Synthesis and Morphology of High-Molecular-Weight Polyisobutylene-Polystyrene Block Copolymers Containing Dynamic Covalent Bonds.

Incorporating dynamic covalent bonds into block copolymers provides useful molecular level information during mechanical testing, but it is currently unknown how the incorporation of these units affects the resultant polymer morphology. High-molecular-weight polyisobutylene-b-polystyrene block copolymers containing an anthracene/maleimide dynamic covalent bond are synthesized through a combination of postpolymerization modification, reversible addition-fragmentation chain-transfer polymerization, and Diels-Alder coupling. The bulk morphologies with and without dynamic covalent bond are characterized by atomic force microscopy  and small-angle X-ray scattering, which reveal a strong dependence on annealing time and casting solvent. Morphology is largely unaffected by the inclusion of the mechanophore. The high-molecular-weight polymers synthesized allow interrogation of a large range of polymer domain sizes.

Prophylactic antibiotics for hemorrhoidectomy: are they really needed?

BACKGROUND: Hemorrhoidectomy is considered by many to be a contaminated operation that requires antibiotic prophylaxis to lower the incidence of surgical site infection. In reality, little evidence exists to either support or refute the use of antibiotic prophylaxis in this setting. OBJECTIVE: This study aimed to determine if antibiotic prophylaxis is associated with reduced incidence of postoperative surgical site infection following hemorrhoidectomy. DESIGN: This is a retrospective database review. SETTING: This study was conducted at multiple institutions. PATIENTS: All patients undergoing hemorrhoidectomy with minimum 3-month follow-up were included. MAIN OUTCOME MEASURES: The primary outcome measure was the incidence of postoperative surgical site infection. RESULTS: Eight hundred fifty-two patients met the inclusion criteria (50.1% female; mean age, 50.0 ± 13.7 years). The prevalence of preoperative risk factors for surgical site infection included 7.7% with a smoking history, 2.5% with diabetes mellitus, 0.8% receiving steroids, and 0.2% with Crohn's disease. Surgery was performed predominately for 3-column prolapsed internal and mixed internal/external hemorrhoidal disease. All surgeries performed were closed hemorrhoidectomies. Antibiotic prophylaxis was used in a fewer number of cases (41.3% vs 58.7%). Overall, there were only 12 documented postoperative infections identified, producing an overall incidence of 1.4%. Of those patients who developed postoperative surgical site infections, 9 (75%) did not receive antibiotic prophylaxis (p = 0.25). On multivariate regression analysis, no perioperative risk factor was associated with an increased risk of developing a posthemorrhoidectomy surgical site infection. Conversely, there were no adverse antibiotic-related complications such as Clostridium difficile colitis or antibiotic-associated diarrhea in those receiving antibiotic prophylaxis. LIMITATIONS: This study was limited by the retrospective nature of the analysis. CONCLUSIONS: Postoperative surgical site infection is an exceedingly rare event following hemorrhoidectomy. Antibiotic prophylaxis does not reduce the incidence of postoperative surgical site infection, and its routine use appears unnecessary.

Epoxides as reducing agents for low-catalyst-concentration atom transfer radical polymerization.

Activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) conditions utilizing a low concentration of catalyst are successfully applied for the preparation of well-defined poly(glycidyl methacrylate) without the addition of external reducing agents. The living character of polymerization is evidenced by successful chain extensions with methyl methacrylate and methyl acrylate, again, in the absence of additional reducing agents, yielding block copolymers. The epoxide groups in glycidyl methacrylate or the corresponding polymer can serve as an intrinsic reducing agent to continuously regenerate the Cu(I) -based ATRP activator from the Cu(II) halide complex present in the systems. The reactivity of various epoxides in the reduction of the Cu(II) Br2 complex of tris(2-pyridylmethyl)amine is compared.

Incorporating population-level variability in orthopedic biomechanical analysis: a review.

Effectively addressing population-level variability within orthopedic analyses requires robust data sets that span the target population and can be greatly facilitated by statistical methods for incorporating such data into functional biomechanical models. Data sets continue to be disseminated that include not just anatomical information but also key mechanical data including tissue or joint stiffness, gait patterns, and other inputs relevant to analysis of joint function across a range of anatomies and physiologies. Statistical modeling can be used to establish correlations between a variety of structural and functional biometrics rooted in these data and to quantify how these correlations change from health to disease and, finally, to joint reconstruction or other clinical intervention. Principal component analysis provides a basis for effectively and efficiently integrating variability in anatomy, tissue properties, joint kinetics, and kinematics into mechanistic models of joint function. With such models, bioengineers are able to study the effects of variability on biomechanical performance, not just on a patient-specific basis but in a way that may be predictive of a larger patient population. The goal of this paper is to demonstrate the broad use of statistical modeling within orthopedics and to discuss ways to continue to leverage these techniques to improve biomechanical understanding of orthopedic systems across populations.

"I Just Want to be Acknowledged": Suicidal Ideation Experiences among Sexual Minority Students at a Religiously Affiliated University.

Research finds that sexual minority university students experience considerable psychological and emotional distress. Furthermore, a recent study at Brigham Young University (BYU)-a university affiliated with The Church of Jesus Christ of Latter-day Saints-found that suicidality prevalence and severity were twice as high among sexual minority students compared to their heterosexual peers. To better understand this finding, we interviewed ten sexual minority students at BYU who reported clinically significant current or previous suicidality. A coding team and auditors then analyzed and categorized the transcripts of these interviews using the Consensual Qualitative Research methodology. Five domains emerged related to suicidality among sexual minority students: deterrents from suicidal ideation and intent; contributors to suicidal ideation and intent; religious and spiritual experiences; experiences with BYU; and suggested improvements. We found patterns consistent with previous literature, including relational and belonging factors contributing to suicidality; we also found that certain doctrinal interpretations were related to increased suicidality. The primary improvement requested by participants was feeling better understood and accepted (rather than ignored or marginalized). We discuss study limitations (including small sample size and low generalizability,), future directions for research, and implications for religious university campuses.

Case report of osteolytic lesions in a patient with multisystem granulomatous disease.

We present a case of a 70-year-old Caucasian woman with multisystem granulomatous disease involving her lungs, bones and lymph nodes. The patient initially presented with cervical lymphadenopathy and subsequently developed progressive breathlessness. Imaging revealed extensive mediastinal, hilar and intra-abdominal lymphadenopathy as well as bilateral pulmonary parenchymal infiltrates. Lymph node and lung biopsy confirmed non-necrotising granulomatous inflammation while a BAL showed scanty growth of Cryptococcus neoformans and moderate growth of Staphylococcus aureus The patient received intravenous ceftriaxone and had a good response to treatment. She also completed 3 months of oral fluconazole. Although a diagnosis of sarcoidosis was considered most likely, the patient was not initially started on systemic corticosteroids due to concern around possible infection and initial response to antimicrobials. However, her exercise tolerance gradually deteriorated. A craniofacial CT revealed multiple lytic lesions involving the skull and visualised cervical spine. Biopsy of a clivus lesion revealed non-necrotising granulomatous inflammation while fungal cultures and histopathological stains were negative. The patient was diagnosed with widespread sarcoidosis and she was initiated on prednisolone and methotrexate which led to marked clinical and radiological improvement.

Case report: Death associated with stroke following intracarotid amobarbital testing.

OBJECTIVE: One previous accidental death during intracarotid amobarbital testing (IAT) associated with cerebral angiography (CA) has been reported in the literature. The objectives of this article are to briefly review morbidity and mortality risks for patients undergoing diagnostic CA and to describe a case with a fatal outcome. METHOD: The case of a 38-year-old man who had a right middle cerebral artery stroke while undergoing IAT is described. The patient was not high risk by Centers for Medicare and Medicaid Services criteria or invasive procedures; neither did he have risk factors for embolic stroke. CONCLUSIONS: A problem noted is that IAT procedures vary from center to center and that IAT may increase the risk for individual patients because of differences between IAT and other CA interventions.

Carotid Disease and Retinal Optical Coherence Tomography Angiography Parameters in Type 2 Diabetes: The Fremantle Diabetes Study Phase II.

OBJECTIVE: To use optical coherence tomography angiography (OCTA) to determine whether retinal microvascular parameters are associated with carotid arterial disease in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: Participants (community-based) underwent detailed assessments including carotid ultrasonography and OCTA. Ultrasound images were assessed for mean intima-media thickness (IMT) and the presence of stenosis. OCTA image analysis provided measures of vessel density, foveal avascular zone (FAZ) area, blood flow areas, and retinal thickness. For each OCTA variable, the most parsimonious model was generated using generalized estimating equations, then ipsilateral and contralateral carotid disease-related variables were added to determine their significance. RESULTS: A total of 474 eyes from 261 participants (mean ± SD age 72.0 ± 9.3 years, 57.1% males, median diabetes duration 15.4 years [interquartile range 11.1-22.4]) were analyzed. When carotid variables were added to the most parsimonious models, the ipsilateral natural logarithm of common carotid artery IMT (coefficient -2.56 [95% CI -4.76, -0.35], P = 0.023) and presence of any ipsilateral stenosis (-0.82 [-1.48, -0.17], P = 0.014) were statistically significantly associated with a lower parafoveal density in the deep capillary plexus. A mean bifurcation IMT ≥1 mm was associated with a decreased vessel density in the 300-µm ring surrounding the FAZ (coefficient -0.79 [-1.50, -0.08], P = 0.030)). Contralateral carotid disease-related variables were also significantly associated with retinal microvascular parameters. CONCLUSIONS: This is the first study to show that carotid disease is an independent associate of retinal microvascular disease assessed by OCTA in type 2 diabetes. Appropriately intensive management of carotid disease may improve the retinal microcirculation.

Compensatory mutations are repeatable and clustered within proteins.

Compensatory mutations improve fitness in genotypes that contain deleterious mutations but have no beneficial effects otherwise. As such, compensatory mutations represent a very specific form of epistasis. We show that intragenic compensatory mutations occur non-randomly over gene sequence. Compensatory mutations are more likely to appear at some sites than others. Moreover, the sites of compensatory mutations are more likely than expected by chance to be near the site of the original deleterious mutation. Furthermore, compensatory mutations tend to occur more commonly in certain regions of the protein even when controlling for clustering around the site of the deleterious mutation. These results suggest that compensatory evolution at the protein level is partially predictable and may be convergent.

Economic Impact of Laparoscopic Conversion to Open in Left Colon Resections.

BACKGROUND AND OBJECTIVES: Studies have shown economic and clinical advantages of laparoscopic left-colon resections. Laparoscopic conversion to open is an important surgical outcome. We estimated conversion incidence, identified risk factors, and measured the clinical and economic impact. METHODS: In this retrospective study, we used the Premier Perspective database to analyze left-sided colectomies from 2009 to 2014. Operating room time (ORT), length of stay (LOS), total hospital cost (2014 U.S. dollars); along with incidence of in-hospital clinical outcomes (anastomotic leak surrogate [Leak], transfusion, and mortality) were evaluated. Multivariable models accounting for hospital clustering were used to identify conversion risk factors and analyze the effect of conversion on economic and clinical outcomes. RESULTS: A total of 41,417 patients: 8,468 left hemicolectomy and 32,949 sigmoidectomy were identified. Lap-Conversion incidence was 13.3% (95% CI, 12.9-13.7). Adjusted mean LOS (±SE) days was significantly lower for the Lap-Successful group (4.9 compared with Lap-Conversion 6.8 and Open-Planned 7.0), but Lap-Conversion and Open-Planned had similar LOS. Adjusted mean cost was higher for Lap-Conversion $20,165 compared to Open-Planned $18,797; but this difference was smaller than the cost savings for Lap-Successful $16,206 ± $219. Open-Planned had lower odds of Leak compared to Lap-Conversion. Open-Planned and Lap-Conversion had similar odds of transfusion and mortality. Conversion risk factors included inflammatory bowel disease and left-hemicolectomy. Colorectal specialists were associated with 38% decreased odds of conversion. CONCLUSIONS: Successful laparoscopic surgery was the most cost effective, with decreased LOS and odds of blood transfusion, leak surrogate, and mortality. Conversion was the most expensive and had increased odds of leak surrogate, but similar LOS compared to Open-Planned. The beneficial effect size of successful laparoscopic surgery was larger than the negative effect of conversion compared to Open-Planned.

Multi-modal image set registration and atlas formation.

In this paper, we present a Bayesian framework for both generating inter-subject large deformation transformations between two multi-modal image sets of the brain and for forming multi-class brain atlases. In this framework, the estimated transformations are generated using maximal information about the underlying neuroanatomy present in each of the different modalities. This modality independent registration framework is achieved by jointly estimating the posterior probabilities associated with the multi-modal image sets and the high-dimensional registration transformations mapping these posteriors. To maximally use the information present in all the modalities for registration, Kullback-Leibler divergence between the estimated posteriors is minimized. Registration results for image sets composed of multi-modal MR images of healthy adult human brains are presented. Atlas formation results are presented for a population of five infant human brains.

The Virtual Pediatric Airways Workbench.

The Virtual Pediatric Airways Workbench (VPAW) is a patient-centered surgical planning software system targeted to pediatric patients with airway obstruction. VPAW provides an intuitive surgical planning interface for clinicians and supports quantitative analysis regarding prospective surgeries to aid clinicians deciding on potential surgical intervention. VPAW enables a full surgical planning pipeline, including importing DICOM images, segmenting the airway, interactive 3D editing of airway geometries to express potential surgical treatment planning options, and creating input files for offline geometric analysis and computational fluid dynamics simulations for evaluation of surgical outcomes. In this paper, we describe the VPAW system and its use in one case study with a clinician to successfully describe an intended surgery outcome.

Comparative genomic and genetic analysis of glioblastoma-derived brain tumor-initiating cells and their parent tumors.

BACKGROUND: Glioblastoma (GBM) is a fatal cancer that has eluded major therapeutic advances. Failure to make progress may reflect the absence of a human GBM model that could be used to test compounds for anti-GBM activity. In this respect, the development of brain tumor-initiating cell (BTIC) cultures is a step forward because BTICs appear to capture the molecular diversity of GBM better than traditional glioma cell lines. Here, we perform a comparative genomic and genetic analysis of BTICs and their parent tumors as preliminary evaluation of the BTIC model. METHODS: We assessed single nucleotide polymorphisms (SNPs), genome-wide copy number variations (CNVs), gene expression patterns, and molecular subtypes of 11 established BTIC lines and matched parent tumors. RESULTS: Although CNV differences were noted, BTICs retained the major genomic alterations characteristic of GBM. SNP patterns were similar between BTICs and tumors. Importantly, recurring SNP or CNV alterations specific to BTICs were not seen. Comparative gene expression analysis and molecular subtyping revealed differences between BTICs and GBMs. These differences formed the basis of a 63-gene expression signature that distinguished cells from tumors; differentially expressed genes primarily involved metabolic processes. We also derived a set of 73 similarly expressed genes; these genes were not associated with specific biological functions. CONCLUSIONS: Although not identical, established BTIC lines preserve the core molecular alterations seen in their parent tumors, as well as the genomic hallmarks of GBM, without acquiring recurring BTIC-specific changes.

Quantitative assessment of the upper airway in infants and children with subglottic stenosis.

OBJECTIVES/HYPOTHESIS: Determine whether quantitative geometric measures and a computational fluid dynamic (CFD) model derived from medical imaging of children with subglottic stenosis (SGS) can be effective diagnostic and treatment planning tools. STUDY DESIGN: Retrospective chart and imaging review in a tertiary care hospital. METHODS: Computed tomography scans (n = 17) of children with SGS were analyzed by geometric and CFD methods. Polysomnograms (n = 15) were also analyzed. Radiographic data were age/weight flow normalized and were compared to an atlas created from radiographically normal airways. Five geometric, seven CFD, and five polysomnography measures were analyzed. Statistical analysis utilized a two-sample t test with Bonferroni correction and area under the curve analysis. RESULTS: Two geometric indices (the ratio of the subglottic to midtracheal airway, the percent relative reduction of the subglottic airway) and one CFD measure (the percent relative reduction of the hydraulic diameter of the subglottic airway) were significant for determining which children with SGS received surgical intervention. Optimal cutoffs for these values were determined. Polysomnography, the respiratory effort-related arousals index, was significant only prior to Bonferroni correction for determining which children received surgical intervention. CONCLUSIONS: Geometric and CFD variables were sensitive at determining which patients with SGS received surgical intervention. Discrete quantitative assessment of the pediatric airway was performed, yielding preliminary data regarding possible objective thresholds for surgical versus nonsurgical treatment of disease. This study is limited by its small, retrospective, single-institution nature. Further studies to validate these findings and possibly optimize treatment threshold recommendations are warranted. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:1225-1231, 2016.

Large deformation three-dimensional image registration in image-guided radiation therapy.

In this paper, we present and validate a framework, based on deformable image registration, for automatic processing of serial three-dimensional CT images used in image-guided radiation therapy. A major assumption in deformable image registration has been that, if two images are being registered, every point of one image corresponds appropriately to some point in the other. For intra-treatment images of the prostate, however, this assumption is violated by the variable presence of bowel gas. The framework presented here explicitly extends previous deformable image registration algorithms to accommodate such regions in the image for which no correspondence exists. We show how to use our registration technique as a tool for organ segmentation, and present a statistical analysis of this segmentation method, validating it by comparison with multiple human raters. We also show how the deformable registration technique can be used to determine the dosimetric effect of a given plan in the presence of non-rigid tissue motion. In addition to dose accumulation, we describe a method for estimating the biological effects of tissue motion using a linear-quadratic model. This work is described in the context of a prostate treatment protocol, but it is of general applicability.

Epigenetic and transcriptional determinants of the human breast.

While significant effort has been dedicated to the characterization of epigenetic changes associated with prenatal differentiation, relatively little is known about the epigenetic changes that accompany post-natal differentiation where fully functional differentiated cell types with limited lifespans arise. Here we sought to address this gap by generating epigenomic and transcriptional profiles from primary human breast cell types isolated from disease-free human subjects. From these data we define a comprehensive human breast transcriptional network, including a set of myoepithelial- and luminal epithelial-specific intronic retention events. Intersection of epigenetic states with RNA expression from distinct breast epithelium lineages demonstrates that mCpG provides a stable record of exonic and intronic usage, whereas H3K36me3 is dynamic. We find a striking asymmetry in epigenomic reprogramming between luminal and myoepithelial cell types, with the genomes of luminal cells harbouring more than twice the number of hypomethylated enhancer elements compared with myoepithelial cells.

Vortex disaggregation for flow cytometry allows direct histologic correlation: a novel approach for small biopsies and inaspirable bone marrows.

BACKGROUND: Many approaches to obtaining single cells from tissue for flow cytometric immunophenotyping are used; however, these methods result in tissue that is too disrupted for subsequent histologic examination. We introduce a new technique for cell dissociation of hematopoietic malignancies that preserves tissue for histology. This is especially important with small specimens for which this type of correlation is critical. METHODS: Fresh tissue from lymph node, gastrointestinal (GI) tract, skin, and other soft tissue biopsies, in addition to cores of inaspirable bone marrows, were briefly vortexed until the RPMI cell culture medium became cloudy. Larger specimens such as lymph nodes were sectioned before disaggregating, whereas smaller ones were vortexed in toto. Resultant flow cytometric analyses were compared with the histology and, in some cases, the immunohistochemistry (IHC) to determine whether the data were concordant. Cell suspensions of 104 specimens-composed of 48 lymph nodes, 19 bone marrow cores (BMCs), 11 GI biopsies, 11 skin/soft tissue biopsies, and 15 miscellaneous specimens-were prepared via vortex disaggregation. RESULTS: Flow cytometric analysis of 96 specimens (92.3%) showed adequacy of material and diagnostic correlation with the histology and IHC. Of the eight cases (7.7%) that were discordant, seven were attributable to significant specimen fibrosis or necrosis. With respect to tissue type, this method produced diagnostic cell suspensions for most lymph nodes (95.8%), GI biopsies (90.9%), and BMCs (89.5%); however, it was less useful for skin/soft tissue samples (81.8%). CONCLUSIONS: Disaggregation of tissue for flow cytometric analysis by vortexing appears to provide adequate and representative cellular material. This technique is ideal for inaspirable bone marrows and small biopsies where tissue preservation for histology is paramount.

The impact of Model for End-Stage Liver Disease-Na in predicting morbidity and mortality following elective colon cancer surgery irrespective of underlying liver disease.

BACKGROUND: The Model for End-Stage Liver Disease Sodium Model (MELD-Na) is a validated scoring system that uses bilirubin, international normalized ratio, serum creatinine, and sodium to predict mortality in cirrhotic patients awaiting liver transplantation. The aim of this study was to identify the utility of MELD-Na to predict patient outcomes, with and without liver disease, after elective colon cancer surgery. METHODS: A review of the American College of Surgeons National Surgical Quality Improvement Program database (2005 to 2010) was conducted to calculate risk-adjusted 30-day outcomes using regression modeling. RESULTS: A total of 10,842 patients (mean age, 68 years; 51% women) were included. MELD-Na scores were higher in men (10.2 vs 9.1, P < .001) and in open procedures (9.9 vs 9.1, P < .001). The overall complication and mortality rates were 26.3% and 3.3%, respectively. Incremental increases in MELD-Na score correlated with a 1.2% increase in mortality and a 1.1% increase in complications. On multivariate analysis, complications increased with MELD-Na score (odds ratio [OR], 1.05 per 1 point increase; 95% confidence interval [CI], 1.038 to 1.066). MELD-Na score was also associated with increased mortality (OR, 1.13; 95% CI, 1.1 to 1.16), along with ascites (OR, 5.7; 95% CI, 3.7 to 8.8) and corticosteroids (OR, 2.1; 95% CI, 1.3 to 3.3). CONCLUSIONS: Elevated preoperative MELD-Na score is significantly associated with worse outcomes after elective resection for colon cancer.

Statistical atlas construction via weighted functional boxplots.

Atlas-building from population data is widely used in medical imaging. However, the emphasis of atlas-building approaches is typically to estimate a spatial alignment to compute a mean/median shape or image based on population data. In this work, we focus on the statistical characterization of the population data, once spatial alignment has been achieved. We introduce and propose the use of the weighted functional boxplot. This allows the generalization of concepts such as the median, percentiles, or outliers to spaces where the data objects are functions, shapes, or images, and allows spatio-temporal atlas-building based on kernel regression. In our experiments, we demonstrate the utility of the approach to construct statistical atlases for pediatric upper airways and corpora callosa revealing their growth patterns. We also define a score system based on the pediatric airway atlas to quantitatively measure the severity of subglottic stenosis (SGS) in the airway. This scoring allows the classification of pre- and post-surgery SGS subjects and radiographically normal controls. Experimental results show the utility of atlas information to assess the effect of airway surgery in children.

Longitudinal image registration with temporally-dependent image similarity measure.

Longitudinal imaging studies are frequently used to investigate temporal changes in brain morphology and often require spatial correspondence between images achieved through image registration. Beside morphological changes, image intensity may also change over time, for example when studying brain maturation. However, such intensity changes are not accounted for in image similarity measures for standard image registration methods. Hence, 1) local similarity measures, 2) methods estimating intensity transformations between images, and 3) metamorphosis approaches have been developed to either achieve robustness with respect to intensity changes or to simultaneously capture spatial and intensity changes. For these methods, longitudinal intensity changes are not explicitly modeled and images are treated as independent static samples. Here, we propose a model-based image similarity measure for longitudinal image registration that estimates a temporal model of intensity change using all available images simultaneously.