
	SRK/T + Hoffer Q	14
	Holladay I	6
	SRK II	3
	Haigis	1
	IOL placement
	In the bag	40
	Optic capture	1
	Wound creation
	Limbal	33
	Scleral	8
	Limbal or scleral	2
	Clear corneal	3
	Anterior capsulotomy technique
	Manual	36
	Diathermy	4
	Vitrectorrhexis	3
	Posterior capsulotomy and vitrectomy
	No posterior capsulotomy	1
	No vitrectomy	9
	Vitrectomy via anterior approach	25
	Vitrectomy via posterior approach	17
	Post operative axial length routinely measured post operatively
	Yes	12
	No	29

Table 2 .

 2 Details of surgical management

Competing Interests: The authors have no competing interests to declare. 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


Retinal thickness measurements and segmentation performance of four different spectral and time domain OCT devices

Mylonas et al evaluate the reliability of different OCT devices and scanning patterns in the assessment of retinal thickness and segmentation performance in 28 eyes with nAMD and 10 healthy eyes. Radial scans (6 mm) were compared between Stratus and Topcon OCT, in addition to raster scans of three SDOCT devices (Topcon, Spectralis, Cirrus). Retinal thickness values were generally higher in SD-OCT analysis. Spectralis SD-OCT demonstrated the highest values of central retinal thickness and Topcon OCT raster scans showed the lowest values. The authors conclude that further development of current algorithms is necessary to improve quantification of retinal thickness.

Intravitreal pegaptanib for proliferative diabetic retinopathy

Gonzalez et al compared the efficacy of intravitreal pegaptanib (IVP) with panretinal laser photocoagulation (PRP) in the treatment of active proliferative diabetic retinopathy (PDR) in a prospective, randomised, controlled, open label, study. Twenty subjects with active PDR were randomly assigned at a 1:1 ratio to receive treatment in one eye either with IVP (0.3 mg) every 6 weeks for 30 weeks or with PRP. All IVP eyes were completely regressed by week 12, and maintained through week 36. In the PRPtreated group, at week 36, two eyes demonstrated complete regression, two showed partial regression, and four showed persistent active PDR. Although, IVP produced rapid regression of PDR, which was maintained throughout the study period, on subsequent follow up, most of the IVP-treated eyes required PRP for recurrent PDR.

Predicting visual success in macular hole surgery

Gupta et al identified factors that predict visual success (better than 6/12) following macular hole surgery by retrospectively analysing the data of 133 patients who underwent standard macular hole surgery. Multivariable regression analysis identified that age, preoperative visual acuity and the preoperative maximum macular hole were significant predictors of visual success. The resulting model correctly classified the visual outcome of 80% of cases.

Cataract surgery and primary IOL implantation in children (UK and Ireland)

Solebo et al (British Isles Congenital Cataract Interest Group) report on current patterns of practice relating to primary intraocular lens (IOL) implantation in children (2 years old in the UK and Ireland). 76% of 928 surveyed ophthalmologists replied. 88% of surgeons used limbal wounds, 80% manual capsulotomies, 98% posterior capsulotomies and 100% hydrophobic acrylic lenses. However, exclusion criteria for primary IOL implantation varied considerably. The authors conclude that there is a need for systematic studies of the outcomes of primary IOL implantation in younger children.

Long-term surgical success of Ahmed Valve implant versus trabeculectomy in POAG

Tran et al compared the long-term intraocular pressure (IOP) outcomes of Ahmed Glaucoma Valve (AGV) implantation to trabeculectomy with mitomycin C (MMC) in 78 POAG patients who underwent AGV implantation with matched 88 POAG patients who underwent trabeculectomy with MMC with a minimum follow-up of 3 years. The 5-year cumulative probability of success (IOP < 21 mm Hg and a reduction of IOP>15% from baseline) was not statistically significant between the 2 groups. However, when a greater IOP reduction was desired (IOP < 18 mm Hg and a reduction of IOP>20% from baseline), trabeculectomy with MMC had a higher rate of success.

HRT-3 Moorfields reference plane

Asaoka et al assessed the effect of the Moorfields Reference Plane on Heidelberg Retina Tomograph (HRT) rim area repeatability and its effect on progression rates using event analysis. The Moorfields RP was applied to HRT images from 198 ocular hypertensives, acquired over 6 years. The frequency of identified progression using Moorfields RP was 40% compared with 28% for the 320 RP. The authors conclude that using Moorfields RP results in greater rates of detection of change.

Orbital decompression for Graves' orbitopathy

Mourits et al analysed data from euthyroid patients with inactive GO who had undergone orbital decompression for disfiguring proptosis from 11 European centers (European Group on Graves' Orbitopathy [EUGOGO]). The swinging eyelid approach was the most popular followed by the coronal and transconjunctival approaches, achieving average proptosis reduction of 5.0 mm. The proptosis reduction was significantly greater than after three-wall than two-wall decompression. Additional fat removal augmented the proptosis reduction. Complications were rare, the most frequent being worsening of motility, occurring more frequently after coronal decompression.

Tends in the incidence of conjunctival melanoma in Sweden

Triay et al studied the time trends (1960 to 2005) in the incidence of conjunctival melanoma in Sweden (n=170). The age-standardised incidence of conjunctival melanoma increased significantly in men from 0.10 cases/million to 0.74 cases/million and in women from 0.06 cases/million to 0.45 cases/million. The annual relative change in agestandardised incidence was 16.9% in men and 19.5% in women. During the period of study, tumours became smaller and thinner at the time of diagnosis and increasingly arose from parts of the conjunctiva exposed to ultraviolet radiation.


Paul Silcocks
email: paul.silcocks@trentcancer.nhs.uk

Keywords: survival analysis, funnel plots, over-dispersion

Objectives: Description of Cox regression model for using hazard ratios to compare survival between institutions with adjustment for covariates and allowance for overdispersion.

Design

: Analysis of simulated and real survival data Setting: Applicable to evaluation of clinician or institutional performance, but illustrated using populations at Primary Care Trust & Local Authority level. Results: It describes how centred hazard ratio estimates adjusted for covariates can be obtained from a Cox regression and gives details of the necessary programming in Stata. Allowance for over-dispersion can be made by multiplying the standard errors by a factor based on either the model or the log-rank chi-squared statistics. Simulated results and a real example are presented. Conclusion: Funnel plots based on Hazard ratios are easier to interpret than multiple Kaplan-Meier survival plots, and in contrast to funnel plots based on survival at, say, 5 years, are less open to accusations of bias and use more information. The interpretation of such plots may be enhanced by using standard meta-analysis methods. Hazard ratio comparisons may now be added to the repertoire of techniques used by Cancer Registries, Primary Care Trusts, and other commissioners of Health Care

INTRODUCTION

A range of statistical procedures exists to ensure quality control of manufacturing processes. One of the simplest is a control chart, in which a measure of some critical aspect of quality for each item manufactured is plotted against time, with boundaries to indicate when quality has become unacceptable -that is, when the process is "out of control". Control charts are closely related to hypothesis tests, in that the control chart tests the null hypothesis that the process is in statistical control.

Although funnel plots have been used as evidence in assessing publication bias since the mid 1980s [START_REF] Light | Summing Up: The Science of Reviewing Research[END_REF], their value as a form of control chart for graphically comparing institutional performance was suggested by Spiegelhalter only relatively recently [START_REF] Spiegelhalter | Funnel plots for comparing institutional performance[END_REF].

The difference between this method and the usual control chart is that the funnel plot gives a snapshot of many institutions at a particular moment in time, as opposed to a measuring performance of a single institution at many moments in time over a defined period. In his paper Spiegelhalter described how control limits could be set for binomial proportions (including various functions of proportions including changes, ratios and odds ratios), standardised rates, ratios of SMRs and continuous response data, but not for survival data.

When survival is to be compared between institutions, comparison at only one time point involves picking an arbitrary time (eg at 5 years) which may hide a real difference that would be obvious if the whole survival curves were compared [START_REF] Esteve | Statistical methods in cancer research volume IV[END_REF][START_REF] Peto | Design and analysis of randomised clinical trials requiring prolonged observation of each patient. II: analysis and examples[END_REF]. Moreover the proportion surviving at a particular time has a relatively large standard error, whereas an overall comparison that reflects the whole survival curve, such as one based on a proportional hazards model, might detect a significant difference [START_REF] Esteve | Statistical methods in cancer research volume IV[END_REF]. A point mentioned by a reviewer is that some restriction of follow-up, for example to 5 years post-diagnosis (or less than this for some purposes), is advisable, to avoid potential biased (or diluted/attenuated) comparisons if later follow-up is available for some groups. While a proportional hazards model may not be suitable for detecting every kind of discrepancy between survival curves, it is reasonable for a control chart in which the null assumption is that the process is "in control" and therefore the survival curves for each institution should differ simply by chance (in addition with a restricted follow-up the proportional hazards model is more likely to hold at least approximately).

While a Cox regression could be used to estimate and formally compare the hazard ratios, two points need to be considered. Firstly, such a comparison uses one of the institutions as a reference category, so to obtain a hazard ratio for each institution the hazard ratios (or rather their logarithms) need to be centred -that is, estimated with reference to a common value. This transformation will also require a transformation of the covariance matrix of the regression coefficients corresponding to the log hazard ratios for each institution. Secondly the control limits correspond to confidence limits assuming the null hypothesis is true (ie that survival curves differ only by chance), and therefore the reported covariance matrix of the regression coefficients is inappropriate.

METHOD

If there are three centres each represented by a 0/1 indicator variable, the proportional hazards model can be represented as: In which D 3 -the indicator for the third (and reference) centre -can effectively be ignored provided its corresponding regression coefficient β 3 is constrained to be zero.

The log hazard ratios are to be shifted so that they sum to a value of zero (which, if the process is in control, should also be close to their common mean). The principle involved in shifting them is as follows:

Define: 3 ) ( 3 2 1 β β β γ + + =
Then the shifted coefficients are:

γ γ β β γ β β γ β β - = - = - = - = 3 * 3 2 * 2 1 * 1
(the last because β 3 is assumed to be constrained to be zero). However it is also necessary to make a corresponding transformation to the variance-covariance matrix, and in particular the variance-covariance matrix evaluated under the null hypothesis of no between-centre differences. This is because the funnel plot can be thought of as a way of displaying significance test results. These processes are explained at greater length in the appendix, using matrix algebra together with some additional tricks required to extract the required values from computer output.

Covariates

Typically allowance needs to be made for covariates that affect case-mix -age, stage and treatment being likely candidates. While in the Cox regression these variables can be adjusted for by inclusion as covariates, in the log-rank test it is necessary to adjust for these variables by stratification. Because the covariance matrix under the null hypothesis is obtained using the log-rank test, for consistency the same stratification is employed in the Cox regression to estimate the log hazard ratios.

Estimating and handling overdispersion

If overdispersion is present, the variance of the hazard ratios will be greater than predicted by the above model. The consequence is that at first sight a higher proportion of centres may appear to be out of control than is really the case. Spiegelhalter [START_REF] Spiegelhalter | Handling overdispersion of performance indicators[END_REF] suggested a number of approaches to handling overdispersion -the simplest being estimation of a dispersion factor that multiplies the variance of the quantity for which control limits are to be found. This dispersion factor φ (a single value common for all k institutions), may be estimated as the value of the logrank chi-squared calculated in the usual way, divided by its degrees of freedom. Note that the over-dispersion factor modifies the control limits, not the log hazard ratios actually observed and plotted.

The standard approach is to regard values of φ less than one as equal to one (that is, under-dispersion is ignored) -the same assumption as is made in the Der Simonian and Laird [START_REF] Dersimonian | Meta-analysis in clinical trials[END_REF] estimate of between-centre variance employed in meta-analysis, so that the basic estimate of overdispersion is given by:

     > = otherwise if 1 ˆ2 2 ν χ ν χ φ ν ν
where υ is the degrees of freedom for the chi-squared test.

One approach to guard against assuming overdispersion when this is just a chance finding is to set the estimate φ ˆ>1 only if the 2 χ is "statistically significant". However "absence of evidence is not evidence of absence" and in addition the statistical significance will reflect both the extent of overdispersion and the precision of the hazard ratio estimates within each centre.

A better approach suggested by Spiegelhalter [START_REF] Spiegelhalter | Handling overdispersion of performance indicators[END_REF] is to use a Winsorised estimate of φ . This is a method of robust estimation that is less sensitive to outliers. For this the upper and lower most extreme x% of the values in an observed set of values are replaced by the x th and 100-x th percentiles to produce a 2x% Winsorised estimate. The estimated overdispersion parameter φ ˆ can be written as:

1 ˆ1 1 2 - = ∑ - = k z k i i φ
where k-1 is the degrees of freedom and the 2 i z denote the squared standard Normal deviates for each regression coefficient (excluding the k th , reference, value). Spiegelhalter suggested Winsorising the z-scores, so that the Winsorised estimate of φ is given by: Clearly this process must be used cautiously and typically 10% (5 th and 95 th percentiles) or at most 20% (10 th and 90 th percentiles) Winsorising is applied. If only the two extreme observations are Winsorised then 20% Winsorising implies that there must be at least 10 centres, which is close to the advice on the minimum number of degrees of freedom (around 12) needed to estimate a variance reliably [START_REF] Van Belle | Statistical rules of thumb[END_REF].

Note that the Winsorising is only needed to estimate φ and the un-Winsorised but centred log hazard ratio estimates are displayed in the funnel plot.

It is arguable that a Winsorised estimate of φ should be used routinely because one cause of overdispersion is the existence of unmeasured prognostic variables that are consequently not adjusted for in the analysis. Such an inadequate case-mix adjustment is probably the norm in the context of routinely available statistics. One prognostic variable that it is typically possible to allow for is age at diagnosis. When stratifying for age however, the definition of the age bands used should be declared in advance because, for instance, the resulting funnel plot based on equal width age bands may be very different from one in which age bands are defined on the basis of equal numbers of events.

The main distinction to be made on the basis of the funnel plot is between a) general variation caused by factors common to all centres such as case-mix (and which may be addressed by allowing for overdispersion) b) the presence of one or two extreme outliers that may require investigation and which may be detected by Winsorising so that such observations don't influence the estimated standard error, c) skewness in the distribution of random effects, for which Winsorising may be ineffective as the effects are spread across many centres. For the latter, one possibility would be to use tests for asymmetry in funnel plots devised for meta-analysis, [START_REF] Begg | Operating characteristics of a rank correlation test for publication bias[END_REF][START_REF] Egger | Bias in meta-analysis detected by a simple, graphical test[END_REF].

Practical implementation

In Stata, the covariance matrix of the score statistic can be accessed by using sts test, with the logrank option.

1. Assuming that the institutions being compared are labelled 1 to k, with the reference category being the first -delete the first row and column (this is necessary because the covariance matrix is singular) 2. invert the resulting matrix 3. augment this matrix with a new first row and column of zeroes, to give the covariance matrix V 0 of the regression coefficients under the null hypothesis 4. transform V 0 as described above 5. take the square root of each diagonal element of V 0 to give the standard error of each regression coefficient under the null hypothesis, 6. identify extent of overdispersion and adjust standard errors if necessary 7. calculate control limits

apply tests for bias in funnel plot

Code fragments to perform these steps are given in the appendix.

. Once the control limits have been calculated it is easy to plot these with the centrespecific log hazard ratios, using the reciprocal of the standard error under the null hypothesis as a measure of precision, and incorporating Stata meta-analysis add-on commands.

RESULTS

Table 1 displays the centred log hazard ratios for simulated survival data for ten centres, roughly mimicking "old" Health Districts, with stratification for a case-mix covariate in seven bands. The standard errors (of the point estimates under H1), plus 95% and 99% control limits are also given, with and without adjustment for overdispersion (which was induced by including the effect of a centre-level random variable not allowed for in the stratified analysis). For this small data set the Winsorisation did not alter phi. An average of 10 deaths per centre was used in accordance with the 10:1 number of events/variable rule [START_REF] Van Belle | Statistical rules of thumb[END_REF]. Figure 1a shows corresponding conventional survival curves by centre, while in figure 1b these have been adjusted for casemix. The adjusted curves are closer together than the unadjusted ones, but in fact the chi-squared test is not much less significant.

Figures 2a and2b display funnel plots for the data in table 1 (without and with allowance for overdispersion). Figure 3 on the other hand displays results allowing for overdispersion when this has arisen from a positively skewed distribution for the between-centre random effect. While figure 3 superficially resembles figure 2b, the statistics for the asymmetry tests are non-significant for the data in table 1 (continuity corrected Begg's test P = 0.118; Egger's test P = 0.129) but are both significant for figure 3 (continuity corrected Begg's test P = 0.029; Egger's test P = 0.001). Figure 4 displays the Egger plot corresponding to figure 3.

Note that the measure of precision used for these analyses is the reciprocal of the standard error under H0. The justification is that, as described by Tang and Liu, the observed standard error is a function of both risk and sample size. Tang and Liu suggested that funnel plots using sample size as a precision measure might be preferable;

for log hazard ratios under H0 the standard error is inversely related to the total number of events (and is thus independent of the hazard ratio estimate). Winsorising and allowance for overdispersion after omitting the LA with centred coefficient closest to zero to ensure independence of the estimates.

DISCUSSION

It is not easy to detect outliers in survival by inspection of cumulative survival plots as is clear from figure 1, let alone in the presence of over-dispersion. A funnel plot, by converting the survival data into a summary value (the centred hazard ratio) together with defined boundaries, does make this task easier and much less subjective. Covariates that affect survival if unevenly distributed across centres may induce additional variation between institutions or centres; their effect can be allowed for directly by performing a stratified analysis, but if these are not measured, then indirectly by incorporating overdispersion in the significance limits. If both analyses are available then possible to see to what extent the stratified analysis has accounted for all the overdispersion (and if not, it implies that still other, unmeasured, variables are having an effect).

Care is necessary not only in choosing the stratification variables for which adjustment is to be made but also in how these are defined. For example, although age-bands defined on equal numbers of deaths might be preferred as having equal precision, this choice is debatable and the method of constructing age bands and other strata must be made before performing the analysis and inspecting the results to avoid accusations of massaging the data.

The funnel plot allowing for overdispersion should also be assessed as to whether the factor(s) inducing the overdispersion are common to all centres (symmetric plot), whether the distribution of the factors is uneven (asymmetric plot) or whether just one or two centres are outliers -which may be detected by employing a Winsorised estimate for the boundaries. Assessment of asymmetry can employ the same methods as used in meta-analysis to assess publication bias. The results for figure 5 are consistent with the fact that the Egger regression asymmetry test is said to suggest the presence of publication bias more frequently than the Begg rank correlation test, that is, the former test is more sensitive. For meta-analyses these tests lack power, but it is likely that for institutional comparisons there will be more data available than in many meta-analyses.

Regardless of covariates used for adjustment or stratification, casemix for institutional comparisons may still be problematic if selection criteria of cases for treatment (such as surgery) vary or if there are variations in referral patterns, treatment plans and so forth which may or may not be detectable through overdispersion or funnel plot asymmetry, depending on the size and frequency of the effect in question, and the size of the sample being studied. If planning a comparative study, as with any formal investigation, consideration should also be given to the eligibility criteria for cases -for instance whether cases diagnosed elsewhere but referred on would be excluded, which would help increase between-institution homogeneity, but also possibly negate the value of the comparison in highlighting such differences.

The method described here requires relatively little programming to implement, and is capable of being incorporated into more sophisticated routines or batch files for routine analyses. The example .do file displays funnel plots both unadjusted and adjusted for over-dispersion in the estimated hazard ratios, with an additional plot incorporating userspecified extent of Winsorising.

An example data set can be downloaded together with the Stata routine to perform the calculations and plots.

  indicates that the Winsorised values are used.

ACKNOWLEDGEMENTS

All views expressed are personal and do not necessarily reflect Registry policy

WHAT THIS PAPER ADDS

What is already known on this topic

Funnel plots are increasingly becoming a standard tool for comparing institutional performance and for comparisons of survival, a summary measure based on the hazard ratio reflects the whole survival experience is preferable.

What this study adds

This paper explains the theory of how centred hazard ratio estimates can be obtained from a Cox regression, with funnel plot control limits obtained from the log-rank test, with or without adjustment for overdispersion. The method for obtaining robust (Winsorised) estimates of the overdispersion parameter is also explained and advice is given on stratification for covariates.

Stata code is given for practical implementation of the methods, and it is suggested that standard meta-analysis tools be used to assess asymmetry as an aid to interpretation of outliers in the funnel plot.

POLICY IMPLICATIONS

Hazard ratio comparisons may be added to the repertoire of techniques used by Cancer Registries, Primary Care Trusts, and other commissioners of Health Care.

Appendix 1: Algebraic details

In order that the log hazard ratios sum to zero (corresponding to the null hazard ratio of 1), the mean of the regression coefficients must be subtracted from each one: With k institutions, the shifted i th regression coefficient is given by:

With k β (for the reference category) being zero. This transformation can be written in matrix form as

where the kxk matrix T has the form:

If the variance-covariance matrix of the untransformed regression coefficients under the null hypothesis is V 0 , then the transformed coefficients have covariance matrix given by:

Where T' is the transpose of T.

Under the null hypothesis, the covariance matrix of the test statistic has elements of the form [START_REF] Le | Applied Survival Analysis[END_REF]:

on the leading diagonal, with off-diagonal elements of the form:

where the ij N , kj N are the number of subjects alive at time j in groups i and k; j d is the number of deaths occurring at time j, and j N is the total number of subjects alive at time j.

The subscript j runs from1 to t, reflecting each death time, while subscripts i, k label different institutions. The Cox model assumes there are no ties on death times, so that all the d j are equal to 1.

It can be shown that the covariance matrix for the regression coefficients is given by minus the inverse of the covariance matrix of the score statistic after deleting the row and column corresponding to the reference category (because the covariance matrix of the score statistic is singular). After inversion, the dropped row and column can be "added back" with entries of zero, because the regression coefficients for the reference category -being a constant (zero) -have variances equal to zero also. After this the covariance matrix of the regression coefficients (under H 0 ) can be transformed as described above.

Appendix 2: Stata Code

/* APPENDIX: Stata example code to create centred log hazard ratios and obtain funnel plots.

In the example data set the institutions to be compared are denoted by the variable "centre", and the observations have been age-stratified into the variable "group".

The stratification variable in the example dataset is ageband

The basic, overdispersed and overdispersed (Winsorised) plots are produced and saved automatically in the current directory

The metabias add-on needs to be installed for evaluation of asymmetry


Alfredo Menéndez-Navarro

Esteban Rodríguez-Ocaña

Hookworm in Rural Spain, 1910-1960: Shifting Paradigms around the Civil War

Keywords: Hookworm disease, Rural Health, Preventive Health Services, Environment and Public Health, Spain

In Spain, hookworm infection was first recognised as a miners' disease at the beginning of the 20 th century, leading to the adoption of legislative and public health measures. From 1924, surface foci were also detected in some highly productive agricultural lands, and specific health campaigns were developed in Murcia to match the successful intervention in mines. Hookworm was explained in terms of the geographical and human environment and largely attributed to poor working and living conditions. New rural foci were detected after the Civil War , but this time the health administration did not intervene, due to economic shortages or because of the leading role taken by the Institute for Colonial Medicine in this field. Understanding of the disease changed, with a new emphasis on its impact on reproduction, and medical explanations pointed to the negative moral conditions of peasants rather than social issues.

INTRODUCTION

Concerns about the role of the environment in health contributed to the development of a specific corpus of knowledge in European countries around Public Health (Higiene Pública in Spanish). During the 19 th century, studies in Spain focused mainly on urban populations, as elsewhere in Europe. Health problems in the countryside attracted little attention from these new experts and from the ruling elites, since the cities were generally understood to be the physical and moral setting of modern life. An urban/rural divide developed, associating rural culture with backwardness and tradition, opposed to progress. At the same time, however, a belief in the healthy qualities of the rural life arose in response to demographic data that consistently depicted higher mortality rates in the urban setting.

Nevertheless, by the early 20 th century, the so-called 'myth of the healthy rural life' had been debunked by new evidence from microbiologists and parasitologists. [START_REF] Barona | Health and Medicine in Rural Europe (1850-1945[END_REF][START_REF] Barona | Health, medicine and cultural interaction in rural Spain 1875-1936[END_REF][START_REF] Galiana | El problema sanitario de España: Saneamiento y medio rural en los primeros decenios del siglo XX[END_REF] Thus, a Rural Health Bureau was founded in Spain in 1910 with the premise that 'the healthy qualities of the countryside are illusions, as soils and sub soils are unclean, air and water are impure, food is not always safe and dwellings are not healthy'. [START_REF]del Campo eleva como resultado de la inspección que ha practicado en las regiones de Castilla la Vieja[END_REF] Ancylostomiasis or hookworm disease undoubtedly played a role in this change. This parasitism was first reported in humans in 1838 and became recognised as an endemic disease in rural environments and a hazard in underground work by the end of the 19 th century. It was generally first framed as an industrial malady in Europe, linked to underground work in mining or tunnel works and held responsible for a chronic weakness that reduced the productivity of the workforce. In Spain, however, as in Italy and some other Mediterranean countries, hookworm also became considered a risk in agriculture. [START_REF] Ettling | The role of the Rockefeller Foundation in hookworm research and control[END_REF][START_REF] Rodríguez-Ocaña | Higiene contra la anemia de los mineros. La lucha contra la anquilostomiasis en España (1897-1936)[END_REF][START_REF] Rodríguez-Ocaña | La tardía intervención higiénica en el medio rural español: el caso de la lucha contra la anquilostomiasis, 1910-1960[END_REF] The aim of this paper was to compare the rationale and content of public health interventions against rural hookworm in Spain between before and after the Civil War . The pre-war period saw a growing interest in rural health problems, as a part of a strategy to promote national regeneration and the democratic concept of citizenship as the sum of personal rights and duties in education, health and welfare. This found its greatest expression in the Republican health reform, which made rural health centres the axes of the entire public health system and preserved the educational approach to massive interventions that had been developed in conjunction with the Rockefeller Foundation in the 1920s. [START_REF] Barona | Health, medicine and cultural interaction in rural Spain 1875-1936[END_REF] Surprisingly, under Franco's dictatorship, the national public health organisation was supplemented with the Institute of Colonial Medicine, which became actively involved in fighting rural hookworm in the Peninsula. While the measures were similar in design to those attempted in the pre-war period, the Institute introduced moral and religious explanations linked to the reactionary values of the winners of the Civil War.

ENTER HOOKWORM: THE FORMING OF A NEW SOCIAL DISEASE

The unequal distribution of land had been a long-lasting social problem in Spain. Liberal policies in early 20 th century Spain fuelled modernisation of agriculture and supported irrigation projects. These policies led to the first health surveys of the countryside by the Rural Health Bureau, which was active between 1910 and 1918. The surveys focused on malaria and drinking water quality and detected no surface foci of hookworm disease. [START_REF]Avances de los inventarios de Paludismo y Aguas Potables. Datos remitidos por los Inspectores Regionales[END_REF] However, findings in the Linares-La Carolina lead-mining district (Southern Spain) provided epidemiological evidence to support the first legislation against hookworm in the mining industry, passed in 1912 and 1916 (Figure 1). Implementation of these measures was resisted by mining employers, who were obliged to fund medical examinations of the workforce and drug treatments and to temporarily exclude infected workers from underground activities. [START_REF] Rodríguez-Ocaña | Higiene contra la anemia de los mineros. La lucha contra la anquilostomiasis en España (1897-1936)[END_REF] The social effects of the First World War in Spain led reformist political sectors to adopt policies to promote social peace, including rural health. Thus, a state anti-malaria campaign was launched in 1920, led by Dr. Gustavo Pittaluga, head of the Spanish human parasitological school. [START_REF] Rodríguez-Ocaña | International Health Goals and Social Reform: The Fight against Malaria in Interwar Spain[END_REF][START_REF] Rodríguez-Ocaña | The birth of the anti-malaria campaign in Spain during the first 30 years of the 20th century: scientific and social aspects[END_REF] As stated by Pittaluga in 1927, the main goal of the antimalaria fight was to provide rural people with a minimum of well-being, 'without which there is no human dignity or consciousness of citizenship'. [START_REF] Pittaluga | Médicos e ingenieros en la lucha contra el paludismo[END_REF] New legislation on the prevention of hookworm in mines was passed in 1926, [12] following implementation of the 1922 agreement between the Rockefeller Foundation and the Spanish government. [START_REF] Rodríguez-Ocaña | Foreign Expertise, Political Pragmatism and Professional Elite: The Rockefeller Foundation in Spain, 1919-39[END_REF] A few weeks after his arrival in December 1924, Dr. Charles Bailey, IHB's envoy to Spain, realised that no-one was concerned about hookworm in Spain, with the exception of a few members of the medical profession. However, as in other countries, the IHB succeeded in making hookworm a health priority for the Spanish authorities, [START_REF] Birn | Marriage of convenience: Rockefeller international health and revolutionary Mexico[END_REF] supported by epidemiological evidence of its high incidence in mining districts (an estimated 10,000 miners were affected in 1925). The Board argued that hookworm could be easily eradicated and therefore offered the possibility of a successful public health intervention. [START_REF] Rodríguez-Ocaña | Higiene contra la anemia de los mineros. La lucha contra la anquilostomiasis en España (1897-1936)[END_REF] From this perspective, the campaign implemented in mining districts can be viewed as a tactic to promote the legitimacy of public health action, considered the sum of educational, environmental and medical practices. Hookworm disease could be diagnosed and easily treated and could be prevented by the use of reliable drugs and latrine construction. This made its eradication an ideal first challenge for the new public health approach that would generate popular support for permanent preventive health services. [START_REF] Luengo | La conquista de la anquilostomiasis[END_REF] A Mining Health Bureau created to enforce the legislation was merged with the Central Anti-Malaria

Commission in 1930.[16]

Surface hookworm disease became visible thanks to successes in treating miners' ancylostomiasis and the development of the malaria campaign, which brought parasitological expertise and free clinical advice to rural populations and organised local screenings, e.g., for schoolchildren. In the late 1920s and pre-war 1930s, there were a number of epidemiological studies in some highly productive agricultural areas, i.e., the irrigated plain around the city of Murcia (La Huerta), irrigated areas along the river Jucar in Valencia (Ribera Baja), the rich lands of La Plana in Castellon and the rice-producing delta of the river Ebro (Figure 1). [START_REF] Fornos | Contribución al estudio de la anquilostomiasis en el Reino de Valencia[END_REF][START_REF] Guillamón | El problema de la anquilostomiasis en la Huerta de Murcia[END_REF][START_REF] Pino | La Anquilostomiasis en Castellón[END_REF][START_REF] De La Cuesta | Aportaciones al estudio de la anquilostomiasis[END_REF][START_REF] Almiñana-Gandía | La anquilostomiasis en los pueblos de la Ribera Baja de Valencia[END_REF][START_REF] Del Rey | Contribución al estudio clínico de la anquilostomiasis[END_REF] Most surveys confirmed the existence of surface endemic foci, linking them to the natural and human environment, including working and living conditions. Two sets of environmental factors were described, differentiated by their susceptibility to human intervention. [START_REF] Guillamón | El problema de la anquilostomiasis en la Huerta de Murcia[END_REF] Records were made of the physical conditions, including the nature and humidity of soils and mean temperatures, in order to relate empirical data [local reality] to available scientific information [universal knowledge]. Winter-summer temperature differences periodically reduced the number of viable larvae on the land, thought to be one reason why the contagion was not universal in these endemic regions. [START_REF] De La Cuesta | Aportaciones al estudio de la anquilostomiasis[END_REF] All of the hookworm surveys, as in malaria studies, also compiled ethnographic data on the daily tasks and employment of peasants. They paid special attention to the common practice of travelling from one area to another for seasonal work. There were medical debates about the risk posed by rice growing, a major agricultural activity in the province of Valencia. Some reports depicted rice fields as 'natural latrines' for the transmission of hookworm. [START_REF] Fornos | Contribución al estudio de la anquilostomiasis en el Reino de Valencia[END_REF] The rice-growing year was considered to comprise three epidemiological stages: an aseptic stage in September-October, a mildly infective stage from February to April and in August, and a fully infective stage in May, June and July. Differences were related to the presence of migrant seasonal workers, the desiccation of lands and the rhythm and the intensity of work. [START_REF] Fornos | Contribución al estudio de la anquilostomiasis en el Reino de Valencia[END_REF] Another report offers a detailed description of the journeys made every year by peasant work-teams or cuadrillas from La Marina county in Alicante. [START_REF] Pino | La Anquilostomiasis en Castellón[END_REF] Ten years later, however, other authors claimed that the epidemiological importance of rice fields had been overestimated. They reported that the flooding of land halted development of Ancylostoma larvae and that desiccation occurred at times of the year when low temperatures acted as a 'natural disinfectant'. They proposed that sandy and very humid lands were much more favourable environments for hookworm transmission, citing the vegetable-and fruit-producing plains of the Ribera Baja. They noted that almost all rice workers also worked actively in vegetable fields and orchards. [START_REF] Del Rey | Contribución al estudio clínico de la anquilostomiasis[END_REF] In all working situations, these peasants, barefoot and with little clothing, would work from sunrise to sunset, having to rest, eat and defecate in the fields. These were permanent high-risk features of the working environment.

The disposal of human and animal excrement in the home was also described. [START_REF] Guillamón | El problema de la anquilostomiasis en la Huerta de Murcia[END_REF][START_REF] Almiñana-Gandía | La anquilostomiasis en los pueblos de la Ribera Baja de Valencia[END_REF] Dung was a vital fertilizer and was stored in the back yard of peasant homes, next to the half of the house used as a barn. Humans defecated in the same yard, which was a playground for children. Only a very few houses in villages or out in the countryside had a lavatory or latrine, sometimes connected to a nearby stream or river. The continuous re-infection of women and young children in the Huerta of Murcia was attributed to these conditions. [START_REF] Guillamón | El problema de la anquilostomiasis en la Huerta de Murcia[END_REF] In contrast, there was a clearly lower presence of hookworm in towns with sanitation and drinking water systems and better nutritional levels. [START_REF] Fornos | Contribución al estudio de la anquilostomiasis en el Reino de Valencia[END_REF] Out of all of the regions with detected endemics, only Murcia succeeded in developing a full-fledged health campaign with a network of rural dispensaries (Figure 2). The campaign started in 1926 and was supported by the Rockefeller Foundation from 1928 until mid-1931, when it came under the National Health Department. [START_REF] Hernández-Pacheco | Ensayo de higiene rural en la huerta de Murcia. Resumen de los trabajos realizados durante el primer semestre de 1931[END_REF][START_REF] Hernández-Pacheco | Estudio sanitario de un partido rural en la Huerta de Murcia[END_REF] Demands for a similar intervention in an endemic area in Valencia province in 1933 do not appear to have been successful, possibly due to the growing political crisis that led to the outbreak of the Civil War. Proposals for a comprehensive prophylaxis policy included: domestic and village sanitation; control of human excrement; a general education campaign; and a full survey of land-workers and families that incorporated a census of hookworm-affected workers, who would be excluded from land work until cured. All measures would be funded by local governments, the National Health Department and the Rockefeller Foundation. [START_REF] Almiñana-Gandía | La anquilostomiasis en los pueblos de la Ribera Baja de Valencia[END_REF] The medical authors cited above all framed surface hookworm infection as a social disease. As in mining districts, they emphasised the impact of this debilitating illness on worker productivity and the Spanish economy.

HOOKWORM IN RURAL SPAIN AFTER THE CIVIL WAR

Health conditions in Spain had considerably worsened by the end of the war. The destruction of health facilities, the extension of malnutrition and the outbreak of smallpox, diphtheria, typhus and malaria epidemics shaped the health landscape in the early 1940s. [START_REF] Cura | Alimentación y enfermedad en tiempo de hambre: España 1937-1947[END_REF][START_REF] Barona | Health and the war. Changing schemes and health conditions during the Spanish civil war[END_REF] Hookworm only re-emerged as a health concern in the 1950s, when there was an improvement in general health standards. Two major foci were identified in the countryside in the mid-1950s. One was around the River Jucar in Valencia Province, the same endemic area that had attracted attention in the 1920s and 1930s (Figure 1). In 1952, officials from the Provincial Health Bureau undertook a ten-year retrospective epidemiological study led by Dr Vidal, former Provincial Health Officer during the Republic, with the collaboration of 232 local municipal physicians. The final report concluded that the hookworm endemic was a long-lasting and severe health problem in a rural area of 270 square kilometres with a population of around 118,000 inhabitants. A morbidity rate of 600 cases per year was estimated. Despite the low mortality rate of the disease, Vidal claimed that severe cases 'could suffer sterility and a tendency to spontaneous abortions'. [START_REF] Vidal Jordana | La anquilostomiasis rural en Valencia. Consideraciones epidemiológicas[END_REF] By emphasising the negative effects of hookworm on reproduction, Vidal connected with one of Franco's key social policy concerns, which was to increase the birth rate.

Vidal called for a campaign that included the construction and use of lavatories and latrines, education of the rural population in health and sanitation matters, and treatment of carriers and sufferers. [START_REF] Vidal Jordana | La anquilostomiasis rural en Valencia. Consideraciones epidemiológicas[END_REF][START_REF] Vidal Jordana | Lucha contra la anquilostomiasis[END_REF] When these plans were laid out at the 4 th National Conference of Health Officers in 1955, the Head of the Provincial Health Bureau of Valencia announced that, although desirable, they could not be implemented because currency shortages prevented importation of the necessary drugs. [START_REF]Actas de la Segunda sesión de la IV Reunión Nacional de Sanitarios[END_REF] While the action taken by provincial health authorities to identify and respond to this endemic speaks to a continuity in their public health role, the lack of governmental support reflects the indifference of the new regime to rural health issues. Apparently, the educational side of the campaign, although not dependent on the supply of medicines, was simply disregarded.

A second endemic focus was in irrigated land around the rivers Henares and Jarama on the South-eastern outskirts of Madrid (Figure 1). In 1947, a warning had been issued by hospital physicians but to no avail. [START_REF] Villasante | Sobre la existencia de un foco de anquilostomiasis en la provincia de Madrid[END_REF] It was not until 1950 that a voluntary hookworm survey was started, surprisingly, by the Spanish Institute of Colonial Medicine. This Institute had been set up in 1944 under the General Directorate for Colonial Administration and participated in the Higher Council for Scientific Research, the main institution supporting science in Franco's Spain. It was under the guidance of Valentin Matilla, Professor of Parasitology and Tropical Diseases, who had replaced the exiled Pittaluga, and was Secretary of the School of Medicine of Madrid University. The main goals of the Institute were to carry out epidemiological surveillance in the Spanish colonies, to provide parasitological training and to arrange medical examinations for officials returning from Africa. [START_REF]Memorias 1940-2005[END_REF][START_REF] Calvo | Una sección de nuestro Instituto Español de Medicina Colonial[END_REF] The Institute essentially comprised only Valentin Matilla and his assistant, and played no role in the colonies. Nevertheless, Matilla, heavily engaged in administrative and religious affairs, used the Institute to exert influence over health administrators, over which he had no official authority. [START_REF] Casado | Vida y obra. La persecución de un sueño[END_REF] It was in this context that Antonio Prieto, a local physician at San Fernando de Henares, approached Matilla in 1949 to develop a thesis on the presence of hookworm disease at his village. This academic endeavour, which earned Prieto a position at the Institute and at the Public Health service, turned into a one-man health campaign. Seven years later, he complained of the continuing risk of a massive regional epidemic due to the lack of support for his intervention. [START_REF] Lorenzo | La anquilostomiasis[END_REF] The Jarama focus appeared as a surface endemic linked to agricultural activity. By mid-1950, Prieto had counted more than 100 clinical cases, which increased to over 300 by 1954, out of a local population of fewer than 4,000 inhabitants in three neighbouring villages. [START_REF] Lorenzo | Orientaciones actuales en la lucha contra los parasitismos intestinales humanos en España[END_REF] Cases were detected among patients at Prieto's surgery in San Fernando or were referred by nearby colleagues. Properly speaking, there was no organised health survey or campaign.

Prieto considered the rural environment to be pathological because of the climatic and topographic conditions and the unsanitary habits of the population. However, he associated the habit of defecating in open spaces and the non-use of latrines with a morally depraved state of rural peasants rather than with the poor living and working conditions. In his opinion, their moral state included a tendency to alcoholism, lack of devotion to the Catholic faith and frequent resort to quacks, which he cited as evidence of the low social, intellectual and natural status of the peasant population. [START_REF] Matilla | Estudios sobre Anquilostomiasis. III. Nuestras observaciones sobre la epidemiología en la Vega del Jarama[END_REF] In this way, Prieto and his colleagues at the Institute of Colonial Medicine shifted the framing of hookworm from a social to a colonial disease, with an approach to Spanish rural populations that was influenced by concepts used to describe African native populations in the colonial setting. [START_REF] Molero-Mesa | Del maestro sangrador al médico…europeo'. Medicina, ciencia y diferencia colonial en el Protectorado español de Marruecos[END_REF] In 1954, following his early involvement with hookworm, Dr Prieto proposed an ambitious national antihelminthic campaign to cover all human intestinal parasitism throughout the country. He called for examinations of the whole population, using coercive measures to ensure compliance. He wanted medical treatment to be freely available and sanitation measures to be carried out, including the compulsory building of lavatories or latrines in homes and close to work sites. Prieto called for persuasive and educational measures to be adapted to the secular profile of the Spanish farm worker, characterized as: 'fatalistic, ignorant, selfish, superstitious and distrustful'. [START_REF] Lorenzo | Orientaciones actuales en la lucha contra los parasitismos intestinales humanos en España[END_REF] The campaign was to be directed by a staff of parasitological experts. In fact, Prieto's proposal appears designed to increase the importance of his particular professional group and to secure better positions in the Public Health administration.

By the mid-and late-1950s, food supply problems in Spain had eased and mortality rates from infections had reduced to general European levels. [START_REF] Rodríguez-Ocaña | La salud pública en la España de la primera mitad del siglo XX[END_REF] Isolated hookworm cases continued to be reported but were described as residual. [START_REF] Hernández-Pacheco | Esquema de campaña sanitaria contra la anquilostomiasis profesional aparecida en un sector de industria rural de superficie[END_REF][START_REF] Hernández-Pacheco | La anquilostomiasis de superficie peligro sanitario en las nuevas[END_REF] In this context, and with the rise of new health concerns, including cancer and viruses, no political priority was going to be given to hookworm or any other parasitological disease.

CONCLUSIONS

Responses to the hookworm threat between before and after the Spanish Civil War illustrate the political dimension of public health interventions and the social values that mediated different approaches. In the 1920s and 1930s, rural health in Spain was perceived in the context of general social unrest, while health campaigns against parasitological diseases were designed to lessen their effects on workers' productivity and dignify peasants as full citizens. In contrast, the Franco regime's approach to rural populations in the 1940s and 1950s was dominated by ideas of their low social and moral status, and hookworm was considered in a colonial framework. This also entailed a narrowing of the environmental conception of the disease. In the pre-war years, the pathological environment was considered to comprise both natural and human factors, the latter mostly related to poor rural working and living conditions. After the war, human factors were given greater weight, mainly in relation to the 'naturally depraved' condition and 'mental inferiority' of the peasants. zonas de regadío. Rev Sanid Hig Publica (Madr)1959;33:487-97.

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Figure 1 .Figure 2 .

 12 Figure 1. Main hookworm foci in Spain 1910-1955

ACKNOWLEDGEMENTS

This research was supported by the Spanish Ministry of Education Projects BHA2001-2979-C05-01 and HUM2006-02885. An earlier version of this article was presented at the International conference of the European Association for the History of Medicine and

Health «Environment Health & History» (London, September 2007). We are grateful to participants for their valuable suggestions and to the anonymous referees of the Journal of Epidemiology and Community Health for their helpful comments.