Effect of tailored practice and patient care plans on secondary prevention of heart disease in general practice: cluster randomised controlled trial

Objective: To test the effectiveness of a complex intervention designed, within a theoretical framework, to improve outcomes for patients with coronary heart disease. Design: Cluster randomised controlled multicentre trial. Setting: General practices in Northern Ireland and the Republic of Ireland, regions with different healthcare systems. Participants: 903 patients with established coronary heart disease registered with one of 48 practices. Intervention: Tailored care plans for practices (practice based training in prescribing and behaviour change, administrative support, quarterly newsletter), and tailored care plans for patients (motivational interviewing, goal identification, and target setting for lifestyle change) with reviews every four months at the practices. Control practices provided usual care. Main outcome measures: The proportion of patients at 18 month follow-up above target levels for blood pressure and total cholesterol concentration, and those admitted to hospital, and changes in physical and mental health status (SF-12). Results: At baseline the numbers (proportions) of patients above the recommended limits were: systolic blood pressure greater than 140 mm Hg (305/899; 33.9%, 95% confidence interval 30.8% to 33.9%), diastolic blood pressure greater than 90 mm Hg (111/901; 12.3%, 10.2% to 14.5%), and total cholesterol concentration greater than 5 mmol/l (188/860; 20.8%, 19.1% to 24.6%). At the 18 month follow-up there were no significant differences between intervention and control groups in the numbers (proportions) of patients above the recommended limits: systolic blood pressure, intervention 98/360 (27.2%) v control, 133/405 (32.8%), odds ratio 1.51 (95% confidence interval 0.99 to 2.30; P=0.06); diastolic blood pressure, intervention 32/360 (8.9%) v control, 40/405 (9.9%), 1.40 (0.75 to 2.64; P=0.29); and total cholesterol concentration, intervention 52/342 (15.2%) v control, 64/391 (16.4%), 1.13 (0.63 to 2.03; P=0.65). The number of patients admitted to hospital over the 18 month study period significantly decreased in the intervention group compared with the control group: 107/415 (25.8%) v 148/435 (34.0%), 1.56 (1.53 to 2.60; P=0.03). Conclusions: Admissions to hospital were significantly reduced after an intensive 18 month intervention to improve outcomes for patients with coronary heart disease, but no other clinical benefits were shown, possibly because of a ceiling effect related to improved management of the disease. Trial registration: Current Controlled Trials ISRCTN24081411.

Gene-environment interactions and aging visual function: a classical twin study.

OBJECTIVE:
To elucidate the contribution of environmental versus genetic factors to the significant losses in visual function associated with normal aging.
DESIGN:
A classical twin study.
PARTICIPANTS:
Forty-two twin pairs (21 monozygotic and 21 dizygotic; age 57-75 years) with normal visual acuity recruited through the Australian Twin Registry.
METHODS:
Cone function was evaluated by establishing absolute cone contrast thresholds to flicker (4 and 14 Hz) and isoluminant red and blue colors under steady state adaptation. Adaptation dynamics were determined for both cones and rods. Bootstrap resampling was used to return robust intrapair correlations for each parameter.
MAIN OUTCOME MEASURES:
Psychophysical thresholds and adaptational time constants.
RESULTS:
The intrapair correlations for all color and flicker thresholds, as well as cone absolute threshold, were significantly higher in monozygotic compared with dizygotic twin pairs (P<0.05). Rod absolute thresholds (P = 0.28) and rod and cone recovery rate (P = 0.83; P = 0.79, respectively) did not show significant differences between monozygotic and dizygotic twins in their intrapair correlations, indicating that steady-state cone thresholds and flicker thresholds have a marked genetic contribution, in contrast with rod thresholds and adaptive processes, which are influenced more by environmental factors over a lifetime.
CONCLUSIONS:
Genes and the environment contribute differently to important neuronal processes in the retina and the role they may play in the decline in visual function as we age. Consequently, retinal structures involved in rod thresholds and adaptive processes may be responsive to appropriate environmental manipulation. Because the functions tested are commonly impaired in the early stages of age-related macular degeneration, which is known to have a multifactorial etiology, this study supports the view that pathogenic pathways early in the disease may be altered by appropriate environmental intervention.

A RCT of peer-mentoring for first-time mothers in socially disadvantaged areas (the moments study)

Objective: Interventions to reduce health inequalities for young children and their mothers are important: involving peers is recommended, but evidence of value for this approach is limited. The authors aimed to examine the effect of an innovative tailored peer-mentoring programme, based on perceived needs, for first-time mothers in socio-economically deprived communities. Design: Randomised controlled trial; parallel qualitative study with purposive samples using semistructured interviews. Setting: Socio-economically disadvantaged areas, Belfast. Participants: Primigravidae, aged 16-30 years, without significant co-morbidity. Intervention: Peer-mentoring by a lay-worker fortnightly during pregnancy and monthly for the following year, tailored to participants' wishes (home visits/telephone contacts), additional to usual care. Main outcome measures: Infant psychomotor and mental development (Bayley Scales of Infant Development (BSID-II)) at 1 year, assessed by an observer blinded to group allocation. Mothers' health at 1 year postnatal (SF-36). Results: Of 534 women invited, 343(64%) participated; 85%, with their children, completed outcome assessments (140 of 172 intervention; 152 of 171 controls). Intervention and control groups did not differ in BSID-II psychomotor (mean difference 1.64, 95% CI -0.94 to 4.21) or mental (-0.81, -2.78 to 1.16) scores, nor SF-36 physical functioning (-5.4, -11.6 to 0.7) or mental health (-1.8, -6.1 to 2.6). Women valued advice given in context of personal experience of child-rearing. Mentors gained health-related knowledge, personal skills and new employment opportunities. Conclusions: Despite possible longer-term social advantage, this peer-mentoring programme showed no benefit for infant development or maternal health at 1 year. Further rigorous evaluation of important outcomes of complex interventions promoting health for children in socially disadvantaged communities is warranted. Trial registration no: ISRCTN 55055030.

Disparities in breast cancer mortality trends between 30 European countries: Retrospective trend analysis of WHO mortality database

Objective: To examine changes in temporal trends in breast cancer mortality in women living in 30 European countries.
Design: Retrospective trend analysis.
Data source: WHO mortality database on causes of deaths
Subjects reviewed: Female deaths from breast cancer from 1989 to 2006
Main outcome measures: Changes in breast cancer mortality for all women and by age group (<50, 50-69, and >= 70 years) calculated from linear regressions of log transformed, age adjusted death rates. Joinpoint analysis was used to identify the year when trends in all age mortality began to change.
Results: From 1989 to 2006, there was a median reduction in breast cancer mortality of 19%, ranging from a 45% reduction in Iceland to a 17% increase in Romania. Breast cancer mortality decreased by >= 20% in 15 countries, and the reduction tended to be greater in countries with higher mortality in 1987-9. England and Wales, Northern Ireland, and Scotland had the second, third, and fourth largest decreases of 35%, 29%, and 30%, respectively. In France, Finland, and Sweden, mortality decreased by 11%, 12%, and 16%, respectively. In central European countries mortality did not decline or even increased during the period. Downward mortality trends usually started between 1988 and 1996, and the persistent reduction from 1999 to 2006 indicates that these trends may continue. The median changes in the age groups were -37% (range -76% to -14%) in women aged <50, -21% (-40% to 14%) in 50-69 year olds, and -2% (-42% to 80%) in >= 70 year olds.
Conclusions: Changes in breast cancer mortality after 1988 varied widely between European countries, and the UK is among the countries with the largest reductions. Women aged <50 years showed the greatest reductions in mortality, also in countries where screening at that age is uncommon. The increasing mortality in some central European countries reflects avoidable mortality.

Patterns of alcohol consumption and ischaemic heart disease in culturally divergent countries: The Prospective Epidemiological Study of Myocardial Infarction (PRIME)

Objective: To investigate the effect of alcohol intake patterns on ischaemic heart disease in two countries with contrasting lifestyles, Northern Ireland and France.
Design: Cohort data from the Prospective Epidemiological Study of Myocardial Infarction (PRIME) were analysed. Weekly alcohol consumption, incidence of binge drinking (alcohol >50 g on at least one day a week), incidence of regular drinking (at least one day a week, and alcohol <50 g if on only one occasion), volume of alcohol intake, frequency of consumption, and types of beverage consumed were assessed once at inclusion. All coronary events that occurred during the 10 year follow-up were prospectively registered. The relation between baseline characteristics and incidence of hard coronary events and angina events was assessed by Cox's proportional hazards regression analysis.
Setting: One centre in Northern Ireland (Belfast) and three centres in France (Lille, Strasbourg, and Toulouse).
Participants: 9778 men aged 50-59 free of ischaemic heart disease at baseline, who were recruited between 1991 and 1994.
Main outcome measures: Incident myocardial infarction and coronary death ("hard" coronary events), and incident angina pectoris.
Results: A total of 2405 men from Belfast and 7373 men from the French centres were included in the analyses, 1456 (60.5%) and 6679 (90.6%) of whom reported drinking alcohol at least once a week, respectively. Among drinkers, 12% (173/1456) of men in Belfast drank alcohol every day compared with 75% (5008/6679) of men in France. Mean alcohol consumption was 22.1 g/day in Belfast and 32.8 g/day in France. Binge drinkers comprised 9.4% (227/2405) and 0.5% (33/7373) of the Belfast and France samples, respectively. A total of 683 (7.0%) of the 9778 participants experienced ischaemic heart disease events during the 10 year follow-up: 322 (3.3%) hard coronary events and 361 (3.7%) angina events. Annual incidence of hard coronary events per 1000 person years was 5.63 (95% confidence interval 4.69 to 6.69) in Belfast and 2.78 (95% CI 2.41 to 3.20) in France. After multivariate adjustment for classic cardiovascular risk factors and centre, the hazard ratio for hard coronary events compared with regular drinkers was 1.97 (95% CI 1.21 to 3.22) for binge drinkers, 2.03 (95% CI 1.41 to 2.94) for never drinkers, and 1.57 (95% CI 1.11 to 2.21) for former drinkers for the entire cohort. The hazard ratio for hard coronary events in Belfast compared with in France was 1.76 (95% CI 1.37 to 2.67) before adjustment, and 1.09 (95% CI 0.79 to 1.50) after adjustment for alcohol patterns and wine drinking. Only wine drinking was associated with a lower risk of hard coronary events, irrespective of the country.
Conclusions: Regular and moderate alcohol intake throughout the week, the typical pattern in middle aged men in France, is associated with a low risk of ischaemic heart disease, whereas the binge drinking pattern more prevalent in Belfast confers a higher risk.

Development of a Diagnostic Genetic Test for Simplex and Autosomal Recessive Retinitis Pigmentosa

PURPOSE: Retinitis pigmentosa (RP) causes hereditary blindness in adults (prevalence, approximately 1 in 4000). Each of the more than 30 causative genes identified to date are responsible for only a small percentage of cases. Genetic diagnosis via traditional methods is problematic, and a single test with a higher probability of detecting the causative mutation would be very beneficial for the clinician. The goal of this study therefore was to develop a high-throughput screen capable of detecting both known mutations and novel mutations within all genes implicated in autosomal recessive or simplex RP. DESIGN: Evaluation of diagnostic technology. PARTICIPANTS AND CONTROLS: Participants were 56 simplex and autosomal recessive RP patients, with 360 population controls unscreened for ophthalmic disease. METHODS: A custom genechip capable of resequencing all exons containing known mutations in 19 disease-associated genes was developed (RP genechip). A second, commercially available arrayed primer extension (APEX) system was used to screen 501 individual previously reported variants. The ability of these high-throughput approaches to identify pathogenic variants was assessed in a cohort of simplex and autosomal recessive RP patients. MAIN OUTCOME MEASURES: Number of mutations and potentially pathogenic variants identified. RESULTS: The RP genechip identified 44 sequence variants: 5 previously reported mutations; 22 known single nucleotide polymorphisms (SNPs); 11 novel, potentially pathogenic variants; and 6 novel SNPs. There was strong concordance with the APEX array, but only the RP genechip detected novel variants. For example, identification of a novel mutation in CRB1 revealed a patient, who also had a single previously known CRB1 mutation, to be a compound heterozygote. In some individuals, potentially pathogenic variants were discovered in more than one gene, consistent with the existence of disease modifier effects resulting from mutations at a second locus. CONCLUSIONS: The RP genechip provides the significant advantage of detecting novel variants and could be expected to detect at least one pathogenic variant in more than 50% of patients. The APEX array provides a reliable method to detect known pathogenic variants in autosomal recessive RP and simplex RP patients and is commercially available. High-throughput genotyping for RP is evolving into a clinically useful genetic diagnostic tool.

Body Mass Index Is More Predictive of Progenitor Number in Bone Marrow Stromal Cell Population Than Age in Men: Expanding the Predictors of the Progenitor Compartment

Research has focused on in vitro expansion of bone marrow stromal cells with the aim of developing cell-based therapies or tissue-engineered constructs. There is debate over whether there is a reduction in stem cells/osteoprogenitors in the bone marrow compartment with increasing age. The aim of this study was to investigate patient factors that affect the progenitor pool in bone marrow samples. Six milliliters of marrow aspirate was obtained from the femoral canal of 38 primary hip replacement patients (aged 28-91). Outcome measures were total nucleated cell count, colony-forming efficiency, alkaline phosphatase expression, and expression of stem cell markers. There was a nonsignificant negative correlation between age and both colony-forming efficiency and stem cell marker expression. However, body mass index showed a positive, significant correlation with colony area and number in men-accounting for up to 75% of the variation. In conclusion, body mass index, not age, was highly predictive of the number of progenitors found in bone marrow, and this relationship was sex specific. These results may inform the clinician's treatment choice when considering bone marrow-based therapies. Further, it highlights the need to widen research into patient factors that affect the adult stem cell population beyond age and reinforces the need to consider sexes separately.

Breast cancer mortality in neighbouring European countries with different level of breast screening but similar access to treatment: An analysis of WHO mortality database

Objective: To compare trends in breast cancer mortality within three pairs of neighbouring European countries in relation to implementation of screening. Design: Retrospective trend analysis.
Setting: Three country pairs (Northern Ireland (United Kingdom) v Republic of Ireland, the Netherlands v Belgium and Flanders (Belgian region south of the Netherlands), and Sweden v Norway).
Data sources: WHO mortality database on cause of death and data sources on mammography screening, cancer treatment, and risk factors for breast cancer mortality.
Main outcome measures: Changes in breast cancer mortality calculated from linear regressions of log transformed, age adjusted death rates. Joinpoint analysis was used to identify the year when trends in mortality for all ages began to change.
Results: From 1989 to 2006, deaths from breast cancer decreased by 29% in Northern Ireland and by 26% in the Republic of Ireland; by 25% in the Netherlands and by 20% in Belgium and 25% in Flanders; and by 16% in Sweden and by 24% in Norway. The time trend and year of downward inflexion were similar between Northern Ireland and the Republic of Ireland and between the Netherlands and Flanders. In Sweden, mortality rates have steadily decreased since 1972, with no downward inflexion until 2006. Countries of each pair had similar healthcare services and prevalence of risk factors for breast cancer mortality but differing implementation of mammography screening, with a gap of about 10-15 years.
Conclusions: The contrast between the time differences in implementation of mammography screening and the similarity in reductions in mortality between the country pairs suggest that screening did not play a direct part in the reductions in breast cancer mortality.

Exercise and Auricular Acupuncture for Chronic Low Back Pain: A Feasibility Randomised Controlled Trial

Objectives: To evaluate the feasibility of a randomized-controlled trial (RCT) investigating the effects of adding auricular acupuncture (AA) to exercise for participants with chronic low-back pain (CLBP). Methods: Participants with CLBP were recruited from primary care and a university population and were randomly allocated (n=51) to 1 of 2 groups: (1) "Exercise Alone (E)"-12-week program consisting of 6 weeks of supervised exercise followed by 6 weeks unsupervised exercise (n=27); or (2) "Exercise and AA (EAA)"-12-week exercise program and AA (n=24). Outcome measures were recorded at baseline, week 8, week 13, and 6 months. The primary outcome measure was the Oswestry Disability Questionnaire. Results: Participants in the EAA group demonstrated a greater mean improvement of 10.7% points (95% confidence interval, -15.3,-5.7) (effect size=1.20) in the Oswestry Disability Questionnaire at 6 months compared with 6.7% points (95% confidence interval, -11.4,-1.9) in the E group (effect size=0.58). There was also a trend towards a greater mean improvement in quality of life, LBP intensity and bothersomeness, and fear-avoidance beliefs in the EAA group. The dropout rate for this trial was lower than anticipated (15% at 6 mo), adherence with exercise was similar (72% E; 65% EAA). Adverse effects for AA ranged from 1% to 14% of participants. Discussion: Findings of this study showed that a main RCT is feasible and that 56 participants per group would need to be recruited, using multiple recruitment approaches. AA was safe and demonstrated additional benefits when combined with exercise for people with CLBP, which requires confirmation in a fully powered RCT.

The back 2 activity trial: education and advice versus education and advice plus a structured walking programme for chronic low back pain.:education and advice versus education and advice plus a structured walking programme for chronic low back pain

BACKGROUND: Current evidence supports the use of exercise-based treatment for chronic low back pain that encourages the patient to assume an active role in their recovery. Walking has been shown it to be an acceptable type of exercise with a low risk of injury. However, it is not known whether structured physical activity programmes are any more effective than giving advice to remain active.

METHODS/DESIGN: The proposed study will test the feasibility of using a pedometer-driven walking programme, as an adjunct to a standard education and advice session in participants with chronic low back pain. Fifty adult participants will be recruited via a number of different sources. Baseline outcome measures including self reported function; objective physical activity levels; fear-avoidance beliefs and health-related quality of life will be recorded. Eligible participants will be randomly allocated under strict, double blind conditions to one of two treatments groups. Participants in group A will receive a single education and advice session with a physiotherapist based on the content of the 'Back Book'. Participants in group B will receive the same education and advice session. In addition, they will also receive a graded pedometer-driven walking programme prescribed by the physiotherapist. Follow up outcomes will be recorded by the same researcher, who will remain blinded to group allocation, at eight weeks and six months post randomisation. A qualitative exploration of participants' perception of walking will also be examined by use of focus groups at the end of the intervention. As a feasibility study, treatment effects will be represented by point estimates and confidence intervals. The assessment of participant satisfaction will be tabulated, as will adherence levels and any recorded difficulties or adverse events experienced by the participants or therapists. This information will be used to modify the planned interventions to be used in a larger randomised controlled trial.

DISCUSSION: This paper describes the rationale and design of a study which will test the feasibility of using a structured, pedometer-driven walking programme in participants with chronic low back pain.

TRIAL REGISTRATION: [ISRCTN67030896].

General and Respiratory Health Outcomes in Adult Survivors of Bronchopulmonary Dysplasia: A Systematic Review

Background: The purpose of this systematic literature review was to examine current empirical research on general and respiratory health outcomes in adult survivors of bronchopulmonary dysplasia (BPD).

Methods: We searched seven databases up to the end of November 2010 (MEDLINE, PubMed, EMBASE, PsycINFO, Maternity and Infant Care, Cumulative Index of Nursing and Allied Health Literature, and Web of Knowledge). We independently screened and included only those studies concerning the assessment of outcome measures in adult survivors of BPD. Data on methodologic design and findings were extracted from each included study; in addition, the methodologic quality of each study was assessed using the Critical Appraisal Skills Programme checklist.

Results: Fourteen cohort studies met the review criteria. Of those, a total of eight studies were considered to be of high quality (score 9-12), five of moderate quality (score 5-8), and only one was of low quality (score 0-4). In all studies of adult survivors of BPD, differences were found between the index and control groups, suggesting that many adults survivors of BPD who were born preterm or with very low birth weight had more respiratory symptoms and pulmonary function abnormalities compared with their peers. Five studies concerning radiologic findings reported structural changes persisting into adulthood. Findings from three studies suggested impairment in exercise capacity, although firm conclusions were limited by the small sample size in the studies reviewed.

Conclusions: Compared with adults born at term, adult survivors of BPD have more impairment in general and respiratory health, which does not seem to diminish over time.

Integrated care: utilisation of complementary and alternative medicine within a conventional cancer treatment centre

Objectives: To estimate the proportion of cancer outpatients who visit a Complementary and Alternative Medicine (CAM) unit that is located within a conventional cancer treatment centre; to compare the characteristics of CAM unit visitors with those of all outpatients; to monitor the demand for 20 CAM therapies delivered by professionals, and the use of the CAM unit for waiting, gathering information and informal support from volunteer staff.

Design: Prospective, observational, over a six month period.

Setting: CAM unit within a NHS cancer treatment centre.

Main outcome measures: Utilisation of the CAM unit for 20 complementary therapies, and for waiting, gathering information, informal support; characteristics of CAM users compared with those of all cancer outpatients attending the cancer centre; predictors of CAM therapy use and frequent use.

Results: 761 (95% of those approached) people were recruited, 498 (65.4%) cancer patients, 202 (26.5%) relatives, 37 (4.8%) friends/carers, 24 (3.2%) staff. Women predominated (n = 560, 73.6%). Of all outpatients attending the cancer centre, 498 (15.8%) visited the CAM unit, 290 (9.2%) accessed therapies. Compared to all outpatients, those visiting the CAM unit were: younger (mean 63.7 vs. 58.4 years), more likely to be female (57.9% vs. 78.7%), have breast (14.8% vs. 51.9%), gynaecological (5.0% vs. 9.1%) cancer, live in local postal district (57.3% vs. 61.6%). Significant predictors of therapy use and frequent visits were being a patient, female, higher education, living closer to the cancer centre.

Conclusions: Despite easy access to CAM therapies, a relatively small number of people regularly used them, whilst a larger number selectively tried a few. The integrated CAM unit meets a demand for information and informal support. The findings inform emerging policy on integrating CAM and conventional cancer treatment to address psychosocial needs of people with cancer. More research is needed on why people do not use integrated CAM services and how charges affect demand. © 2008.

Massage for symptom relief in patients with cancer: systematic review

Aim. This paper is a report of a review to assess evidence of the effectiveness of massage for patients with cancer, in terms of reducing physical or psychological symptoms, improving quality of life, or producing unwanted side effects. Background. Patients with cancer may use complementary therapies, including massage and aromatherapy massage. However, their use and provision by state-financed healthcare services is controversial. Data sources. A systematic review was carried out, using the Cochrane principles. No meta-analysis was appropriate. An initial comprehensive search of electronic databases search was carried out in 2003 and updated in 2006. Eligible trials were randomized controlled trials, controlled before-and-after (pre-post) studies and interrupted time-series studies. Participants were adults with a diagnosis of cancer and receiving care in any healthcare setting. Interventions were limited to massage and/or aromatherapy massage carried out by a qualified therapist. Outcome measures to be included were patient-reported levels of physical and psychological indices of symptom distress and quality of life (measured using validated assessment tools). Findings. In the review, 1325 papers were considered. Ten trials met the inclusion criteria and their results suggest that massage might reduce anxiety in patients with cancer in the short term and may have a beneficial effect on physical symptoms of cancer, such as pain and nausea. However, the lack of rigorous research evidence precludes drawing definitive conclusions. Conclusion. Further well-designed large trials with longer follow-up periods are needed to be able to draw firm conclusions about the efficacy and effectiveness of massage for cancer patients. © 2008 The Authors

Reflexology for symptom relief in patients with cancer

Complementary therapies are increasingly being used in hospices and hospitals alongside orthodox treatments in an attempt to improve patients' emotional, spiritual, psychological, and physical well-being. An average of 31% of UK patients with cancer use some form of complementary therapy. Many UK cancer centers, out-patient units, and hospices are providing complementary services. There is strong anecdotal evidence that complementary therapies assist in the palliation of physical and psychological symptoms. This systematic review examines the research evidence base for the effectiveness of reflexology in cancer care. The study reports the results of a systematic review following the Cochrane principles of systematic reviewing. No meta-analysis was possible. Studies were retrieved from a comprehensive search of electronic databases from their start dates. An initial search was carried out in 2003 and updated in 2005 to 2006. Eligible studies were randomized controlled trials, controlled before and after studies, and interrupted time-series studies. Participants were adults with a diagnosis of cancer, receiving care in any healthcare setting. Interventions were limited to reflexology carried out by a qualified therapist as distinguished from another healthcare professional carrying out a reflexology intervention. Outcome measures were patient-reported levels of physical and psychological indices of symptom distress and quality of life (measured using validated assessment tools). Copyright © 2008 Lippincott Williams & Wilkins

Limbal stem cell deficiency and ocular phenotype in ectrodactyly-ectodermal dysplasia-clefting syndrome caused by p63 mutations

Objective: To describe the ocular phenotype in patients with ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome (MIM#604292) and to determine the pathogenic basis of visual morbidity. Design: Retrospective case series. Participants: Nineteen families (23 patients) affected by EEC syndrome from the United Kingdom, Ireland, and Italy. Methods: General medical examination to fulfill the diagnostic criteria for EEC syndrome and determine the phenotypic severity. Mutational analysis of p63 was performed by polymerase chain reaction-based bidirectional Sanger sequencing. All patients with EEC syndrome underwent a complete ophthalmic examination and ocular surface assessment. Limbal stem cell deficiency (LSCD) was diagnosed clinically on the basis of corneal conjunctivalization and anatomy of the limbal palisades of Vogt. Impression cytology using immunofluorescent antibodies was performed in 1 individual. Histologic and immunohistochemical analyses were performed on a corneal button and corneal pannus from 2 EEC patients. Main Outcome Measures: The EEC syndrome phenotypic severity (EEC score), best-corrected Snellen visual acuity (decimal fraction), slit-lamp biomicroscopy, tear function index, tear breakup time, LSCD, p63 DNA sequence variants, impression cytology, and corneal histopathology. Results: Eleven heterozygous missense mutations in the DNA binding domain of p63 were identified in all patients with EEC syndrome. All patients had ocular involvement and the commonest was an anomaly of the meibomian glands and lacrimal drainage system defects. The major cause of visual morbidity was progressive LSCD, which was detected in 61% (14/23). Limbal stem cell deficiency was related to advancing age and caused a progressive keratopathy, resulting in a dense vascularized corneal pannus, and eventually leading to visual impairment. Histologic analysis and impression cytology confirmed LSCD. Conclusions: Heterozygous p63 mutations cause the EEC syndrome and result in visual impairment owing to progressive LSCD. There was no relationship of limbal stem cell failure with the severity of EEC syndrome, as classified by the EEC score, or the underlying molecular defect in p63. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. © 2012 American Academy of Ophthalmology.