Perceived Sufficiency of Full-Field Digital Mammograms With and Without Irreversible Image Data Compression for Comparison with Next-Year Mammograms

Problems associated with the large file sizes of digital mammograms have impeded the integration of digital mammography with picture archiving and communications systems. Digital mammograms irreversibly compressed by the novel wavelet Access Over Network (AON) compression algorithm were compared with lossless-compressed digital mammograms in a blinded reader study to evaluate the perceived sufficiency of irreversibly compressed images for comparison with next-year mammograms. Fifteen radiologists compared the same 100 digital mammograms in three different comparison modes: lossless-compressed vs 20:1 irreversibly compressed images (mode 1), lossless-compressed vs 40:1 irreversibly compressed images (mode 2), and 20:1 irreversibly compressed images vs 40:1 irreversibly compressed images (mode 3). Compression levels were randomly assigned between monitors. For each mode, the less compressed of the two images was correctly identified no more frequently than would occur by chance if all images were identical in compression. Perceived sufficiency for comparison with next-year mammograms was achieved by 97.37% of the lossless-compressed images and 97.37% of the 20:1 irreversibly compressed images in mode 1, 97.67% of the lossless-compressed images and 97.67% of the 40:1 irreversibly compressed images in mode 2, and 99.33% of the 20:1 irreversibly compressed images and 99.19% of the 40:1 irreversibly compressed images in mode 3. In a random-effect analysis, the irreversibly compressed images were found to be noninferior to the lossless-compressed images. Digital mammograms irreversibly compressed by the wavelet AON compression algorithm were as frequently judged sufficient for comparison with next-year mammograms as lossless-compressed digital mammograms

Coarsened exact matching of phaco-trabectome to trabectome in phakic patients: Lack of additional pressure reduction from phacoemulsification

Purpose To compare intraocular pressure (IOP) after trabectome-mediated ab interno trabeculectomy surgery in phakic patients (T) and trabectome with same session phacoemulsification (PT) using Coarsened Exact Matching. Although phacoemulsification is associated with IOP reduction when performed on its own, it is not known how much it contributes in PT. Methods Subjects were divided into phakic T and PT. Exclusion criteria were follow-up for <12 months and additional glaucoma surgery. Demographics were compared by the Mann- Whitney U test and chi-squared test for continuous and categorical variables, respectively. Multiple imputation was utilized to avoid eliminating data with missing values. Groups were then matched using Coarsened Exact Matching based on age, race, type of glaucoma, baseline IOP, and number of preoperative glaucoma medications. Univariate linear regression was used to examine IOP reduction after surgery; those variables that were statistically significant were included in the final multivariate regression model. Results A total of 753 cases were included (T: 255, PT: 498). When all variables except for age were kept constant, there was an additional IOP reduction of 0.05±0.01 mmHg conferred for every yearly increment in age. Every 1 mmHg increase in baseline IOP correlated to an additional IOP reduction of 0.80±0.02 mmHg. Phacoemulsification was not found to be a statistically significant contributor to IOP when comparing T and PT (p≥0.05). T had a 21% IOP reduction to 15.9±3.5 mmHg (p<0.01) while PT had an 18% reduction to 15.5±3.6 mmHg (p<0.01). Number of medications decreased (p<0.01) in both groups from 2.4±1.2 to 1.9±1.3 and from 2.3±1.1 to 1.7±1.3, respectively. Conclusion Phacoemulsification does not make a significant contribution to postoperative IOP or number of medications when combined with trabectome surgery in phakic patients

Impact of a glaucoma severity index on results of trabectome surgery: Larger pressure reduction in more severe glaucoma

Purpose: To stratify outcomes of trabectome-mediated ab interno trabeculectomy (AIT) by glaucoma severity using a simple and clinically useful glaucoma index. Based on prior data of trabectome after failed trabeculectomy, we hypothesized that more severe glaucoma might have a relatively more reduced facility compared to mild glaucoma and respond with a larger IOP reduction to trabecular meshwork ablation. Methods: Patients with primary open angle glaucoma who had undergone AIT without any other same session surgery and without any second eye surgery during the following 12 months were analyzed. Eyes of patients that had less than 12 months follow up or were diagnosed with neovascular glaucoma were excluded. A glaucoma index (GI) was created to capture glaucoma severity based on visual field, number of preoperative medications, and preoperative IOP. Visual field (VF) was separated into 3 categories: mild, moderate, and advanced (assigned 1,2, and 3 points, respectively). Preoperative number of medications (meds) was divided into 4 categories: ≤1, 2,3 or ≥4, and assigned with a value of 1 to 4. Baseline IOP (IOP) was divided into 3 categories: 12-18 (Group 3) and >18 (Group 4). Linear regression was used to determine if there was an association between GI group and IOP reduction after one year or age, gender, race, diagnosis, cup to disc (C/D) ratio, and Shaffer grade. Results: Out of 1340 patients, 843 were included in the analysis. The GI group distribution was GI1 = 164, GI2 = 202, GI3 = 260, and GI4 = 216. Mean IOP reduction after one year was 4.0±5.4, 6.4±5.8, 9.0±7.6,12.0±8.0 mmHg for GI groups 1 to 4, respectively. Linear regression showed that IOP reduction was associated with GI group after adjusting for age, gender, race, diagnosis, cup to disc ratio, and Shaffer grade. Each GI group increase of 1 was associated with incremental IOP reductions of 2.95±0.29 mmHg. Success rate at 12 months was 90%, 77%, 77%, and 71% for GI groups 1 to 4. The log-rank test suggested significant differences between GI groups. Conclusion: A simple glaucoma index, GI, was created to capture glaucoma severity and a relative resistance to treatment. A higher GI was associated with a larger IOP reduction in trabectome surgery. This indicates that there is a role for AIT beyond mild glaucoma and ocular hypertension

Associations of snoring frequency and intensity in pregnancy with time‐to‐delivery

BackgroundSleep‐disordered breathing (SDB) is linked to adverse pregnancy outcomes. However, little is known about the association of SDB with timing of delivery. We examined the association of snoring frequency, a key SDB marker, and snoring intensity, a correlate of SDB severity, with time‐to‐delivery among a cohort of pregnant women.MethodsIn this prospective cohort study, 1483 third trimester pregnant women were recruited from the University of Michigan prenatal clinics. Women completed a questionnaire about their sleep, and demographic and pregnancy information was abstracted from medical charts. After exclusion of those with hypertension or diabetes, 954 women were classified into two groups by their snoring onset timing, chronic or pregnancy‐onset. Within each of these groups, women were divided into four groups based on their snoring frequency and intensity: non‐snorers; infrequent‐quiet; frequent‐quiet; or frequent‐loud snorers. Cox proportional hazard regression models were used to investigate the association between snoring frequency and intensity and time‐to‐delivery, adjusting for maternal characteristics.ResultsChronic snoring was reported by half of the pregnant women, and of those, 7% were frequent‐loud snorers. Deliveries before 38 weeks’ gestation are completed occurred among 25% of women with chronic, frequent‐loud snoring. Compared with pre‐pregnancy non‐snorers, women with chronic frequent‐loud snoring had an increased hazard ratio for delivery (adjusted hazard ratio 1.60, 95% confidence interval 1.04, 2.45).ConclusionsSnoring frequency and intensity is associated with time‐to‐delivery in women absent of hypertension or diabetes. Frequent‐loud snoring may have a clinical utility to identify otherwise low‐risk women who are likely to deliver earlier.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146650/1/ppe12511.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146650/2/ppe12511_am.pd

Comprehensive Brain MRI Segmentation in High Risk Preterm Newborns

Most extremely preterm newborns exhibit cerebral atrophy/growth disturbances and white matter signal abnormalities on MRI at term-equivalent age. MRI brain volumes could serve as biomarkers for evaluating the effects of neonatal intensive care and predicting neurodevelopmental outcomes. This requires detailed, accurate, and reliable brain MRI segmentation methods. We describe our efforts to develop such methods in high risk newborns using a combination of manual and automated segmentation tools. After intensive efforts to accurately define structural boundaries, two trained raters independently performed manual segmentation of nine subcortical structures using axial T2-weighted MRI scans from 20 randomly selected extremely preterm infants. All scans were re-segmented by both raters to assess reliability. High intra-rater reliability was achieved, as assessed by repeatability and intra-class correlation coefficients (ICC range: 0.97 to 0.99) for all manually segmented regions. Inter-rater reliability was slightly lower (ICC range: 0.93 to 0.99). A semi-automated segmentation approach was developed that combined the parametric strengths of the Hidden Markov Random Field Expectation Maximization algorithm with non-parametric Parzen window classifier resulting in accurate white matter, gray matter, and CSF segmentation. Final manual correction of misclassification errors improved accuracy (similarity index range: 0.87 to 0.89) and facilitated objective quantification of white matter signal abnormalities. The semi-automated and manual methods were seamlessly integrated to generate full brain segmentation within two hours. This comprehensive approach can facilitate the evaluation of large cohorts to rigorously evaluate the utility of regional brain volumes as biomarkers of neonatal care and surrogate endpoints for neurodevelopmental outcomes

The transcription factor Spores Absent A is a PKA dependent inducer of Dictyostelium sporulation

Abstract Sporulation in Dictyostelium fruiting bodies evolved from amoebozoan encystation with both being induced by cAMP acting on PKA, but with downstream components still being unknown. Using tagged mutagenesis to find missing pathway components, we identified a sporeless mutant defective in a nuclear protein, SpaA. Expression of prespore genes was strongly reduced in spaA- cells, while expression of many spore stage genes was absent. Chromatin immunoprecipitation (ChIP) of a SpaA-YFP gene fusion showed that (pre)spore gene promoters bind directly to SpaA, identifying SpaA as a transcriptional regulator. SpaA dependent spore gene expression required PKA in vivo and was stimulated in vitro by the membrane-permeant PKA agonist 8Br-cAMP. The PKA agonist also promoted SpaA binding to (pre)spore promoters, placing SpaA downstream of PKA. Sequencing of SpaA-YFP ChIPed DNA fragments revealed that SpaA binds at least 117 (pre)spore promoters, including those of other transcription factors that activate some spore genes. These factors are not in turn required for spaA expression, identifying SpaA as the major trancriptional inducer of sporulation

Systematic review and meta-analysis: Opportunistic infections and malignancies during treatment with anti-integrin antibodies in inflammatory bowel disease

Background: Anti-integrin antibodies are effective therapies for Crohn's disease (CD) and ulcerative colitis (UC). However, these drugs carry theoretical risks of opportunistic infection and malignancy. Aim: To pool data from all placebo-controlled studies, to estimate risk of opportunistic infection or malignancy with anti-integrin antibodies. Methods: MEDLINE, EMBASE and the Cochrane central register of controlled trials were searched (up to December 2014). Randomised placebo-controlled trials of anti-integrin antibodies in adults with active or quiescent CD or UC were eligible. Dichotomous data were pooled to obtain a relative risk (RR) of opportunistic infection or malignancy, with 95% confidence intervals (CIs). Results: The search strategy identified 1579 citations, 12 of which were eligible (four trials of natalizumab, six of vedolizumab and two of etrolizumab). The RR of developing an opportunistic infection was not significantly higher with non-gut specific (2.34; 95% CI 0.05-108.72) or gut specific anti-integrin antibodies (1.55; 95% CI 0.16-14.83). The RR was generally higher in trials of non-gut specific anti-integrin antibodies with duration of therapy ≥52 weeks (RR = 15.00; 95% CI 0.86-261), but remained non-significant. The RR of malignancy was not elevated with non-gut specific (1.57; 95% CI 0.19-12.74) or gut specific anti-integrin antibodies (0.78; 95% CI 0.15-4.02). Conclusions: Absolute numbers of opportunistic infections were higher with anti-integrin antibodies, but this difference is not statistically significant. There was no increased risk of malignancy detected. Long-term data in large prospective cohorts are needed to further assess this issue

A Template-Dependent Dislocation Mechanism Potentiates K65R Reverse Transcriptase Mutation Development in Subtype C Variants of HIV-1

Numerous studies have suggested that the K65R reverse transcriptase (RT) mutation develops more readily in subtype C than subtype B HIV-1. We recently showed that this discrepancy lies partly in the subtype C template coding sequence that predisposes RT to pause at the site of K65R mutagenesis. However, the mechanism underlying this observation and the elevated rates of K65R development remained unknown. Here, we report that DNA synthesis performed with subtype C templates consistently produced more K65R-containing transcripts than subtype B templates, regardless of the subtype-origin of the RT enzymes employed. These findings confirm that the mechanism involved is template-specific and RT-independent. In addition, a pattern of DNA synthesis characteristic of site-specific primer/template slippage and dislocation was only observed with the subtype C sequence. Analysis of RNA secondary structure suggested that the latter was unlikely to impact on K65R development between subtypes and that Streisinger strand slippage during DNA synthesis at the homopolymeric nucleotide stretch of the subtype C K65 region might occur, resulting in misalignment of the primer and template. Consequently, slippage would lead to a deletion of the middle adenine of codon K65 and the production of a -1 frameshift mutation, which upon dislocation and realignment of the primer and template, would lead to development of the K65R mutation. These findings provide additional mechanistic evidence for the facilitated development of the K65R mutation in subtype C HIV-1

Uracil DNA N-Glycosylase Promotes Assembly of Human Centromere Protein A

Uracil is removed from DNA by the conserved enzyme Uracil DNA N-glycosylase (UNG). Previously, we observed that inhibiting UNG in Xenopus egg extracts blocked assembly of CENP-A, a histone H3 variant. CENP-A is an essential protein in all species, since it is required for chromosome segregation during mitosis. Thus, the implication of UNG in CENP-A assembly implies that UNG would also be essential, but UNG mutants lacking catalytic activity are viable in all species. In this paper, we present evidence that UNG2 colocalizes with CENP-A and H2AX phosphorylation at centromeres in normally cycling cells. Reduction of UNG2 in human cells blocks CENP-A assembly, and results in reduced cell proliferation, associated with increased frequencies of mitotic abnormalities and rapid cell death. Overexpression of UNG2 induces high levels of CENP-A assembly in human cells. Using a multiphoton laser approach, we demonstrate that UNG2 is rapidly recruited to sites of DNA damage. Taken together, our data are consistent with a model in which the N-terminus of UNG2 interacts with the active site of the enzyme and with chromatin