Subjective and objective evaluation of corneal haze after accelerated corneal crosslinking for corneal ectasias.

PURPOSE: To evaluate the relationship between subjective (slit lamp examination [SLE]) and objective (densitometry) measurements of corneal haze after accelerated corneal crosslinking (aCXL), assess the relationship between densitometry and corrected distance visual acuity (CDVA), and determine the effect of baseline characteristics on densitometry after aCXL in eyes with progressive keratoconus and other ectasias. SETTING: Kensington Eye Institute and Bochner Eye Institute, Toronto, Canada. DESIGN: Retrospective analysis of a prospective interventional cohort study. METHODS: Scheimpflug-derived corneal densitometry, CDVA, maximum keratometry (Kmax ), and central corneal thickness were measured preoperatively and up to 1 year after aCXL, and post-operative haze was estimated with SLE (n = 483 eyes). A random effect model was used to examine the relationship between post-operative subjective haze with SLE and densitometry. Linear mixed models were used to examine the relationship between densitometry, pre-operative baseline characteristics, and CDVA. RESULTS: There was a significant association between subjective haze with SLE and densitometry (p < 0.001). There was a significant relationship between CDVA and densitometry: for every 10 GSUs of increased densitometry in the 0-2 mm zone, CDVA worsened by approximately half a Snellen line (p < 0.001). Age and pre-operative Kmax were significant predictors of densitometry. For every 10 years of age, densitometry increased by 0.68 GSUs (95% CI [0.27 to 1.07], p < 0.001). For every 10 D of increased preoperative Kmax , densitometry increased by 0.69 GSUs (95% CI [0.41 to 0.98], p < 0.001). CONCLUSIONS: Subjective haze after aCXL estimated with SLE, is significantly associated with densitometry. Increased densitometry after aCXL is associated with a reduction in CDVA.

Randomized Prospective Evaluation of Microblepharoexfoliation BlephEx as Adjunctive Therapy in the Treatment of Chalazia.

PURPOSE: Chalazia are benign eyelid lesions caused by the obstruction and inflammatory reaction of the meibomian glands. Demodex mites are one potential cause of chalazia leading to mechanical obstruction of the meibomian gland. In this prospective randomized study, we examine a novel approach to treating chalazia with the use of microblepharoexfoliation (MBE), an in-office lid hygiene technique that exfoliates the eyelid margins. METHODS: Fifty patients with clinical evidence of acute chalazion were enrolled in this study. Subjects were randomly assigned to a MBE plus lid hygiene group (23 patients, mean age 66.6 ± 16.6 years) or a lid hygiene alone group (27 patients, mean age 62.1 ± 14.4). The MBE plus lid hygiene group received MBE treatment and were evaluated 1 month after the baseline visit. The main outcome measured was the resolution of the chalazion at the 1-month follow-up visit. RESULTS: The lid hygiene plus MBE treatment group demonstrated a statistically significant resolution of the chalazion compared with the lid hygiene group alone ( P = 0.007; chi-square test). Among the MBE plus hygiene group, 87% of the patients had resolution of their chalazion as opposed to the lid hygiene alone group, which had 44% resolution. CONCLUSIONS: This is the first prospective, randomized clinical trial that demonstrated efficacy of MBE as a noninvasive adjunctive treatment method for chalazion resolution.

Evaluation of a novel treatment, selenium disulfide, in killing Demodex folliculorum in vitro.

OBJECTIVE: To evaluate the effectiveness of varying concentrations of selenium sulfide, an active ingredient in antidandruff shampoo, in killing Demodex folliculorum. METHODS: Sixty-five eyelashes with live Demodex from 29 patients seen at the Nassau University Medical Center (17 patients) and Ophthalmic Consultants of Long Island (12 patients) were observed under light microscopy for 90 minutes in 0.1%, 0.5%, 1.0%, and 4% selenium sulfide with either carboxymethyl cellulose (CMC) solution or petroleum jelly ointment (Vaseline, Unilever, London) as excipients. Positive and negative controls also were evaluated as separate solutions of CMC, petroleum jelly, basic saline solution, 50% tea tree oil, and 100% tea tree oil. The number of Demodex deaths and time of death were recorded. RESULTS: Demodex deaths in the selenium sulfide reagents were observed in the 4% selenium sulfide solution with CMC (36.4% kill rate, 4 of 11 Demodex, average time of death 17.5 minutes, p = 0.038) and 4% selenium sulfide with petroleum jelly ointment (12.5% kill rate, 1 of 8 Demodex, time of death 75 minutes, p = 0.351). No Demodex deaths were witnessed in the other selenium sulfide treatment groups. All Demodex died in the 50% and 100% tea tree oil positive control group. CONCLUSIONS: Selenium sulfide has shown efficacy in killing Demodex at a 4% concentration with the CMC solution and mild activity with 4% petroleum jelly. More research on selenium sulfide solutions at higher concentrations is indicated.

Update on the Management of Demodex Blepharitis.

ABSTRACT: Demodex blepharitis is a common ophthalmologic disease that is often overlooked in the workup of blepharitis. Demodex infestation occurs in both symptomatic and asymptomatic individuals at similar rates; consequently, its role in the development of blepharitis has not been well elucidated. Two species have been confirmed to inhabit the human eyelid- Demodex folliculorum and Demodex brevis. These species differ in their preferred location of infestation, with D. folliculorum occupying the base of the eyelash and D. brevis inhabiting the meibomian glands, contributing to anterior and posterior Demodex blepharitis, respectively. A clinical index of suspicion must be developed from the history when blepharitis, conjunctivitis, or keratitis in adults and blepharoconjunctivitis or chalazia in children are resistant to treatment. The diagnosis can be strongly suspected by the presence of cylindrical dandruff at the base of the eyelash and confirmed by light microscopy of an epilated lash or by in vivo confocal microscopy. No cure is currently available. Management most frequently includes topical tea tree oil and its active ingredient terpinen-4-ol, both of which have produced good clinical outcomes. Topical tea tree oil is typically applied by a professional due to risk of toxicity. Several second-line treatment options have been studied, including ivermectin, metronidazole, selenium sulfide, microblepharoexfoliation, and lid hygiene. Novel, targeted therapies such as TP-03 (Tarsus Pharmaceuticals) are also currently being investigated in phase 2b/3 clinical trials. The purpose of this review purpose is to characterize Demodex blepharitis in detail, including its historical perspective and various classifications, and describe the latest diagnostic and management strategies.

Pain control and reduction of opioid use associated with intracameral phenylephrine1.0%-ketorolac 0.3% administered during cataract surgery.

PURPOSE: To compare pain and the need for the opioid fentanyl use associated with the administration of phenylephrine 1.0%-ketorolac 0.3% (P/K) with those of epinephrine administration during cataract surgery. SETTING: Ambulatory surgery center. DESIGN: Single-center, prospective, randomized, double-masked, self-controlled trial. METHODS: Patients undergoing bilateral, topical anesthetic cataract surgery were randomized to receive either intracameral P/K or epinephrine in their balanced salt solution for the first eye and the other for the second eye, 2 weeks later. Fentanyl was used to manage intraoperative pain. The primary end point was the need for fentanyl administration intraoperatively. Secondary outcomes included pain measurements; surgery duration; effective phacoemulsification time; pupil size; and complications. RESULTS: 112 eyes of 56 patients were enrolled. Significantly fewer eyes in the P/K group (7 [12.5%]) than in the epinephrine group (19 [33.9%]; P = .013) required intraoperative fentanyl administration. Mean pain scores were lower in the P/K group than those in the control group at all timepoints. For patients with no pain to mild pain (pain scores ≤ 3), 85.7% (n = 48) of the P/K group and 58.9% (n = 33) of the epinephrine group met this benchmark ( P = .003) intraoperatively. The combined outcome, the number of patients not receiving intravenous fentanyl and experiencing no pain to mild pain, was significantly higher in the study (82.1%, n = 46) than in the control group (58.9%, n = 33; P = .013). CONCLUSIONS: P/K administration significantly reduced pain and the need for fentanyl use. Using P/K is a practical way for cataract surgeons to provide better patient care and reduce the need for intraoperative opioids.

Diagnostic Testing During Pediatric Hospitalizations: The Role of Attending In-House Coverage and Daytime Exposure.

OBJECTIVE: Overuse of diagnostic tests is of particular concern for pediatric academic medical centers. Our objective was to measure variation in testing based on proportion of hospitalization during the day versus night and the association between attending in-house coverage on the teaching service and test utilization for hospitalized pediatric patients. METHODS: Electronic health record data from 11,567 hospitalizations to a large, Northeastern, academic pediatric hospital were collected between January 2007 and December 2010. The patient-level dataset included orders for laboratory and imaging tests, information about who placed the order, and the timing of the order. Using a cross-sectional effect modification analysis, we estimated the difference in test utilization attributable to attending in-house coverage. RESULTS: We found that admission to the teaching service was independently associated with higher utilization of laboratory and imaging tests. However, the number of orders was 0.76 lower (95% confidence interval:-1.31 to -0.21, P = .006) per 10% increase in the proportion in the share of the hospitalization that occurred during daytime hours on the teaching services, which is attributable to direct attending supervision. CONCLUSIONS: Direct attending care of hospitalized pediatric patients at night was associated with slightly lower diagnostic test utilization.

Magnetic resonance imaging findings of empyema necessitatis in a child with a group A streptococcus infection.

Empyema necessitatis is a process defined and characterized by the transpleural spread of an infected pleural collection into the adjacent chest wall. Symptoms may be referable to the associated pleural and consolidative infection, but sometimes are associated with chest wall involvement. To our knowledge, the magnetic resonance imaging findings of this process have not yet been previously described in children. We present the magnetic resonance imaging findings of a rare case of a child with empyema necessitatis due to a group A streptococcal agent. The aggressive findings make differentiating infection from a tumor difficult.

Rapid detection of viable salmonellae in produce by coupling propidium monoazide with loop-mediated isothermal amplification.

Recent outbreaks linked to Salmonella-contaminated produce heightened the need to develop simple, rapid, and accurate detection methods, particularly those capable of determining cell viability. In this study, we examined a novel strategy for the rapid detection and quantification of viable salmonellae in produce by coupling a simple propidium monoazide sample treatment with loop-mediated isothermal amplification (PMA-LAMP). We first designed and optimized a LAMP assay targeting Salmonella. Second, the performance of PMA-LAMP for detecting and quantifying viable salmonellae was determined. Finally, the assay was evaluated in experimentally contaminated produce items (cantaloupe, spinach, and tomato). Under the optimized condition, PMA-LAMP consistently gave negative results for heat-killed Salmonella cells with concentrations up to 10(8) CFU/ml (or CFU/g in produce). The detection limits of PMA-LAMP were 3.4 to 34 viable Salmonella cells in pure culture and 6.1 × 10(3) to 6.1 × 10(4) CFU/g in spiked produce samples. In comparison, PMA-PCR was up to 100-fold less sensitive. The correlation between LAMP time threshold (T(T)) values and viable Salmonella cell numbers was high (R(2) = 0.949 to 0.993), with a quantification range (10(2) to 10(5) CFU/reaction in pure culture and 10(4) to 10(7) CFU/g in produce) comparable to that of PMA in combination with quantitative real-time PCR (PMA-qPCR). The complete PMA-LAMP assay took about 3 h to complete when testing produce samples. In conclusion, this rapid, accurate, and simple method to detect and quantify viable Salmonella cells in produce may present a useful tool for the produce industry to better control potential microbial hazards in produce.

Determinants of hospitalist efficiency: a qualitative and quantitative study.

Using qualitative and quantitative methods, the authors develop and test hypotheses about the impact of hospitalists on efficiency and quality of care relative to teaching teams. Departure of actual from self-perceived benefits for hospitalists, both individually and collectively, is studied. It was found that hospitalists are, on average, more efficient diagnosticians and/or enhance throughput, as evidenced by having relatively lower charges, through reductions in testing and length-of-stay, than teaching teams. Much of that benefit is concentrated among patients admitted by intensivists. The authors find little evidence of quality focus or of greater use of community resources among hospitalists. Indeed, hospitalists were found to have no effect on the choice of postdischarge outlets. The authors document variation in care delivery among hospitalists. In particular, it was found that among hospitalists there is more variation in achieving shorter length of stay but less variation in use of diagnostic testing.

Estrogen-related receptor alpha induces the expression of vascular endothelial growth factor in breast cancer cells.

Estrogen-related receptor alpha (ERRalpha) is an orphan member of the nuclear receptor family of transcription factors. In addition to its function as a metabolic regulator, ERRalpha has been implicated in the growth and progression of several malignancies. In the setting of breast cancer, not only is ERRalpha a putative negative prognostic factor, but we have recently found that knock-down of its expression retards tumor growth in a xenograft model of this disease. The specific aspects of ERRalpha function that are responsible for its actions in breast cancer, however, remain unclear. Using the coactivator PGC-1alpha as a protein ligand to regulate ERRalpha activity, we analyzed the effects of this receptor on gene expression in the ERalpha-positive MCF-7 cell line. This analysis led to the identification of a large number of potential ERRalpha target genes, many of which were subsequently validated in other breast cancer cell lines. Importantly, we demonstrate in this study that activation of ERRalpha in several different breast cancer cell lines leads to a significant increase in VEGF mRNA expression, an activity that translates into an increase in VEGF protein secretion. The induction of VEGF results from the interaction of ERRalpha with specific ERR-responsive elements within the VEGF promoter. These findings suggest that ERRalpha-dependent induction of VEGF may contribute to the overall negative phenotype observed in tumors in which ERRalpha is expressed and provide validation for its use as a therapeutic target in cancer.

Estrogen-related receptor alpha is critical for the growth of estrogen receptor-negative breast cancer.

Expression of estrogen-related receptor alpha (ERRalpha) has recently been shown to carry negative prognostic significance in breast and ovarian cancers. The specific role of this orphan nuclear receptor in tumor growth and progression, however, is yet to be fully understood. The significant homology between estrogen receptor alpha (ERalpha) and ERRalpha initially suggested that these receptors may have similar transcriptional targets. Using the well-characterized ERalpha-positive MCF-7 breast cancer cell line, we sought to gain a genome-wide picture of ERalpha-ERRalpha cross-talk using an unbiased microarray approach. In addition to generating a host of novel ERRalpha target genes, this study yielded the surprising result that most ERRalpha-regulated genes are unrelated to estrogen signaling. The relatively small number of genes regulated by both ERalpha and ERRalpha led us to expand our study to the more aggressive and less clinically treatable ERalpha-negative class of breast cancers. In this setting, we found that ERRalpha expression is required for the basal level of expression of many known and novel ERRalpha target genes. Introduction of a small interfering RNA directed to ERRalpha into the highly aggressive breast carcinoma MDA-MB-231 cell line dramatically reduced the migratory potential of these cells. Although stable knockdown of ERRalpha expression in MDA-MB-231 cells had no effect on in vitro cell proliferation, a significant reduction of tumor growth rate was observed when these cells were implanted as xenografts. Our results confirm a role for ERRalpha in breast cancer growth and highlight it as a potential therapeutic target for estrogen receptor-negative breast cancer.

On the intractability of estrogen-related receptor alpha as a target for activation by small molecules.

The estrogen-related receptor alpha (ERRalpha) is a potential target for activation in the treatment of metabolic disease. To date, no small-molecule agonists of ERRalpha have been identified despite several high-throughput screening campaigns. We describe the synthesis and profiling of a small array of compounds designed on the basis of a previously reported agonist-bound crystal structure of the closely related receptor ERRgamma. The results suggest that ERRalpha may be intractable as a direct target for pharmacologic activation.

Profiling the array of Ca(v)3.1 variants from the human T-type calcium channel gene CACNA1G: alternative structures, developmental expression, and biophysical variations.

We describe the regulated transcriptome of CACNA1G, a human gene for T-type Ca(v)3.1 calcium channels that is subject to extensive alternative RNA splicing. Fifteen sites of transcript variation include 2 alternative 5'-UTR promoter sites, 2 alternative 3'-UTR polyadenylation sites, and 11 sites of alternative splicing within the open reading frame. A survey of 1580 fetal and adult human brain full-length complementary DNAs reveals a family of 30 distinct transcripts, including multiple functional forms that vary in expression with development. Statistical analyses of fetal and adult transcript populations reveal patterns of linkages among intramolecular splice site configurations that change dramatically with development. A shift from nearly independent, biased splicing in fetal transcripts to strongly concerted splicing in adult transcripts suggests progressive activation of multiple "programs" of splicing regulation that reorganize molecular structures in differentiating cells. Patch-clamp studies of nine selected variants help relate splicing regulation to permutations of the gating parameters most likely to modify T-channel physiology in expressing neurons. Gating behavior reflects combinatorial interactions between variable domains so that molecular phenotype depends on ensembles of coselected domains, consistent with the observed emergence of concerted splicing during development. We conclude that the structural gene and networks of splicing regulatory factors define an integrated system for the phenotypic variation of Ca(v)3.1 biophysics during nervous system development.

Employer health insurance offerings and employee enrollment decisions.

OBJECTIVE: To determine how the characteristics of the health benefits offered by employers affect worker insurance coverage decisions. DATA SOURCES: The 1996-1997 and the 1998-1999 rounds of the nationally representative Community Tracking Study Household Survey. STUDY DESIGN: We use multinomial logistic regression to analyze the choice between own-employer coverage, alternative source coverage, and no coverage among employees offered health insurance by their employer. The key explanatory variables are the types of health plans offered and the net premium offered. The models include controls for personal, health plan, and job characteristics. PRINCIPAL FINDINGS: When an employer offers only a health maintenance organization married employees are more likely to decline coverage from their employer and take-up another offer (odds ratio (OR)=1.27, p<.001), while singles are more likely to accept the coverage offered by their employer and less likely to be uninsured (OR=0.650, p<.001). Higher net premiums increase the odds of declining the coverage offered by an employer and remaining uninsured for both married (OR=1.023, p<.01) and single (OR=1.035, p<.001) workers. CONCLUSIONS: The type of health plan coverage an employer offers affects whether its employees take-up insurance, but has a smaller effect on overall coverage rates for workers and their families because of the availability of alternative sources of coverage. Relative to offering only a non-HMO plan, employers offering only an HMO may reduce take-up among those with alternative sources of coverage, but increase take-up among those who would otherwise go uninsured. By modeling the possibility of take-up through the health insurance offers from the employer of the spouse, the decline in coverage rates from higher net premiums is less than previous estimates.

The magnitude and nature of risk selection in employer-sponsored health plans.

OBJECTIVE: To determine whether health maintenance organizations (HMOs) attract enrollees who use relatively few medical resources and whether a simple risk-adjustment system could mitigate or eliminate the inefficiency associated with risk selection. DATA SOURCES: The first and second rounds of the Community Tracking Study Household Survey (CTSHS), a national panel data set of households in 60 different markets in the United States. STUDY DESIGN: We use regression analysis to examine medical expenditures in the first round of the survey between enrollees who switched plan types (i.e., from a non-HMO plan to an HMO plan, or vice versa) between the first and second rounds of the survey versus enrollees who remained in their original plan. The dependent variable is an enrollee's medical resource use, measured in dollars, and the independent variables include gender, age, self-reported health status, and other demographic variables. DATA COLLECTION METHODS: We restrict our analysis to the 6,235 non-elderly persons who were surveyed in both rounds of the CTSHS, received health insurance from their employer or the employer of a household member in both years of the survey, and were offered a choice of an HMO and a non-HMO plan in both years. PRINCIPAL FINDINGS: We find that people who switched from a non-HMO to an HMO plan used 11 percent fewer medical services in the period prior to switching than people who remained in a non-HMO plan, and that this relatively low use persisted once they enrolled in an HMO. Furthermore, people who switched from an HMO to a non-HMO plan used 18 percent more medical services in the period prior to switching than those who remained in an HMO plan. CONCLUSIONS: HMOs are experiencing favorable risk selection and would most likely continue to do so even if employers adjusted health plan payments based on enrollees' gender and age because the selection is based on enrollee characteristics that are difficult to observe, such as preferences for medical care and health status.