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1.  Plastic Surgeons’ Perceptions of the Affordable Care Act: Results of a National Survey 
The Affordable Care Act (ACA) aims to expand coverage to the uninsured, improve quality, and contain costs. The goal of this study was to ascertain how plastic surgeons perceive the ACA.
An electronic questionnaire was e-mailed to members of the American Society of Plastic Surgeons between May and June 2014. The survey was anonymous and voluntary and included questions to assess understanding and opinions of the ACA.
The survey was sent to 3070 members of the American Society of Plastic Surgeons, and the response rate was 17%. Sixty-eight percent agree or strongly agree that they understand the basic concepts of the ACA. The majority of respondents disagree (38% strongly disagree, 31% disagree) with the notion that the ACA will positively affect their practice, and 51% agree with the statement, “I do not support the ACA, and I believe it did too much.” Two thirds (66%) believe that the ACA deserves a grade of D or F. When answers were analyzed across demographics, 42% of respondents with “Academic” practice background identify with the statement, “I support the ACA but I think it needs more work,” compared to 15% of those who selected “Solo Practice” (p <0.001).
The ACA will affect all specialties, including plastic surgery. The results of this survey suggest that many plastic surgeons believe that they have a baseline understanding of current health-care reform. The majority of surveyed surgeons do not support the Act. It is imperative that plastic surgeons possess the knowledge of the ACA; its changes, both current and impending, will likely affect patient mix, coverage of procedures, and reimbursement.
PMCID: PMC4323397
2.  Changes in nucleosome occupancy associated with metabolic alterations in aged mammalian liver 
Cell reports  2014;9(3):996-1006.
Aging is accompanied by physiological impairments, which, in insulin-responsive tissues, including the liver, predispose individuals to metabolic disease. However, the molecular mechanisms underlying these changes remain largely unknown. Here, we analyze genome-wide profiles of RNA and chromatin organization in the liver of young (3 months) and old (21 months) mice. Transcriptional changes suggest that de-repression of the nuclear receptors PPARα, PPARγ, and LXRα in aged mouse liver leads to activation of targets regulating lipid synthesis and storage, whereas age-dependent changes in nucleosome occupancy are associated with binding sites for both known regulators (forkhead factors and nuclear receptors) and for novel candidates associated with nuclear lamina (Hdac3 and Srf) implicated to govern metabolic function of aging liver. Winged-helix transcription factor Foxa2 and nuclear receptor co-repressor Hdac3 exhibit reciprocal binding pattern at PPARα targets contributing to gene expression changes that lead to steatosis in aged liver.
PMCID: PMC4250828  PMID: 25437555
3.  Exercise-based cardiac rehabilitation for coronary heart disease 
The burden of coronary heart disease (CHD) worldwide is one of great concern to patients and healthcare agencies alike. Exercise-based cardiac rehabilitation aims to restore patients with heart disease to health.
To determine the effectiveness of exercise-based cardiac rehabilitation (exercise training alone or in combination with psychosocial or educational interventions) on mortality, morbidity and health-related quality of life of patients with CHD.
Search methods
RCTs have been identified by searching CENTRAL, HTA, and DARE (using The Cochrane Library Issue 4, 2009), as well as MEDLINE (1950 to December 2009), EMBASE (1980 to December 2009), CINAHL (1982 to December 2009), and Science Citation Index Expanded (1900 to December 2009).
Selection criteria
Men and women of all ages who have had myocardial infarction (MI), coronary artery bypass graft (CABG) or percutaneous transluminal coronary angioplasty (PTCA), or who have angina pectoris or coronary artery disease defined by angiography.
Data collection and analysis
Studies were selected and data extracted independently by two reviewers. Authors were contacted where possible to obtain missing information.
Main results
This systematic review has allowed analysis of 47 studies randomising 10,794 patients to exercise-based cardiac rehabilitation or usual care. In medium to longer term (i.e. 12 or more months follow-up) exercise-based cardiac rehabilitation reduced overall and cardiovascular mortality [RR 0.87 (95% CI 0.75, 0.99) and 0.74 (95% CI 0.63, 0.87), respectively], and hospital admissions [RR 0.69 (95% CI 0.51, 0.93)] in the shorter term (< 12 months follow-up) with no evidence of heterogeneity of effect across trials. Cardiac rehabilitation did not reduce the risk of total MI, CABG or PTCA. Given both the heterogeneity in outcome measures and methods of reporting findings, a meta-analysis was not undertaken for health-related quality of life. In seven out of 10 trials reporting health-related quality of life using validated measures was there evidence of a significantly higher level of quality of life with exercise-based cardiac rehabilitation than usual care.
Authors’ conclusions
Exercise-based cardiac rehabilitation is effective in reducing total and cardiovascular mortality (in medium to longer term studies) and hospital admissions (in shorter term studies) but not total MI or revascularisation (CABG or PTCA). Despite inclusion of more recent trials, the population studied in this review is still predominantly male, middle aged and low risk. Therefore, well-designed, and adequately reported RCTs in groups of CHD patients more representative of usual clinical practice are still needed. These trials should include validated health-related quality of life outcome measures, need to explicitly report clinical events including hospital admission, and assess costs and cost-effectiveness.
PMCID: PMC4229995  PMID: 21735386
*Exercise Therapy; Coronary Disease [mortality; *rehabilitation]; Health Status; Myocardial Infarction [mortality; rehabilitation]; Myocardial Revascularization [statistics & numerical data]; Outcome Assessment (Health Care); Quality of Life; Randomized Controlled Trials as Topic; Female; Humans; Male
4.  Automated Discovery of Tissue-Targeting Enhancers and Transcription Factors from Binding Motif and Gene Function Data 
PLoS Computational Biology  2014;10(1):e1003449.
Identifying enhancers regulating gene expression remains an important and challenging task. While recent sequencing-based methods provide epigenomic characteristics that correlate well with enhancer activity, it remains onerous to comprehensively identify all enhancers across development. Here we introduce a computational framework to identify tissue-specific enhancers evolving under purifying selection. First, we incorporate high-confidence binding site predictions with target gene functional enrichment analysis to identify transcription factors (TFs) likely functioning in a particular context. We then search the genome for clusters of binding sites for these TFs, overcoming previous constraints associated with biased manual curation of TFs or enhancers. Applying our method to the placenta, we find 33 known and implicate 17 novel TFs in placental function, and discover 2,216 putative placenta enhancers. Using luciferase reporter assays, 31/36 (86%) tested candidates drive activity in placental cells. Our predictions agree well with recent epigenomic data in human and mouse, yet over half our loci, including 7/8 (87%) tested regions, are novel. Finally, we establish that our method is generalizable by applying it to 5 additional tissues: heart, pancreas, blood vessel, bone marrow, and liver.
Author Summary
Enhancers are distal gene regulatory elements that can activate tissue- and time-point specific gene expression. Identification of active enhancers is challenging, and is the subject of intense investigation. We developed an automated computational framework to predict transcription factors (TFs) and enhancers that target a tissue of interest by combining two growing resources: TF binding motifs and target gene function annotations. We applied our framework to the placenta, and confirmed our enhancer predictions are more active in placental cell types than others. To demonstrate generalizability, we applied our approach to 5 additional tissues. The combination of experimental sampling with computational prediction approaches will aid in the identification of those enhancers that are most likely active in a particular tissue, as well as the characterization of groups of TFs associated with these enhancers.
PMCID: PMC3907286  PMID: 24499934
5.  Prone breast forward intensity-modulated radiotherapy for Asian women with early left breast cancer: factors for cardiac sparing and clinical outcomes 
Journal of Radiation Research  2013;54(5):899-908.
Since December 2009, after breast-conserving surgery for Stage 0–I cancer of the left breast, 21 women with relatively pendulous breasts underwent computed tomography prone and supine simulations. The adjuvant radiotherapy was 50 Gy in 25 fractions to the left breast alone. Four plans—conventional wedged tangents and forward intensity-modulated radiotherapy (fIMRT) in supine and prone positions—were generated. fIMRT generated better homogeneity in both positions. Prone position centralized the breast tissue by gravity and also shortened the breast width which led to better conformity in both planning techniques. Prone fIMRT significantly reduced doses to left lung, Level I and Level II axilla. The mean cardiac doses did not differ between positions. Among the four plans, prone fIMRT produced the best target dosimetry and normal organ sparing. In subgroup analysis, patients with absolute breast depth > 7 cm in the prone position or breast depth difference > 3 cm between positions had significant cardiac sparing with prone fIMRT. Sixteen patients with significant cardiac sparing in prone position were treated using prone fIMRT and the others using supine fIMRT. All patients received a supine electron tumor bed boost of 10 Gy in 5 fractions. No patients developed Grade 2 or worse acute or late toxicities. There was no difference in the number of segments or beams, monitor units, treatment time, or positioning reproducibility between prone and supine positions. At a median follow-up time of 26.8 months, no locoregional or distant recurrence or death was noted.
PMCID: PMC3766291  PMID: 23504450
breast cancer; prone breast radiotherapy; intensity-modulated radiotherapy; breast tangents; Asian women
6.  Comparison of Autophotomontage Software Programs in Eyes with CMV Retinitis 
Three commercially available autophotomontage programs were examined for their ability to stitch together fundus photographs without errors. Significant differences were found in the performance of these programs.
Automated mosaic software programs are used to stitch together overlapping retinal fundus photographs. The performance of these programs in eyes with retinal diseases has not been independently evaluated. This study compares the quality of the mosaic products of three autophotomontage software programs, using digital fundus photographs of eyes with cytomegalovirus (CMV) retinitis.
Photographs of 99 eyes with CMV retinitis of 94 patients with HIV were taken at Maharaj Nakorn Chiang Mai Hospital in Chiang Mai, Thailand. Automated mosaic images were created for each of the 99 eyes by three different commercially available programs: IMAGEnet (Topcon, Oakland, NJ), i2k Retina (DualAlign LLC, Clifton Park, NY), and AutoMontage (OIS, Sacramento, CA). Three masked graders ranked each set of mosaics for each eye. The graders also assessed the overall image quality and documented mosaic artifacts in each image.
i2k Retina was ranked as the best program (70%–88%) more often than AutoMontage (10%–33%, P < 0.001) or IMAGEnet (0%–4%, P < 0.001) for creating automontages from digital fundus photographs of eyes with CMV retinitis. Acceptable quality mosaic images were reported most commonly for i2k Retina (93%–94%) and AutoMontage (91%–95%), followed by IMAGEnet (27%–56%, P < 0.001). IMAGEnet had a significantly higher percentage of mosaic errors than did either i2k Retina or AutoMontage (P < 0.001).
In eyes with CMV retinitis, both the i2k Retina and AutoMontage software packages appear to create higher quality mosaics than does IMAGEnet. Automated retinal mosaic imaging may be valuable in diagnosing CMV retinitis and observing disease progression.
PMCID: PMC3250113  PMID: 22064986
7.  The Number of X Chromosomes Causes Sex Differences in Adiposity in Mice 
PLoS Genetics  2012;8(5):e1002709.
Sexual dimorphism in body weight, fat distribution, and metabolic disease has been attributed largely to differential effects of male and female gonadal hormones. Here, we report that the number of X chromosomes within cells also contributes to these sex differences. We employed a unique mouse model, known as the “four core genotypes,” to distinguish between effects of gonadal sex (testes or ovaries) and sex chromosomes (XX or XY). With this model, we produced gonadal male and female mice carrying XX or XY sex chromosome complements. Mice were gonadectomized to remove the acute effects of gonadal hormones and to uncover effects of sex chromosome complement on obesity. Mice with XX sex chromosomes (relative to XY), regardless of their type of gonad, had up to 2-fold increased adiposity and greater food intake during daylight hours, when mice are normally inactive. Mice with two X chromosomes also had accelerated weight gain on a high fat diet and developed fatty liver and elevated lipid and insulin levels. Further genetic studies with mice carrying XO and XXY chromosome complements revealed that the differences between XX and XY mice are attributable to dosage of the X chromosome, rather than effects of the Y chromosome. A subset of genes that escape X chromosome inactivation exhibited higher expression levels in adipose tissue and liver of XX compared to XY mice, and may contribute to the sex differences in obesity. Overall, our study is the first to identify sex chromosome complement, a factor distinguishing all male and female cells, as a cause of sex differences in obesity and metabolism.
Author Summary
Differences exist between men and women in the development of obesity and related metabolic diseases such as type 2 diabetes and cardiovascular disease. Previous studies have focused on the sex-biasing role of hormones produced by male and female gonads, but these cannot account fully for the sex differences in metabolism. We discovered that removal of the gonads uncovers an important genetic determinant of sex differences in obesity—the presence of XX or XY sex chromosomes. We used a novel mouse model to tease apart the effects of male and female gonads from the effects of XX or XY chromosomes. Mice with XX sex chromosomes (relative to XY), regardless of their type of gonad, had increased body fat and ate more food during the sleep period. Mice with two X chromosomes also had accelerated weight gain, fatty liver, and hyperinsulinemia on a high fat diet. The higher expression levels of a subset of genes on the X chromosome that escape inactivation may influence adiposity and metabolic disease. The effect of X chromosome genes is present throughout life, but may become particularly significant with increases in longevity and extension of the period spent with reduced gonadal hormone levels.
PMCID: PMC3349739  PMID: 22589744
8.  A5-Positive Primary Sensory Neurons Are Nonpermissive for Productive Infection with Herpes Simplex Virus 1 In Vitro▿ 
Journal of Virology  2011;85(13):6669-6677.
Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) establish latency and express the latency-associated transcript (LAT) preferentially in different murine sensory neuron populations, with most HSV-1 LAT expression in A5+ neurons and most HSV-2 LAT expression in KH10+ neurons. To study the mechanisms regulating the establishment of HSV latency in specific subtypes of neurons, cultured dissociated adult murine trigeminal ganglion (TG) neurons were assessed for relative permissiveness for productive infection. In contrast to that for neonatal TG, the relative distribution of A5+ and KH10+ neurons in cultured adult TG was similar to that seen in vivo. Productive infection with HSV was restricted, and only 45% of cultured neurons could be productively infected with either HSV-1 or HSV-2. A5+ neurons supported productive infection with HSV-2 but were selectively nonpermissive for productive infection with HSV-1, a phenomenon that was not due to restricted viral entry or DNA uncoating, since HSV-1 expressing β-galactosidase under the control of the neurofilament promoter was detected in ∼90% of cultured neurons, with no preference for any neuronal subtype. Infection with HSV-1 reporter viruses expressing enhanced green fluorescent protein (EGFP) from immediate early (IE), early, and late gene promoters indicated that the block to productive infection occurred before IE gene expression. Trichostatin A treatment of quiescently infected neurons induced productive infection preferentially from non-A5+ neurons, demonstrating that the nonpermissive neuronal subtype is also nonpermissive for reactivation. Thus, HSV-1 is capable of entering the majority of sensory neurons in vitro; productive infection occurs within a subset of these neurons; and this differential distribution of productive infection is determined at or before the expression of the viral IE genes.
PMCID: PMC3126511  PMID: 21507969
9.  Attenuation of HIV-associated human B cell exhaustion by siRNA downregulation of inhibitory receptors 
The Journal of Clinical Investigation  2011;121(7):2614-2624.
Chronic immune activation in HIV-infected individuals leads to accumulation of exhausted tissue-like memory B cells. Exhausted lymphocytes display increased expression of multiple inhibitory receptors, which may contribute to the inefficiency of HIV-specific antibody responses. Here, we show that downregulation of B cell inhibitory receptors in primary human B cells led to increased tissue-like memory B cell proliferation and responsiveness against HIV. In human B cells, siRNA knockdown of 9 known and putative B cell inhibitory receptors led to enhanced B cell receptor–mediated (BCR-mediated) proliferation of tissue-like memory but not other B cell subpopulations. The strongest effects were observed with the putative inhibitory receptors Fc receptor–like–4 (FCRL4) and sialic acid–binding Ig-like lectin 6 (Siglec-6). Inhibitory receptor downregulation also led to increased levels of HIV-specific antibody-secreting cells and B cell–associated chemokines and cytokines. The absence of known ligands for FCRL4 and Siglec-6 suggests these receptors may regulate BCR signaling through their own constitutive or tonic signaling. Furthermore, the extent of FCLR4 knockdown effects on BCR-mediated proliferation varied depending on the costimulatory ligand, suggesting that inhibitory receptors may engage specific pathways in inhibiting B cell proliferation. These findings on HIV-associated B cell exhaustion define potential targets for reversing the deleterious effect of inhibitory receptors on immune responses against persistent viral infections.
PMCID: PMC3127436  PMID: 21633172
10.  The Sandwell Project: A controlled evaluation of a programme of targeted screening for prevention of cardiovascular disease in primary care 
BMC Public Health  2008;8:73.
A pilot cardiovascular disease prevention project was implemented in the inner-city West Midlands. It was evaluated by comparing its effectiveness to a control group where full implementation was delayed by a year.
Cardiovascular risk factor data were extracted on all untreated patients 35 to 74 years old from electronic medical databases in six general practices. A best estimate of ten-year CVD risk cardiovascular risk was calculated on all patients using the extracted risk factor data. Default risk-factor values were used for all missing risk factor data. High risk patients were thus identified. In four practices a project nurse systematically invited, assessed and referred high risk patients for treatment. Two control practices were provided with a list of their high risk patients. The outcomes were the proportions of untreated high-risk patients who were assessed, identified as eligible for treatment and treated under two strategies for identifying and treating such patients in primary care.
Of all high-risk patients suitable for inclusion in the project, 40.6% (95% CI: 36.7 to 45.7%) of patients in intervention practices were started on treatment were started on at least one treatment, compared to 12.7% (95% CI: 9.8% to 16.1%) in control practices.
A strategy using electronic primary care records to identify high risk patients for CVD prevention works best with a process for acting on information, ensuring patients are invited, assessed and treated.
PMCID: PMC2278139  PMID: 18298863

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