Unilateral renal fungus ball caused by Candida glabrata.

A 46-year-old diabetic woman with unilateral renal fungus ball was successfully treated with antifungal therapy, endoscopic extraction and ureteral stent placement. The patient was initially treated for a right staghorn calculus, thereafter developed urinary symptoms. Imaging revealed distal left ureter filling defects and a previous stent at the ureteropelvic junction. Urine culture confirmed Candida glabrata sensitive to Micafungin. Bilateral ureteroscopy facilitated the extraction of a left renal pelvis fungus ball. This case underscores the challenges in diagnosing fungal UTIs in patients with predisposing factors, and highlights a combined medical and surgical approach for effective treatment of renal fungus balls.

Incidence of Significant Findings of Microhematuria Workup in Women-What Guidelines Work Best?

OBJECTIVE: To apply the American Urogynecological Society (AUGS)/American College of Obstetricians and Gynecologists (ACOG) recommendations of foregoing workup in patients under 50 years of age with less than 25 red cells per high-powered field, to a cohort of asymptomatic microscopic hematuria (AMH) patients, and assess diagnostic accuracy, sensitivity, specificity, positive, and negative predictive value compared to the American Urologic Association (AUA) guidelines. METHODS: Retrospective review of female patients who underwent AMH evaluation from 2012 to 2015. The number of patients who would have avoided workup following the AUGS/ACOG recommendations was determined. Sensitivity, specificity, positive- and negative-predictive value and accuracy of the AUGS/ACOG recommendations compared to AUA guidelines were determined. RESULTS: Six hundred twenty women underwent AMH workup with 265 women undergoing full workup as per the AUA guidelines. Applying the AUGS/ACOG recommendations to this cohort would not have resulted in missed malignant diagnoses. Two tumors were found, both in patients who had undergone complete workup, and for whom AUGS/ACOG recommends workup. Following the AUGS/ACOG recommendations would have avoided workup in 126/620 of all women and 44/265 women who underwent the full AUA workup. In looking at findings of malignancy, the AUGS/ACOG workup had a sensitivity of 100% and a negative predictive value of 100% as compared to the AUA guidelines. CONCLUSION: AUA guidelines may over screen female low risk AMH patients. Extensive workup in a low risk group of female patients does not result in increased cancer diagnoses. Perhaps a more nuanced approach could result in fewer workups without compromising cancer detection.

Use of a Risk Stratification Tool to Guide Evaluation of Patients With Asymptomatic Microscopic Hematuria.

OBJECTIVE: To determine if use of the hematuria risk index can reduce testing and cost, while maintaining equivalent lesion detection in patients with asymptomatic microscopic hematuria. MATERIALS AND METHODS: Retrospective cohort study of 1049 patients at single institution. Hematuria risk index score was calculated based on clinical factors including age, sex, smoking history, and degree of hematuria for each patient along with evaluation studies performed and total number of tumors discovered. Cost benefit analysis was performed based on published Medicare averages. RESULTS: Tumor detection rate in overall, low-risk, and moderate-risk groups were 1.2%, 0%, and 2.96% at a total cost of $408,376. When low-risk group is not screened cost decreases to $166,252 with no lesions missed. The cost to discover one lesion/cancer in the overall group was $34,031.3, the cost to find one high-grade clinically significant lesion/cancer was $136,125.3 for the overall group. When the low-risk group was removed, the cost to find a high-grade clinically significant lesion/cancer decreased to $55,417.3 without missing any significant lesions. Ultrasound may be utilized instead of computed tomography with minimal loss of lesion detection in select moderate risk patients. CONCLUSION: None of the low-risk hematuria risk patients were diagnosed with any lesions, as such these patients may not need an evaluation. Furthermore, by utilizing a risk-stratified approach to the assessment of asymptomatic microscopic hematuria health care costs can be significantly decreased with limited negative consequences in terms of lesion detection.

United States v. Caronia: Off-Label Drug Promotion and First Amendment Balancing.

Off-label drug promotion is commonplace in the United States, but it is not without its dangers. While the Food, Drug, and Cosmetic Act does not explicitly ban off-label promotion, the Food & Drug Administration (FDA)--in order to protect consumers from unsafe and ineffective drugs--has taken steps to regulate it. The FDA does so through its intended-use regulation, which lists the types of evidence the FDA can consider in determining whether a drug is misbranded. It is a crime to sell a misbranded drug into interstate commerce or to conspire to do so. On September 25, 2015, the FDA proposed an amendment to the regulation, which has drawn opposition from various industry groups due to its potential to restrict the type of speech that is often used in off-label promotion. The First Amendment challenge to the proposed amendment rests on United States v. Caronia, in which the FDA was prevented from using truthful, nonmisleading speech to convict a pharmaceutical representative of a conspiracy to sell a misbranded drug. This Note examines whether the amendment to the regulation is permissible under Caronia. It first contends that the regulation does not facially violate the First Amendment. It further argues that the rule is constitutional and does not pose the same First Amendment issue as was seen in Caronia as long as the FDA implements it with care. This Note concludes by exploring various ways that the FDA can constitutionally regulate off-label drug promotion under the proposed rule.

Cholesterol, lipoproteins and subclinical interstitial lung disease: the MESA study.

We investigated associations of plasma lipoproteins with subclinical interstitial lung disease (ILD) by measuring high attenuation areas (HAA: lung voxels between -600 and -250 Hounsfield units) in 6700 adults and serum MMP-7 and SP-A in 1216 adults age 45-84 without clinical cardiovascular disease in Multi-Ethnic Study of Atherosclerosis. In cross-sectional analyses, each SD decrement in high density lipoprotein cholesterol (HDL-C) was associated with a 2.12% HAA increment (95% CI 1.44% to 2.79%), a 3.53% MMP-7 increment (95% CI 0.93% to 6.07%) and a 6.37% SP-A increment (95% CI 1.35% to 11.13%), independent of demographics, smoking and inflammatory biomarkers. These findings support a novel hypothesis that HDL-C might influence subclinical lung injury and extracellular matrix remodelling.

Using Whole Exome Sequencing to Identify Candidate Genes With Rare Variants In Nonsyndromic Cleft Lip and Palate.

Studies suggest that nonsyndromic cleft lip and palate (NSCLP) is polygenic with variable penetrance, presenting a challenge in identifying all causal genetic variants. Despite relatively high prevalence of NSCLP among Amerindian populations, no large whole exome sequencing (WES) studies have been completed in this population. Our goal was to identify candidate genes with rare genetic variants for NSCLP in a Honduran population using WES. WES was performed on two to four members of 27 multiplex Honduran families. Genetic variants with a minor allele frequency > 1% in reference databases were removed. Heterozygous variants consistent with dominant disease with incomplete penetrance were ascertained, and variants with predicted functional consequence were prioritized for analysis. Pedigree-specific P-values were calculated as the probability of all affected members in the pedigree being carriers, given that at least one is a carrier. Preliminary results identified 3,727 heterozygous rare variants; 1,282 were predicted to be functionally consequential. Twenty-three genes had variants of interest in ≥3 families, where some genes had different variants in each family, giving a total of 50 variants. Variant validation via Sanger sequencing of the families and unrelated unaffected controls excluded variants that were sequencing errors or common variants not in databases, leaving four genes with candidate variants in ≥3 families. Of these, candidate variants in two genes consistently segregate with NSCLP as a dominant variant with incomplete penetrance: ACSS2 and PHYH. Rare variants found at the same gene in all affected individuals in several families are likely to be directly related to NSCLP.

Mapping Purkinje Cell Placement Along the Purkinje Cell Layer: an Analysis of Postmortem Tissue from Essential Tremor Patients vs. Controls.

Postmortem studies have reported Purkinje cell loss in essential tremor (ET), and we recently demonstrated a significant increase in the mean distance between Purkinje cell bodies (i.e., a larger gap length distance) in ET cases vs. controls, likely reflecting a disease-associated reduction in Purkinje cells. We now analyze the regularity of distribution of Purkinje cells along the Purkinje cell layer to determine whether there is greater disorganization in ET cases than in age-matched controls. A standard parasagittal, formalin-fixed, tissue block was harvested from the neocerebellum of 50 ET cases and 25 age-matched controls. The gap length distance (µm) between Purkinje cells was quantified using a nearest neighbor analysis in which the distance between each Purkinje cell body was measured in OpenLAB software, version 5 (Improvision, Waltham, MA) by drawing a freehand line between adjacent Purkinje cell bodies along the entirety of the Purkinje cell layer within a given image. We analyzed the subject-specific variation in the organization of Purkinje cells along the Purkinje cell layer. The 50 ET cases and 25 controls were similar in age at death, gender, and brain weight. Overall, greater variation in gap length distance (i.e., more disorganization) was associated with greater gap length distance (p < 0.001) and younger age (p = 0.020). However, the variation in the Purkinje cell gap length distance (i.e., Purkinje cell organization) did not differ in ET cases and controls (p = 0.330). We observed that the regularity of the distribution of Purkinje cells along the Purkinje cell layer did not differ between ET cases and controls. Several alternative biological interpretations for this finding are discussed.

An LC-MS/MS method for serum methylmalonic acid suitable for monitoring vitamin B12 status in population surveys.

Methylmalonic acid (MMA), a functional indicator of vitamin B12 insufficiency, was measured in the US population in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2004 using a GC/MS procedure that required 275 µL of sample and had a low throughput (36 samples/run). Our objective was to introduce a more efficient yet highly accurate LC-MS/MS method for NHANES 2011-2014. We adapted the sample preparation with some modifications from a published isotope-dilution LC-MS/MS procedure. The procedure utilized liquid-liquid extraction and generation of MMA dibutyl ester. Reversed-phase chromatography with isocratic elution allowed baseline resolution of MMA from its naturally occurring structural isomer succinic acid within 4.5 min. Our new method afforded an increased throughput (≤160 samples/run) and measured serum MMA with high sensitivity (LOD = 22.1 nmol/L) in only 75 µL of sample. Mean (±SD) recovery of MMA spiked into serum (2 d, 4 levels, 2 replicates each) was 94 % ± 5.5 %. Total imprecision (41 d, 2 replicates each) for three serum quality control pools was 4.9 %-7.9 % (97.1-548 nmol/L). The LC-MS/MS method showed excellent correlation (n = 326, r = 0.99) and no bias (Deming regression, Bland-Altman analysis) compared to the previous GC/MS method. Both methods produced virtually identical mean (±SD) MMA concentrations [LC-MS/MS: 18.47 ± 0.71 ng/mL (n = 17), GC/MS: 18.18 ± 0.67 ng/mL (n = 11)] on a future plasma reference material compared with a GC/MS method procedure from the National Institute of Standards and Technology [18.41 ± 0.70 ng/mL (n = 15)]. No adjustment will be necessary to compare previous (1999-2004) to future (2011-2014) NHANES MMA data.

Urine sodium excretion increased slightly among U.S. adults between 1988 and 2010.

Little information is available on temporal trends in sodium intake in the U.S. population using urine sodium excretion as a biomarker. Our aim was to assess 1988-2010 trends in estimated 24-h urine sodium (24hUNa) excretion among U.S. adults (age 20-59 y) participating in the cross-sectional NHANES. We used subsamples from a 1988-1994 convenience sample, a 2003-2006 one-third random sample, and a 2010 one-third random sample to comply with resource constraints. We estimated 24hUNa excretion from measured sodium concentrations in spot urine samples by use of calibration equations (for men and women) derived from the International Cooperative Study on Salt, Other Factors, and Blood Pressure study. Estimated 24hUNa excretion increased over the 20-y period [1988-1994, 2003-2006, and 2010; means ± SEMs (n): 3160 ± 38.4 mg/d (1249), 3290 ± 29.4 mg/d (1235), and 3290 ± 44.4 mg/d (525), respectively; P-trend = 0.022]. We observed significantly higher mean estimated 24hUNa excretion in each survey period (P < 0.001) for men compared with women (31-33%) and for persons with a higher body mass index (BMI; 32-35% for obese vs. normal weight) or blood pressure (17-26% for hypertensive vs. normal blood pressure). After adjusting for age, sex, and race-ethnicity, temporal trends in mean estimated 24hUNa excretion remained significant (P-trend = 0.004). We observed no temporal trends in mean estimated 24hUNa excretion among BMI subgroups, nor after adjusting for BMI. Although several limitations apply to this analysis (the use of a convenience sample in 1988-1994 and using estimated 24hUNa excretion as a biomarker of sodium intake), these first NHANES data suggest that mean estimated 24hUNa excretion increased slightly in U.S. adults over the past 2 decades, and this increase may be explained by a shift in the distribution of BMI.

The feasibility of measuring frailty to predict disability and mortality in older medical intensive care unit survivors.

PURPOSE: To determine whether frailty can be measured within 4 days prior to hospital discharge in older intensive care unit (ICU) survivors of respiratory failure and whether it is associated with post-discharge disability and mortality. MATERIALS AND METHODS: We performed a single-center prospective cohort study of 22 medical ICU survivors age 65 years or older who had received noninvasive or invasive mechanical ventilation for at least 24 hours. Frailty was defined as a score of ≥3 using Fried's 5-point scale. We measured disability with the Katz Activities of Daily Living. We estimated unadjusted associations between Fried's frailty score and incident disability at 1-month and 6-month mortality using Cox proportional hazard models. RESULTS: The mean (SD) age was 77 (9) years, mean Acute Physiology and Chronic Health Evaluation II score was 27 (9.7), mean frailty score was 3.4 (1.3), and 18 (82%) were frail. Nine subjects (41%) died within 6 months, and all were frail. Each 1-point increase in frailty score was associated with a 90% increased rate of incident disability at 1-month (rate ratio: 1.9, 95% CI 0.7-4.9) and a threefold increase in 6-month mortality (rate ratio: 3.0, 95% CI 1.4-6.3). CONCLUSIONS: Frailty can be measured in older ICU survivors near hospital discharge and is associated with 6-month mortality in unadjusted analysis. Larger studies to determine if frailty independently predicts outcomes are warranted.

Development of a Standard Reference Material for metabolomics research.

The National Institute of Standards and Technology (NIST), in collaboration with the National Institutes of Health (NIH), has developed a Standard Reference Material (SRM) to support technology development in metabolomics research. SRM 1950 Metabolites in Human Plasma is intended to have metabolite concentrations that are representative of those found in adult human plasma. The plasma used in the preparation of SRM 1950 was collected from both male and female donors, and donor ethnicity targets were selected based upon the ethnic makeup of the U.S. population. Metabolomics research is diverse in terms of both instrumentation and scientific goals. This SRM was designed to apply broadly to the field, not toward specific applications. Therefore, concentrations of approximately 100 analytes, including amino acids, fatty acids, trace elements, vitamins, hormones, selenoproteins, clinical markers, and perfluorinated compounds (PFCs), were determined. Value assignment measurements were performed by NIST and the Centers for Disease Control and Prevention (CDC). SRM 1950 is the first reference material developed specifically for metabolomics research.

Timeliness of pediatric influenza vaccination compared with seasonal influenza activity in an urban community, 2004-2008.

OBJECTIVES: We assessed pediatric influenza vaccination in relation to community influenza activity. METHODS: We examined seasonal influenza vaccination in 34,012 children aged 6 months through 18 years from 5 academically affiliated clinics in northern Manhattan, New York (an urban low-income community) during the 2004-2008 seasons using hospital and city immunization registries. We calculated the cumulative number of administered influenza vaccine doses and proportion of children with any (≥ 1 dose) or full (1-2 doses per age recommendations) vaccination at the onset and peak of community polymerase chain reaction-confirmed influenza activity according to state surveillance reports and by March 31 each season. RESULTS: Influenza vaccine administration began before October 1, peaked before influenza activity onset, and declined gradually over each season. Coverage at influenza activity onset, peak, and by March 31 increased over the 5 seasons. However, most children lacked full vaccination at these time points, particularly adolescents, minorities, and those requiring 2 doses. CONCLUSIONS: Despite early initiation of influenza vaccination, few children were fully vaccinated when influenza began circulating. Interventions should address factors negatively affecting timely influenza vaccination, especially in high-risk populations.

Pulmonary hyperinflation and left ventricular mass: the Multi-Ethnic Study of Atherosclerosis COPD Study.

BACKGROUND: Left ventricular (LV) mass is an important predictor of heart failure and cardiovascular mortality, yet determinants of LV mass are incompletely understood. Pulmonary hyperinflation in chronic obstructive pulmonary disease (COPD) may contribute to changes in intrathoracic pressure that increase LV wall stress. We therefore hypothesized that residual lung volume in COPD would be associated with greater LV mass. METHODS AND RESULTS: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited smokers 50 to 79 years of age who were free of clinical cardiovascular disease. LV mass was measured by cardiac magnetic resonance. Pulmonary function testing was performed according to guidelines. Regression models were used to adjust for age, sex, body size, blood pressure, and other cardiac risk factors. Among 119 MESA COPD Study participants, the mean age was 69±6 years, 55% were male, and 65% had COPD, mostly of mild or moderate severity. Mean LV mass was 128±34 g. Residual lung volume was independently associated with greater LV mass (7.2 g per 1-SD increase in residual volume; 95% confidence interval, 2.2-12; P=0.004) and was similar in magnitude to that of systolic blood pressure (7.6 g per 1-SD increase in systolic blood pressure; 95% confidence interval, 4.3-11; P<0.001). Similar results were observed for the ratio of LV mass to end-diastolic volume (P=0.02) and with hyperinflation measured as residual volume to total lung capacity ratio (P=0.009). CONCLUSIONS: Pulmonary hyperinflation, as measured by residual lung volume or residual lung volume to total lung capacity ratio, is associated with greater LV mass.

Predicting age of onset in familial essential tremor: how much does age of onset run in families?

BACKGROUND: The extent to which age of onset of essential tremor (ET) aggregates in families is unknown; hence, it is unclear whether information about the age of onset in one family member can be used to predict the age of onset in others. METHODS: ET probands and relatives were enrolled in a genetic study at Columbia University. RESULTS: Data from 26 probands and 52 relatives were analyzed. The probands' age of onset correlated significantly with their relatives' age of onset (r = 0.50, p = 0.001). In 57.7% of cases, the relative's age of onset was within 10 years of the proband's onset (i.e. a 20-year age range). The proportion of affected relatives with age at onset <20 years was 64.7% in the families of probands with onset younger than 20 years, but only 7.7% in the families of probands with onset ≥20 years (p < 0.001). There was little evidence for genetic anticipation; 9/18 (50.0%) children reported a younger age of onset than the proband. CONCLUSIONS: In families containing multiple individuals with ET, the age at onset of probands and relatives was significantly correlated. Age of onset may be most tightly linked in families in which the proband had a young age of onset.

Influenza vaccination coverage and timeliness among children requiring two doses, 2004-2009.

OBJECTIVE: To assess influenza vaccination coverage and timeliness among children requiring two doses in a season. METHODS: This study examined seasonal influenza vaccination of 17,800 children from five academically-affiliated clinics in New York City using hospital and city immunization registries. Eligible children were 6 months-8 years and needed two influenza vaccine doses in a given season between 2004-05 and 2009-10. Any (≥ 1 dose) and full (2 doses) vaccination coverage by December 15 and March 31 as well as interval between doses were calculated. Vaccination trends over time, determinants, and missed opportunities were assessed. RESULTS: Children were primarily Latino and publicly insured. Full coverage by March 31 increased between the 2004-05 and 2009-10 seasons (9% vs. 29%, p<0.001). Few children received both doses by December 15 (2-13%). The interval between doses was almost twice as long as recommended and increased over time (2004-05: 52 days; 2009-10: 64 days; p<0.001). Older age and Latino ethnicity were negative predictors of full vaccination by March 31. Missed opportunities for the second dose were common. CONCLUSION: Despite improvements, low-income, minority children requiring two influenza vaccine doses remain at risk of incomplete and delayed vaccination. Barriers to and strategies for timely full vaccination should be explored.

Activation of the TLR4 signaling pathway and abnormal cholesterol efflux lead to emphysema in ApoE-deficient mice.

Smokers with airflow obstruction have an increased risk of atherosclerosis, but the relationship between the pathogenesis of these diseases is not well understood. To determine whether hypercholesterolemia alters lung inflammation and emphysema formation, we examined the lung phenotype of two hypercholesterolemic murine models of atherosclerosis at baseline and on a high-fat diet. Airspace enlargement developed in the lungs of apolipoprotein E-deficient (Apoe(-/-)) mice exposed to a Western-type diet for 10 wk. An elevated number of macrophages and lymphocytes accompanied by an increase in matrix metalloproteinase-9 (MMP-9) activity and MMP-12 expression was observed in the lungs of Apoe(-/-) mice on a Western-type diet. In contrast, low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice did not exhibit lung destruction or inflammatory changes. Most importantly, we revealed augmented expression of the downstream targets of the Toll-like receptor (TLR) pathway, interleukin-1 receptor-associated kinase 1, and granulocyte colony-stimulating factor, in the lungs of Apoe(-/-) mice fed with a Western-type diet. In addition, we demonstrated overexpression of MMP-9 in Apoe(-/-) macrophages treated with TLR4 ligand, augmented with the addition of oxidized LDL, suggesting that emphysema in these mice results from the activation of the TLR pathway secondary to known abnormal cholesterol efflux. Our findings indicate that, in Apoe(-/-) mice fed with an atherogenic diet, abnormal cholesterol efflux leads to increased systemic inflammation with subsequent lung damage and emphysema formation.

Mapping a mouse limbic seizure susceptibility locus on chromosome 10.

PURPOSE: Mapping seizure susceptibility loci in mice provides a framework for identifying potentially novel candidate genes for human epilepsy. Using C57BL/6J × A/J chromosome substitution strains (CSS), we previously identified a locus on mouse chromosome 10 (Ch10) conferring susceptibility to pilocarpine, a muscarinic cholinergic agonist that models human temporal lobe epilepsy by inducing initial limbic seizures and status epilepticus (status), followed by hippocampal cell loss and delayed-onset chronic spontaneous limbic seizures. Herein we report further genetic mapping of pilocarpine quantitative trait loci (QTLs) on Ch10. METHODS: Seventy-nine Ch10 F(2) mice were used to map QTLs for duration of partial status epilepticus and the highest stage reached in response to pilocarpine. Based on those results we created interval-specific congenic lines to confirm and extend the results, using sequential rounds of breeding selectively by genotype to isolate segments of A/J Ch10 genome on a B6 background. KEY FINDINGS: Analysis of Ch10 F(2) genotypes and seizure susceptibility phenotypes identified significant, overlapping QTLs for duration of partial status and severity of pilocarpine-induced seizures on distal Ch10. Interval-specific Ch10 congenics containing the susceptibility locus on distal Ch10 also demonstrated susceptibility to pilocarpine-induced seizures, confirming results from the F(2) mapping population and strongly supporting the presence of a QTL between rs13480781 (117.6 Mb) and rs13480832 (127.7 Mb). SIGNIFICANCE: QTL mapping can identify loci that make a quantitative contribution to a trait, and eventually identify the causative DNA-sequence polymorphisms. We have mapped a locus on mouse Ch10 for pilocarpine-induced limbic seizures. Novel candidate genes identified in mice can be investigated in functional studies and tested for their role in human epilepsy.

Unbiased and locally efficient estimation of genetic effect on quantitative trait in the presence of population admixture.

Population admixture can be a confounding factor in genetic association studies. Family-based methods (Rabinowitz and Larid, 2000, Human Heredity 50, 211-223) have been proposed in both testing and estimation settings to adjust for this confounding, especially in case-only association studies. The family-based methods rely on conditioning on the observed parental genotypes or on the minimal sufficient statistic for the genetic model under the null hypothesis. In some cases, these methods do not capture all the available information due to the conditioning strategy being too stringent. General efficient methods to adjust for population admixture that use all the available information have been proposed (Rabinowitz, 2002, Journal of the American Statistical Association 92, 742-758). However these approaches may not be easy to implement in some situations. A previously developed easy-to-compute approach adjusts for admixture by adding supplemental covariates to linear models (Yang et al., 2000, Human Heredity 50, 227-233). Here is shown that this augmenting linear model with appropriate covariates strategy can be combined with the general efficient methods in Rabinowitz (2002) to provide computationally tractable and locally efficient adjustment. After deriving the optimal covariates, the adjusted analysis can be carried out using standard statistical software packages such as SAS or R. The proposed methods enjoy a local efficiency in a neighborhood of the true model. The simulation studies show that nontrivial efficiency gains can be obtained by using information not accessible to the methods that rely on conditioning on the minimal sufficient statistics. The approaches are illustrated through an analysis of the influence of apolipoprotein E (APOE) genotype on plasma low-density lipoprotein (LDL) concentration in children.

Interexpert agreement in the identification of macular location in infants at risk for retinopathy of prematurity.

OBJECTIVE: To characterize variability in the identification of the macular center among retinopathy of prematurity (ROP) experts. METHODS: A printed set of 25 wide-angle retinal images was compiled from infants at risk for ROP using a commercially available camera. Ten recognized ROP experts were asked to mark the macular center on each image. For each image, we measured the distance from the optic disc center to the marked macular center. Distances were standardized by normalizing the horizontal optic disc diameter in each image to 0.93 mm. In images with visible peripheral disease, interexpert agreement on the presence of zone I disease was also determined. RESULTS: For the image with the least variability among experts, mean (SD) distance from the optic disc to the macular center was 3.69 (0.21) mm (range, 3.13-3.81 mm). For the image with the greatest variability among experts, distance from the optic disc to the macular center was 4.32 (1.19) mm (range, 3.21-7.19 mm). In 7 of 21 images (33%) with visible peripheral disease, there would have been disagreement among experts in the diagnosis of zone I disease based on identification of the macular center. Among the 10 experts, in 17 of 25 images (68%), 1 expert identified the distance between the optic disc and macular center to be greater than 1 SD from the mean. CONCLUSION: Significant variability exists among experts in identification of the macular center from wide-angle images, which raises concerns about the reliability of zone I ROP diagnosis.

Telemedical diagnosis of retinopathy of prematurity: accuracy of expert versus non-expert graders.

BACKGROUND/AIMS: To assess accuracy of telemedical retinopathy of prematurity (ROP) diagnosis by trained non-expert graders compared with expert graders. METHODS: Eye examinations (n=248) from 67 consecutive infants were captured using wide-angle retinal photography (RetCam-II, Clarity Medical Systems, Pleasanton, California, USA). Non-expert graders attended two 1-h training sessions on image-based ROP diagnosis. Using a web-based telemedicine system, 14 non-expert and three expert graders provided a diagnosis for each eye: no ROP, mild ROP, type 2 pre-threshold ROP or treatment-requiring ROP. All diagnoses were compared with a reference standard of dilated indirect ophthalmoscopy by an experienced paediatric ophthalmologist. RESULTS: For detection of type 2 or worse ROP, the mean (range) sensitivities and specificities were 0.95 (0.94-0.97) and 0.93 (0.91-0.96) for experts, 0.87 (0.71-0.97) and 0.73 (0.39-0.95) for resident non-experts, and 0.73 (0.41-0.88) and 0.91 (0.84-0.96) for student non-experts, respectively. For detection of treatment-requiring ROP, the mean (range) sensitivities and specificities were 1.00 (1.00-1.00) and 0.93 (0.88-0.96) for experts, 0.88 (0.50-1.00) and 0.84 (0.71-0.98) for resident non-experts, and 0.82 (0.42-1.00) and 0.92 (0.83-0.97) for student non-experts, respectively. CONCLUSIONS: Mean sensitivity and specificity of trained non-experts were lower than that of experts, although several non-experts had high accuracy. Development of methods for training non-expert graders may help support telemedical ROP evaluation.