Shared decision making in the treatment of pediatric strabismus.

PURPOSE: To quantify the results of shared decision making in pediatric strabismus surgery from the parent perspective using the nine-item Shared Decision Making (SDM) Questionnaire and the associations of SDM score with parental education level; secondarily, to evaluate postoperative parental satisfaction as a function of child age, parental education level, SDM scores, and motor outcomes. METHODS: Consecutive parents of children 2-14 years of age with concomitant manifest strabismus that consented to strabismus surgery were surveyed using the SDM Questionnaire. A four-point Likert scale was used to gauge the level of postoperative satisfaction (POS). Potential predictors were estimated in multivariable regression analysis, with results adjusted for education level, children's age, and motor outcomes. RESULTS: A total of 100 parents (86 women) completed the survey and were included. Significant differences for SDM score were found between individuals with university-level versus the other three educational levels (P < 0.001 for primary and secondary levels; P = 0.017 for college or lyceum level). Categorical regression analysis showed that POS level was inversely correlated with education level and positively correlated with SDM score. Children's age at time of surgery and postoperative motor outcome were not significantly associated with POS. CONCLUSIONS: In our study cohort, SDM score was correlated with educational level. Satisfaction was greater among responders with higher SDM scores, indicating that SDM may help improve parent-reported satisfaction with treatment results.

Does Surgical Resection of Horizontal Extraocular Muscles Disrupt Ocular Proprioceptors?

Purpose: It has been promoted that disturbance of ocular proprioception may play a role in the pathogenesis of concomitant strabismus and other types of oculomotor anomalies. The aim of the study was to obtain knowledge about how surgical foreshortening of the myotendinous region potentially affects the proprioceptors that resides in this area of the muscles and to test the hypothesis that avoiding disruption of ocular proprioceptors result in a more favorable long term postoperative result. Patients and Methods: The distal end of the lateral and medial rectus muscles from patients with manifest concomitant strabismus with a deviation of ≥15 prism diopters (PD) were collected during strabismus surgery and processed for light microscopy by standard histochemical techniques. Histological analysis served to differentiate between the tissue samples containing pure tendon, versus samples containing the myotendinous junction. Criteria for successful outcome was defined as a residual angle of deviation less than 10 PD. The binocular status of the patient was measured pre- and post-operatively at 6-months of follow-up. Results: Tissue samples from 43 patients (median age 19 years old, range 3-58 years) were collected during surgery. Twenty-six of the samples contained pure tendon, while 17 contained muscle fibres. The evolution of the post-operative result revealed a moderate reduction in the residual angle of deviation in patient-samples containing pure tendon. In contrast, the residual angle of deviation clearly increased in patient-samples containing muscle fibres. The difference between the two groups reached statistical significance after 6 months. Successful outcome was found to be more than three times more likely in cases where surgery was performed in pure tendon, compared to muscle fibres. Conclusion: The current study supports the hypothesis that avoiding disruption of ocular proprioceptors, located in the distal myotendinous region, results in a more favorable postoperative result.

Harbingers of Hope: Scientists and the Pursuit of World Peace.

The ongoing wars in many regions-such as the conflict between Israel and Hamas-as well as the effects of war on communities, social services, and mental health are covered in this special editorial. This article emphasizes the need for international efforts to promote peace, offer humanitarian aid, and address the mental health challenges faced by individuals and communities affected by war and violence.

Comparison of Short-Term Effects of Treatment of Accommodative Infacility with Low Plus Addition in Single Vision Rx or Vision Therapy: A Pilot Study.

Purpose: To compare the short-term treatment effect of low plus reading addition (ADD) and home-based vision therapy (VT) in a small group of symptomatic children with accommodative infacility (AIF) being the most significant dysfunction. Methods: Nineteen children, 8 to 12 years of age, with a first-time diagnosis of AIF were consecutively and alternately allocated to treatment with ADD (+0.50 D addition in single vision Rx) or VT (accommodation exercises using Hart Charts) for a period of 6 weeks. Accommodation facility (AF) was measured monocularly (MAF-R, MAF-L) and binocularly (BAF) with +2 D/-2 D flipper and registered in cycles per minute (cpm). Symptoms were graded using the convergence insufficiency symptom survey (CISS). Measurements were compared before and after treatment and between groups using nonparametric statistics (p < 0.05). Results: Ten children were allocated to ADD (median age 9.0 F:5) and 9 to VT (median age 11.0 F:7). Baseline median measurements of MAF-R, MAF-L, BAF and CISS were 3.0, 3.0, 2.2 cpm, and 27.5 points, respectively, for ADD, and 2.0, 2.0, 2.0 cpm, and 27.0 points, respectively, for VT. There were no significant differences between groups at baseline. After 6 weeks of treatment, the median change of MAF-R, MAF-L, BAF and CISS was +5.0, +4.5, +4.7 cpm, and -7.5 points, respectively, for ADD and +8.0, +8.0, +10.0 cpm, and -20.0 points, respectively for VT. All changes within groups were significant. Comparison of groups showed a significantly greater effect of treatment with VT compared to ADD for BAF (p = 0.008) and CISS (p = 0.017). Conclusion: In children with newly diagnosed AIF, treatment with accommodation exercises for 6 weeks gives greater short-term relief of symptoms and improvement of binocular accommodative facility compared to treatment with spectacle single vision correction with a weak plus addition.

Dysregulated light/dark cycle impairs sleep and delays the recovery of patients in intensive care units: A call for action for COVID-19 treatment.

Exposure to an adequate light-dark cycle is important for the speedy recovery of hospitalized and institutionalized patients. Light exposure, including natural light, offers several health benefits to both patients and nursing staff. This includes physical (e.g., decreased confusion and disorientation) and mental health benefits (e.g., prevention of depression) and a reduction in the hospital stay. Improved alertness and performance can also be noted among hospital staff. In this commentary, we discuss disrupting factors that include light during the nighttime along with noise and physical procedures on the patient and others. We then address some of the important steps that can be undertaken to restore a more normal environment for patients in the intensive care unit, which can be particularly important for COVID-19 patients.

Extraocular muscle resection, recession length and surgery outcome modelling in strabismus treatment: a pilot study.

BACKGROUND: Many surgical formulas have been developed and proposed based on the experience of surgeons to improve the predictability of strabismus surgery. However, the consent among strabismus surgeons regarding the dose effect of the extraocular muscle (EOM) recession or resection was not achieved yet and the disagreement about the appropriate amount of strabismus surgery still exists. OBJECTIVE: Our study aimed to propose an instrument for EOM resection (RsL) and recession length (RcL) estimation before the surgery and second to elaborate an postoperative angle of deviation (PAD) predictive model using simple potential predictors. METHODS AND ANALYSIS: The analytical prospective clinical study was conducted from April 2016 to July 2019, on a sample of 216 patients (aged between 2-58) with concomitant strabismus who underwent strabismus surgery in Clinical Republican Hospital 'Timofei Mosneaga'and Children Hospital 'Em Cotaga' from Republic of Moldova. The correlations of patients' age, strabismus type, amblyopia degree, RsL, RcL, preoperative angle of deviation (PreAD) with PAD were estimated using Pearson's correlation analysis. Multiple linear regression analysis, multicollinearity analysis and residual analysis were performed. RESULTS: The EOM RsL was predicted using strabismus type, patient's age, PreAD and EOM RcL. EOM RcL, in turn, was estimated by the similar covariates set, instead of RcL being RsL. PAD modelling showed the PreAD, EOM RsL and EOM RcL predictive ability for strabismus surgery outcome prediction. CONCLUSION: In our study, we propose four mathematical models as potential instruments for EOM RsL, EOM RcL and PAD modelling in esotropia and exotropia surgery.

Causes of concomitant strabismus surgery delay in teenagers and adults.

To reveal the reasons for strabismus surgery delay and motivations for seeking surgical treatment in adulthood. Prospective survey among 91 adult patients, suffering from concomitant strabismus acquired in the childhood that underwent delayed strabismus surgery. The mean age of participants was 24 years (from 16 to 58 years); 48 females (52.7%), and 43 males (47.3%). Strabismus surgery has been delayed for about 20 years in adult patients who could potentially benefit of it in childhood. The most common reasons for strabismus surgery delay, reported by patients, included the following: lack of awareness about surgery (37.4%); surgery was recommended but declined by patients' parents/guardians in their childhood (6.6%); fear of surgery (17.6%); eye specialists affirmation that surgery would not lead to strabismus improvement (27.5%); previous poor surgical experience (6.6%); and non-affordability (4.4%). The main motivations for seeking strabismus surgery in adulthood among our patients were the following: appearance improvement (38.5%), strengthening of self-confidence (30.8%), better social relationship (16.5%), better job opportunities (7.7%), and advice from family and friends (6.6%). About 80% of strabismus surgery delays in teenagers and adults were caused by lack of awareness regarding strabismus surgery and even the misconception among primary health-care practitioners and some eye doctors who considered that surgery would not lead to strabismus correction. The main reasons for seeking strabismus surgery in adulthood were: esthetical ones, self-confidence strengthening, and building better social relationship. All factors mentioned below confirmed the negative impact of oculomotor disorders on patient's psychological condition. The focus on patient's individual concerns and needs was especially important for recovery and well-being of adult patients with strabismus and formed a central feature of patient centered medical approach.

Refractive Precision of Ray Tracing IOL Calculations Based on OCT Data versus Traditional IOL Calculation Formulas Based on Reflectometry in Patients with a History of Laser Vision Correction for Myopia.

PURPOSE: To compare the refractive predictability of ray tracing IOL calculations based on OCT data versus traditional IOL calculation formulas based on reflectometry in patients with a history of previous myopic laser vision correction (LVC). PATIENTS AND METHODS: This was a prospective interventional single-arm study of IOL calculations for cataract and refractive lens exchange (RLE) patients with a history of myopic LVC. Preoperative biometric data were collected using an optical low coherence reflectometry (OLCR) device (Haag-Streit Lenstar 900) and two optical coherence tomography (OCT) devices (Tomey Casia SS-1000 and Heidelberg Engineering Anterion). Traditional post LVC formulas (Barret True-K no-history and Haigis-L) with reflectometry data, and ray tracing IOL calculation software (OKULIX, Panopsis GmbH, Mainz, Germany) with OCT data were used to calculate IOL power. Follow-up examination was 2 to 3 months after surgery. The main outcome measure, refractive prediction error (RPE), was calculated as the achieved postoperative refraction minus the predicted refraction. RESULTS: We found that the best ray tracing combination (Anterion-OKULIX) resulted in an arithmetic prediction error statistically significantly lower than that achieved with the best formula calculation (Barret True-K no-history) (-0.13 D and -0.32 D, respectively, adjusted p = 0.01), while the Barret TK NH had the lowest SD. The absolute prediction error was 0.26 D and 0.35 D for Anterion-OKULIX and Barret TK NH, respectively, but this was not statistically significantly different. The Anterion-OKULIX calculation also had the highest percentage of eyes within ± 0.25, compared to both formulas and within ±0.50 and ±0.75 compared to the Haigis-L (p = 0.03). CONCLUSION: Ray tracing calculation based on OCT data from the Anterion device can yield similar or better results than traditional post LVC formulas. Ray tracing calculations are based on individual measurements and do not rely on the ocular history of the patient and are therefore applicable for any patient, also without previous refractive surgery.

Shared decision making and patients satisfaction with strabismus care-a pilot study.

BACKGROUND: Strabismus is a complex disease that has various treatment approaches each with its own advantages and drawbacks. In this context, shared decisions making (SDM) is a communication process with the provider sharing all the relevant treatment alternatives, all the benefits, and risks of each procedure, while the patient shares all the preferences and values regarding his/her choices. In that way, SDM is a bidirectional process that goes beyond the typical informed consent. Therefore, it is known a little of the extent to which SDM influences the satisfaction with the treatment outcome along with strabismus patients. To study this correlation, an SDM-Q-9 questionnaire was provided within surgical consultations where treatment decisions were made; the SDM-Q-9 aims to assess the relationship between the post-operative patient's satisfaction and their SMD score. METHODS: The study is considered a prospective observational pilot study. Eligible patients were adult patients diagnosed with strabismus, who had multiple treatment options, were given at the right of choice without being driven into a physician's preference. Ninety-three strabismus patients were asked to fill out the SDM-Q-9 questionnaire related to their perception of SDM during the entire period of strabismus treatment. After the treatment, patients were asked to rate their satisfaction level with the surgical outcome as excellent, good, fair, and poor. Descriptive statistics and the linear regression statistical tests (Spearman, Mann Whitney U, and Kriskal-Wallis) were used as analysis tools. RESULTS: The average age of the participants was 24, where 50.6% were women. The mean SDM-Q-9 score among patients was 32 (IQR = 3). The postoperative patient satisfaction was rated as being excellent by 16 (17.2%) patients, good by 38 (40.9%), fair by 32 (34.4%), and poor by 7 patients (7.5%). Data analysis by linear regression statistical tests showed a positive correlation between the SDM-Q-9 score and the patient satisfaction related to the surgery outcome (B = 0.005, p < 0.001). Criteria in assessing patients' satisfaction were age, gender, and strabismus type. A positive correlation between SDM and real satisfaction (r = 0.834, p < 0.01) was found with age, and no significant relationship was found while taking into consideration the responder's gender and the strabismus type. CONCLUSIONS: Assessing patient satisfaction after choosing a treatment for strabismus method helped us evaluate the gaps in constructive dialogue that would lead to a positive outcome for both patient and clinician. The correlation between the SDM process and the patients' satisfaction with surgery outcome, adjusted by age, has been established. These findings can serve as a springboard to further communicative improvements related to the SDM process and between patients and physicians, thereby consequently leading to patients' satisfaction raise in strabismus care. The study underlines the importance of further analysis and validation of on-ground interactions among the adolescent and adult patients and the clinicians across the strabismus management trajectory. A multicentral study and its validation will follow.

Repeatability of OCT-Based versus Scheimpflug- and Reflection-Based Keratometry in Patients with Hyperosmolar and Normal Tear Film.

PURPOSE: To compare the repeatability of keratometry between different instruments in patients with hyperosmolar tear film and a control group. PATIENTS AND METHODS: Subjects with tear-film osmolarity of 316 mOsm/L or more in either eye or 308 m/Osm/L or lower in both eyes were assigned to the hyperosmolar and the control group, respectively. The test eye was the eye with higher osmolarity in the hyperosmolar group and randomly chosen in the control group. The repeatability of keratometry was compared between a reflectometry device (Haag-Streit Lenstar 900), a Scheimpflug device (Oculus Pentacam HR) and two optical coherence tomography (OCT) devices (Tomey Casia SS-1000 and Heidelberg Anterion), based on two measurements from each device. RESULTS: The study included 94 subjects (31 hyperosmolar and 63 controls). Both OCT devices had higher mean differences of average simulated keratometry (SimK) vs the Lenstar in both groups, though all differences in means were <0.07 D. The Casia had the highest mean vector difference of SimK astigmatism in the control group (differences in means <0.11 D). These differences of the instruments were statistically significant (p < 0.02), except for the Anterion in the control group. With all subjects, the coefficient of repeatability varied from 0.1 to 0.3 for average SimK (highest for both OCT devices) and from 0.4 to 0.7 for SimK astigmatism (highest for the Casia). Similar results were found for total corneal power (OCT devices compared to the Pentacam). CONCLUSION: Both OCT devices show more variability in average SimK and the Casia more variability in SimK astigmatism compared to the Lenstar and the Pentacam. However, the results suggested that repeatability was not influenced by osmolarity.

Epidemiology of childhood manifest strabismus in the Republic of Moldova.

The purpose of this study was to determine the prevalence and the rate of newly detected pediatric manifest strabismus cases in the Republic of Moldova. A descriptive study was conducted in the Republic of Moldova. The data about the number of children that passed the prophylactic ophthalmological examination every year (children of 3 months- 17 years), the number of new strabismus cases found annually and the number of manifest strabismus cases under evidence were collected from the Health Family Centers in the Northern, Southern, and Central districts of the Republic of Moldova. The study period was performed in 2011- 2017. The prevalence rate of pediatric manifest strabismus in the study was 1.3%. The rate of newly diagnosed strabismus was 0.2%, with a higher ratio for esotropia versus exotropia (16.7/4.9 cases per 10000 children). The age of esotropia detection was mainly in the first 6 years of life (76.1%); beyond this age, exotropia predominates until the teenage years (75.6%). The study revealed a lower prevalence of pediatric manifest strabismus in comparison with the prevalence reported in other European countries. Esotropia was the most common type among patients with strabismus, this being detected mainly at first 6 years of life. The prevalence rate of exotropia was lower and the detection age was more frequent beyond the age of 6 years. The age at which most pediatric manifest strabismus cases were detected ranged between 3 and 6 years.

Prevalence of Signs and Symptoms of Dry Eye Disease 5 to 15 After Refractive Surgery.

PURPOSE: To compare the prevalence of dry eye disease (DED) as determined by signs and symptoms in patients with a history of laser vision correction (LVC) or implantable collamer lens (ICL) implantation 5-15 years ago with a matched control group with no history of refractive surgery. PATIENT AND METHODS: This was a cross-sectional case-control study. The subject population included patients who had LVC or ICL 5 to 15 years ago. The control group was age matched. A test eye was randomly chosen. Subjects were required to have good ocular health. DED was evaluated using categorical cut-off criteria for tear film osmolarity (measured in both eyes), the subjective Ocular Surface Disease Index (OSDI), the dynamic Objective Scatter Index (OSI), non-invasive keratography tear break-up time (NIKBUT), meibography, and the Schirmer 1 test. RESULTS: The study included 257 subjects (94 LVC, 80 ICL, 83 control). The frequency of hyperosmolarity was significantly higher in the LVC group vs the control (73% vs 50%, p = 0.002), In contrast, the frequency of subjective symptoms tended to be lower in the LVC group than in the control group (19% vs 31%; p = 0.06). These differences were not seen between the ICL and control group. CONCLUSION: The results suggest that LVC may cause tear film instability as indicated by hyperosmolar tears up to 15 years after surgery, with few subjective symptoms of dry eye. This may have implications for IOL calculations for cataract or refractive lens exchange later in life.

Presbyopic refractive lens exchange with trifocal intraocular lens implantation after corneal laser vision correction: Refractive results and biometry analysis.

PURPOSE: To evaluate the refractive and biometry results of presbyopic refractive lens exchange (RLE) with trifocal intraocular lens (IOL) implantation in eyes with previous myopic or hyperopic corneal laser vision correction (LVC). SETTINGS: Memira AS, Norway, Sweden, and Denmark. DESIGN: Retrospective case series. METHODS: The refractive results included the manifest refraction spherical equivalent, uncorrected near (UNVA) and distance (UDVA) visual acuities, corrected distance visual acuity, safety, efficacy, and precision. The biometry analysis included the refractive prediction error (RPE), median absolute error (MedAE), and percentage of eyes within a certain RPE range for the formulas from the American Society of Cataract and Refractive Surgery (ASCRS) online calculator. RESULTS: The study comprised 241 eyes. Six months postoperatively, 60.0% of eyes were within ±0.25 diopter (D), 80.9% within ±0.50 D, and 97.9% within ±1.00 D of emmetropia. There were no statistical differences in the mean monocular UDVA (0.87 ± 0.20 [SD]), safety index (0.98 ± 0.09), or efficacy index (0.81 ± 0.18) between the myopic ablation group and hyperopic ablation group. Binocularly, 85% of patients had simultaneous UDVA and UNVA of 0.9 or better and Jaeger 3, respectively. The ASCRS online calculator formulas gave different performances for previous myopic and hyperopic ablation profiles. Using optimized constants and nomogram for correcting the mean RPE improved the MedAE. CONCLUSIONS: Presbyopic RLE was safe and effective in selected cases with a history of LVC. The use of optimized IOL constants and nomograms can improve the refractive precision of lens-based refractive surgery.

Prevalence and Predictors of Ocular Complications in Obstructive Sleep Apnea Patients: A Cross-sectional Case-control Study.

PURPOSE: This study sought to identify the magnitude and the possible risk factors of ocular complications in patients with Obstructive Sleep Apnea (OSA). METHODS: A hospital-based cross-sectional study with a nested case-control design was conducted. Qualifying study subjects were patients who had been diagnosed with moderate to severe OSA (AHI index of ≥ 5, n=80), and control subjects (n=20) who had an AHI index of ≤ 5 ("normal"). Study participants were recruited from Mansoura University Hospital's Sleep Disorders Clinic in Mansoura, Egypt.Selected subjects were assessed for ocular complications at Mansoura Univerity Hospital Ophthalmic Center, (Mansoura), Egypt. An ophthalmic history was recorded, and opthalmic testing was carried out. The testing included unaided visual acuity measurement, refraction, best-corrected visual acuity measurement, slit lamp bio-microscopic evaluation of the anterior segment and anterior segment photography, dilated fundus examination, intraocular pressure measurement, fundus photo, and fluorescein angiography, and visual field assessment. Various tests of OSA symptoms were also monitored, including the AHI, lowest oxygen concentrations and desaturation index plus the overall severity index. . RESULTS: It was found that OSA patients n=28 (35%), n=24 (30%), n=4 (5%) had senile cataract, normal tension glaucoma, and retinal ischemia, respectively, with an overall prevalence of 45%. Additionally, the OSA group had seven times greater risk (OR=7.36, 95%CI: 1.6-33.86) of vision-threatening disorders compared to the controls. OSA patients were observed to be at a greater risk of senile cataract 28 (35%), normal tension glaucoma 24 (30%), retinal ischemia 4 (5%) and conjunctival hyperemia and dry eye (OR=3.77, 95%CI: 1.02-13.95, OR=4.36, 95%CI: 1.26-17.08). Also, multivariate logistic regression analysis testing showed that the lowest oxygen saturation index was the only significant predictor negatively associated with vision-threatening disorders (OR=0.84, 95%CI: 0.75-0.93). CONCLUSION: The risk of vision-threatening and non-threatening ocular disorders is higher among OSA cases. The lowest oxygen saturation index was the only significant predictor of vision-threatening disorders. These findings support the recommendation that a full ophthalmic examination should be carried out on patients with confirmed OSA.

Survey of referrals and medical reports in optometric practices in Norway: midterm findings from a 3-year prospective Internet-based study.

PURPOSE: The increasing demand for primary eye care due to an aging population implicates an enhanced role of optometrists in the communities. The primary objective of this study was to investigate the rate of referrals and returning medical reports between optometrists and health care professionals in Norway. The secondary objectives were to investigate the conformity of diagnoses in referrals and medical reports, the extent of optometric follow-up examinations and the use of ophthalmic diagnostic drugs in optometric practice. MATERIALS AND METHODS: This study is an ongoing prospective electronic survey administered on the Internet between November 2014 and December 2017. Optometrists in private optometric practice are eligible. Participants register data for up to 1 year, including examinations and the use of ophthalmic diagnostic drugs; referrals, including International Classification of Primary Care, second edition (ICPC-2) codes; medical reports, including the ICD-10 codes; and optometric follow-up enquiries. Analysis of agreement between referred and diagnosed conditions was made possible by encoding patients' ID. RESULTS: Seventeen months into the study, 67 optometrists were included (Female: 60%, mean age: 41 years.). There were 49,510 registered examinations (60% general, 28% contact lens, 12% auxiliary). Diagnostic drugs were used in 4% of these and in 14% of the examinations that resulted in a referral. There were 1,779 referrals (97% to ophthalmologists). Top three diagnoses were cataract (36%), glaucoma (11%), and age-related macular degeneration (7%). There were 1,036 returned medical reports, of which 76% could be linked with registered referrals. Diagnostic agreement was observed in 80% of the cases (74% for primary diagnoses). There were only 17 registered cases of optometric follow-ups. CONCLUSION: In Norway, nearly all referrals from optometrists are to ophthalmologists. More than half of these result in a returned medical report. Nonreturned reports do not seem to trigger optometric follow-ups. The diagnostic agreement between referrals and medical reports is high. Diagnostic ophthalmic drugs are used sparsely by optometrists and mostly in relation to referrals.

Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs.

Most complex disease-associated genetic variants are located in non-coding regions and are therefore thought to be regulatory in nature. Association mapping of differential allelic expression (AE) is a powerful method to identify SNPs with direct cis-regulatory impact (cis-rSNPs). We used AE mapping to identify cis-rSNPs regulating gene expression in 55 and 63 HapMap lymphoblastoid cell lines from a Caucasian and an African population, respectively, 70 fibroblast cell lines, and 188 purified monocyte samples and found 40-60% of these cis-rSNPs to be shared across cell types. We uncover a new class of cis-rSNPs, which disrupt footprint-derived de novo motifs that are predominantly bound by repressive factors and are implicated in disease susceptibility through overlaps with GWAS SNPs. Finally, we provide the proof-of-principle for a new approach for genome-wide functional validation of transcription factor-SNP interactions. By perturbing NFκB action in lymphoblasts, we identified 489 cis-regulated transcripts with altered AE after NFκB perturbation. Altogether, we perform a comprehensive analysis of cis-variation in four cell populations and provide new tools for the identification of functional variants associated to complex diseases.

Single nucleotide polymorphisms with cis-regulatory effects on long non-coding transcripts in human primary monocytes.

We applied genome-wide allele-specific expression analysis of monocytes from 188 samples. Monocytes were purified from white blood cells of healthy blood donors to detect cis-acting genetic variation that regulates the expression of long non-coding RNAs. We analysed 8929 regions harboring genes for potential long non-coding RNA that were retrieved from data from the ENCODE project. Of these regions, 60% were annotated as intergenic, which implies that they do not overlap with protein-coding genes. Focusing on the intergenic regions, and using stringent analysis of the allele-specific expression data, we detected robust cis-regulatory SNPs in 258 out of 489 informative intergenic regions included in the analysis. The cis-regulatory SNPs that were significantly associated with allele-specific expression of long non-coding RNAs were enriched to enhancer regions marked for active or bivalent, poised chromatin by histone modifications. Out of the lncRNA regions regulated by cis-acting regulatory SNPs, 20% (n = 52) were co-regulated with the closest protein coding gene. We compared the identified cis-regulatory SNPs with those in the catalog of SNPs identified by genome-wide association studies of human diseases and traits. This comparison identified 32 SNPs in loci from genome-wide association studies that displayed a strong association signal with allele-specific expression of non-coding RNAs in monocytes, with p-values ranging from 6.7×10(-7) to 9.5×10(-89). The identified cis-regulatory SNPs are associated with diseases of the immune system, like multiple sclerosis and rheumatoid arthritis.

Genetic variation in the CYP2B6 gene is related to circulating 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) concentrations: an observational population-based study.

BACKGROUND: Since human CYP2B6 has been identified as the major CYP enzyme involved in the metabolism of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and that human 2B6 is a highly polymorphic CYP, with known functional variants, we evaluated if circulating concentrations of a major brominated flame retardant, BDE-47, were related to genetic variation in the CYP2B6 gene in a population sample. METHODS: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (men and women all aged 70), 25 single nucleotide polymorphisms (SNPs) in the CYP2B6 gene were genotyped. Circulating concentrations of BDE-47 were analyzed by high-resolution gas chromatography coupled to high-resolution mass spectrometry (HRGC/ HRMS). RESULTS: Several SNPs in the CYP2B6 gene were associated with circulating concentrations of BDE-47 (P = 10-4 to 10-9). The investigated SNPs came primarily from two haplotypes, although the correlation between the haplotypes was rather high. Conditional analyses adjusting for the SNP with the strongest association with the exposure (rs2014141) did not provide evidence for independent signals. CONCLUSION: Circulating concentrations of BDE-47 were related to genetic variation in the CYP2B6 gene in an elderly population.

Large-scale association analysis identifies new risk loci for coronary artery disease.

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.

Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation.

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.