Polygenic risk score predicts risk of primary sclerosing cholangitis in inflammatory bowel disease.

BACKGROUND: Forty distinct primary sclerosing cholangitis (PSC) genomic loci have been identified through multiancestry meta-analyses. The polygenic risk score (PRS) could serve as a promising tool to discover unique disease behaviour, like PSC, underlying inflammatory bowel disease (IBD). AIM: To test whether PRS indicates PSC risk in patients with IBD. MATERIALS AND METHODS: Mayo Clinic and Washington University at St Louis IBD cohorts were used to test our hypothesis. PRS was modelled through the published PSC loci and weighted with their corresponding effect size. Logistic regression was applied to predict the PSC risk. RESULTS: In total, 63 (5.6%) among 1130 patients with IBD of European ancestry had PSC. Among 381 ulcerative colitis (UC), 12% had PSC; in contrast to 1.4% in 761 Crohn disease (CD). Compared with IBD alone, IBD-PSC had significantly higher PRS (PSC risk: 3.0% at the lowest PRS quartile vs 7.2% at the highest PRS quartile, Ptrend =.03). In IBD subphenotypes subgroup analysis, multivariate analysis shows that UC-PSC is associated with more extensive UC disease (OR, 5.60; p=0.002) and younger age at diagnosis (p=0.02). In CD, multivariate analysis suggests that CD-PSC is associated with colorectal cancer (OR, 50; p=0.005). CONCLUSIONS: We found evidence that patients with IBD with PSC presented with a clinical course difference from that of patients with IBD alone. PRS can influence PSC risk in patients with IBD. Once validated in an independent cohort, this may help identify patients with the highest likelihood of developing PSC.

Novel Genetic Risk Variants and Clinical Predictors Associated With Primary Sclerosing Cholangitis in Patients With Ulcerative Colitis.

INTRODUCTION: Patients with ulcerative colitis (UC) who are likely to have primary sclerosing cholangitis (PSC) should be identified because PSC can influence UC clinical behavior and outcomes.The aim of this study was to establish a model incorporating clinical and genetic risk predictors that identifies patients with UC at risk of developing PSC. METHODS: We conducted a retrospective case-control study. Inflammatory bowel disease cohorts from multiple institutions were used as discovery and replicate datasets. Quality control criteria, including minor allele frequency, call rates, Hardy-Weinberg equilibrium, cryptic relatedness, and population stratification (through principal components), were used. Discriminative accuracy was evaluated with area under the receiver operating characteristic curve. RESULTS: Fifty-seven of 581 patients (9.8%) with UC had PSC. Multivariate analysis showed that patients with UC-PSC had more extensive disease (odds ratio [OR], 5.42; P = 1.57E-04), younger diagnosis age (younger than 20 years; OR, 2.22; P = 0.02), and less smoking (OR, 0.42; P = 0.02) than those with UC. After linkage disequilibrium pruning and multivariate analyses, 3 SNPs (rs3131621 at 6p21.33; rs9275596 and rs11244 at 6p21.32) at the HLA region were found associated with a 2- to 3-fold increased risk of PSC. Our model demonstrated good discriminatory power (area under the receiver operating characteristic curve, 88%). DISCUSSION: Three variants in HLA (6p21.3) region significantly distinguished patients with UC-PSC from patients with UC alone. Once further validated in an independent large cohort, our model could be used to identify patients with UC at risk of PSC, and it could also help guide disease management.

Novel Genetic Variant Predicts Surgical Recurrence Risk in Crohn's Disease Patients.

BACKGROUND: We aimed to identify a model of clinical and genetic risk factors through hypothesis-free search across genome that can predict the surgical recurrence risk after the first abdominal surgery in CD patients. MATERIALS AND METHODS: Two independent inflammatory bowel disease (IBD) cohort studies were used to derive and validate the genetic risk profile. The study subjects were genotyped using Illumina Immunochip custom genotyping array. Surgical recurrence was defined as having the second or more abdominal bowel resections after the first abdominal surgery at the time of study enrollment; nonsurgical recurrence was defined as having no further abdominal resection after the first abdominal surgery. RESULTS: Among 372 CD patients who had at least 1 abdominal surgery at the study enrollment, 132 (35.5%) had subsequent surgical recurrence after their first abdominal surgery, and 240 (64.5%) required no subsequent abdominal surgery at the end of follow up. Among clinical factors, multivariable analysis showed that history of immunomodulatory use (odds ratio [OR], 3.96; P = 0.002) and early era of CD first surgery (OR, 1.12; P = 1.01E-04) remained significant. Genotypic association tests identified a genome-wide significant locus rs2060886 in TCF4 at chr18q21.2 associated with surgical recurrence risk (OR, dom, 4.10 [2.37-7.11]; P = 4.58E-08). CONCLUSIONS: Novel genetic locus rs2060886 in TCF4 was associated with surgical recurrence risk at genome-wide significance level among CD patients after their first abdominal surgery. Early era of CD first intestinal surgery predicts higher surgical recurrence risk. These results suggest that genetic variants may help guide the CD management strategy in patients at the highest risk of repeated abdominal surgeries.

Unique Phenotypic Characteristics and Clinical Course in Patients With Ulcerative Colitis and Primary Sclerosing Cholangitis: A Multicenter US Experience.

INTRODUCTION: Ulcerative colitis (UC) associated with primary sclerosing cholangitis (PSC) is a rare phenotype. We aimed to assess patients with UC-PSC or UC alone and describe differences in clinical and phenotypic characteristics, antitumor necrosis factor (TNF) therapy, and long-term clinical outcomes. METHODS: This retrospective multicenter cohort study included patients who received a diagnosis of UC from 1962 through 2015. We evaluated clinical factors associated with UC-PSC vs UC alone and assessed associations by using multivariable logistic regression models. RESULTS: Among 522 patients with UC, 56 (10.7%) had PSC. Compared with UC alone, patients with UC-PSC were younger (younger than 20 years) at diagnosis (odds ratios [OR], 2.35; adjusted P = 0.02) and had milder UC severity (adjusted P = 0.05), despite having pancolonic involvement (OR, 7.01; adjusted P < 0.001). In the biologics era (calendar year 2005 to 2015), patients with UC-PSC less commonly received anti-TNF therapy compared with patients with UC (OR, 0.38; adjusted P = 0.009), but their response rates were similar. Fewer patients with UC-PSC received corticosteroids (OR, 0.24; adjusted P = 0.005) or rectal 5-aminosalicyte acid (OR, 0.26; adjusted P < 0.001). Other differences were identified that were not statistically significant in a multivariable model: patients with UC-PSC more commonly were male, had lower rates of smoking, and had higher rates of colorectal cancer and colectomy. DISCUSSION: This study identified a unique phenotype of UC with concurrent PSC, which had different clinical behavior compared with UC only. These phenotypic characteristics can help identify high-risk patients with UC before PSC is diagnosed and guide different management and monitoring strategies.

Not-so-benign massive cardiac lipoma.

Cardiac lipomas are rare and usually benign tumors that often remain asymptomatic throughout one's lifetime. We report a case of a 60-year-old man with a cardiac lipoma diagnosed early in childhood. However, due to the lack of surgical expertise in rural India, the lipoma was not removed. After moving to the United States, he received irregular follow-up with serial chest x-ray and computed tomography, which demonstrated an enlarging lipomatous mass occupying the pericardial space. After remaining asymptomatic for more than 37 years, he presented to the hospital with dyspnea. He underwent a surgical resection but, unfortunately, given the extension of the mass into multiple critical portions of the heart, he ultimately died.

Novel Genetic Risk Variants Can Predict Anti-TNF Agent Response in Patients With Inflammatory Bowel Disease.

BACKGROUND: It is important to identify patients with inflammatory bowel disease [IBD] refractory to anti-tumour necrosis factor [TNF] therapy, to avoid potential adverse effects and to adopt different treatment strategies. We aimed to identify and validate clinical and genetic factors to predict anti-TNF response in patients with IBD. MATERIALS AND METHODS: Mayo Clinic and Washington University IBD genetic association study cohorts were used as discovery and replicate datasets, respectively. Clinical factors included sex, age at diagnosis, disease duration and phenotype, disease location, bowel resection, tobacco use, family history of IBD, extraintestinal manifestations, and response to anti-TNF therapy. RESULTS: Of 474 patients with IBD treated with anti-TNF therapy, 41 [8.7%] were refractory to therapy and 433 [91.3%] had response. Multivariate analysis showed history of immunomodulator use (odds ratio 10.2, p = 8.73E-4) and bowel resection (odds ratio 3.24, p = 4.38E-4) were associated with refractory response to anti-TNF agents. Among genetic loci, two [rs116724455 in TNFSF4/18, rs2228416 in PLIN2] were successfully replicated and another four [rs762787, rs9572250, rs144256942, rs523781] with suggestive evidence were found. An exploratory risk model predictability [area under the curve] increased from 0.72 [clinical predictors] to 0.89 after adding genetic predictors. Through identified clinical and genetic predictors, we constructed a preliminary anti-TNF refractory score to differentiate anti-TNF non-responders (mean [standard deviation] score, 5.49 [0.99]) from responders (2.65 [0.39]; p = 4.33E-23). CONCLUSIONS: Novel and validated genetic loci, including variants in TNFSF, were found associated with anti-TNF response in patients with IBD. Future validation of the exploratory risk model in a large prospective cohort is warranted.

A photochemical approach for a fast and self-limited covalent modification of surface supported graphene with photoactive dyes.

Herein, we report a simple method for a covalent modification of surface supported graphene with photoactive dyes. Graphene was fabricated on cubic-SiC/Si(001) wafers due to their low cost and suitability for mass-production of continuous graphene fit for electronic applications on millimetre scale. Functionalisation of the graphene surface was carried out in solution via white light induced photochemical generation of phenazine radicals from phenazine diazonium salt. The resulting covalently bonded phenazine-graphene hybrid structure was characterised by scanning tunnelling microscopy (STM) and spectroscopy (STS), Raman spectroscopy and density functional theory (DFT) calculations. It was found that phenazine molecules form an overlayer, which exhibit a short range order with a rectangular unit cell on the graphene surface. DFT calculations based on STM results reveal that molecules are standing up in the overlayer with the maximum coverage of 0.25 molecules per graphene unit cell. Raman spectroscopy and STM results show that the growth is limited to one monolayer of standing molecules. STS reveals that the phenazine-graphene hybrid structure has a band gap of 0.8 eV.

White light induced covalent modification of graphene using a phenazine dye.

Herein, we report a novel strategy for a covalent modification of graphene nanoplatelets with photoactive dyes. The functionalization of the graphene surface was carried out using white light to photochemically generate phenazine radicals and the reaction progress was followed up spectrophotometrically. The characterization of the modified material was carried out using FTIR, XRD, UV-vis absorption, fluorescence, Raman spectroscopy and SEM imaging. The hybrid material has improved solubility, shows an optical band gap of 1.95 eV and is highly emissive in the visible wavelength region.

Human-mediated evolution in a threatened species? Juvenile life-history changes in Snake River salmon.

Evaluations of human impacts on Earth's ecosystems often ignore evolutionary changes in response to altered selective regimes. Freshwater habitats for Snake River fall Chinook salmon (SRFCS), a threatened species in the US, have been dramatically changed by hydropower development and other watershed modifications. Associated biological changes include a shift in juvenile life history: Historically essentially 100% of juveniles migrated to sea as subyearlings, but a substantial fraction have migrated as yearlings in recent years. In contemplating future management actions for this species should major Snake River dams ever be removed (as many have proposed), it will be important to understand whether evolution is at least partially responsible for this life-history change. We hypothesized that if this trait is genetically based, parents who migrated to sea as subyearlings should produce faster-growing offspring that would be more likely to reach a size threshold to migrate to sea in their first year. We tested this with phenotypic data for over 2,600 juvenile SRFCS that were genetically matched to parents of hatchery and natural origin. Three lines of evidence supported our hypothesis: (i) the animal model estimated substantial heritability for juvenile growth rate for three consecutive cohorts; (ii) linear modeling showed an association between juvenile life history of parents and offspring growth rate; and (iii) faster-growing juveniles migrated at greater speeds, as expected if they were more likely to be heading to sea. Surprisingly, we also found that parents reared a full year in a hatchery produced the fastest growing offspring of all-apparently an example of cross-generational plasticity associated with artificial propagation. We suggest that SRFCS is an example of a potentially large class of species that can be considered to be "anthro-evolutionary"-signifying those whose evolutionary trajectories have been profoundly shaped by altered selective regimes in human-dominated landscapes.

Crystal Structure of the PdAu24(SR)18(0) Superatom.

The single-crystal X-ray structure of Pd-doped Au25(SR)18 was solved. The crystal structure reveals that in PdAu24(SR)18, the Pd atom is localized only to the centroid of the Au25(SR)18 cluster. This single-crystal X-ray structure shows that PdAu24(SR)18(0) is well conceptualized with the superatom theory. The PdAu24(SR)18(0) charge state is isoelectronic with Au25(SR)18(+1) as determined by a first order Jahn-Teller effect of similar magnitude and by electrochemical comparison. The previously reported increased stability of PdAu24(SR)18 can be rationalized in terms of Pd-Au bonds that are shorter than the Au-Au bonds in Au25(SR)18.

Continuum Nanofluidics.

This paper introduces the fundamental continuum theory governing momentum transport in isotropic nanofluidic systems. The theory is an extension of the classical Navier-Stokes equation, and includes coupling between translational and rotational degrees of freedom as well as nonlocal response functions that incorporate spatial correlations. The continuum theory is compared with molecular dynamics simulation data for both relaxation processes and fluid flows, showing excellent agreement on the nanometer length scale. We also present practical tools to estimate when the extended theory should be used. It is shown that in the wall-fluid region the fluid molecules align with the wall, and in this region the isotropic model may fail and a full anisotropic description is necessary.

Non-Newtonian behavior and molecular structure of Cooee bitumen under shear flow: A non-equilibrium molecular dynamics study.

The rheology and molecular structure of a model bitumen (Cooee bitumen) under shear are investigated in the non-Newtonian regime using non-equilibrium molecular dynamics simulations. The shear viscosity, normal stress differences, and pressure of the bitumen mixture are computed at different shear rates and different temperatures. The model bitumen is shown to be a shear-thinning fluid at all temperatures. In addition, the Cooee model is able to reproduce experimental results showing the formation of nanoaggregates composed of stacks of flat aromatic molecules in bitumen. These nanoaggregates are immersed in a solvent of saturated hydrocarbon molecules. At a fixed temperature, the shear-shinning behavior is related not only to the inter- and intramolecular alignments of the solvent molecules but also to the decrease of the average size of the nanoaggregates at high shear rates. The variation of the viscosity with temperature at different shear rates is also related to the size and relative composition of the nanoaggregates. The slight anisotropy of the whole sample due to the nanoaggregates is considered and quantified. Finally, the position of bitumen mixtures in the broad literature of complex systems such as colloidal suspensions, polymer solutions, and associating polymer networks is discussed.

Beliefs about GI medications and adherence to pharmacotherapy in functional GI disorder outpatients.

OBJECTIVES: Pharmacotherapy is a mainstay in functional gastrointestinal (GI) disorder (FGID) management, but little is known about patient attitudes toward medication regimens. Understanding patient concerns and adherence to pharmacotherapy is particularly important for off-label medication use (e.g., antidepressants) in FGID. METHODS: Consecutive tertiary GI outpatients completed the Beliefs About Medications questionnaire (BMQ). Subjects were categorized as FGID and structural GI disease (SGID) using clinician diagnoses and Rome criteria; GI-specific medications and doses were recorded, and adherence to medication regimens was determined by patient self-report. BMQ domains (overuse, harm, necessity, and concern) were compared between FGID and SGID, with an interest in how these beliefs affected medication adherence. Psychiatric measures (depression, anxiety, and somatization) were assessed to gauge their influence on medication beliefs. RESULTS: A total of 536 subjects (mean age 54.7±0.7 years, range 22-100 years; n=406, 75.7% female) were enrolled over a 5.5-year interval: 341 (63.6%) with FGID (IBS, 64.8%; functional dyspepsia, 51.0%, ≥2 FGIDs, 38.7%) and 142 (26.5%) with SGID (IBD, 28.9%; GERD, 23.2%). PPIs (n=231, 47.8%), tricyclic antidepressants (TCAs) (n=167, 34.6%), and anxiolytics (n=122, 25.3%) were common medications prescribed. FGID and SGID were similar across all BMQ domains (P>0.05 for overuse, harm, necessity, and concern). SGID subjects had higher necessity-concern framework (NCF) scores compared with FGID subjects (P=0.043). FGID medication adherence correlated negatively with concerns about medication harm (r=-0.24, P<0.001) and overuse (r=-0.15, P=0.001), whereas higher NCF differences predicted medication compliance (P=0.006). Medication concern and overuse scores correlated with psychiatric comorbidity among FGID subjects (P<0.03 for each). FGID patients prescribed TCAs (n=142, 41.6%) expressed a greater medication necessity (17.4±0.4 vs. 16.2±0.4, P=0.024) and found their GI regimen to be more helpful (P=0.054). FGID subjects not on TCAs expressed a greater apprehension about medication overuse (10.7±0.3 vs. 9.7±0.2, P=0.002) on the BMQ. CONCLUSIONS: FGID subjects report medication necessity and concern scores comparable to patients with SGID but have negative perceptions about medications, particularly in the presence of psychiatric comorbidity; these factors may affect treatment adherence and willingness to initiate neuromodulator regimens.

Structural basis for ligand exchange on Au(25)(SR)(18).

The single-crystal X-ray structure of Au25(SC2H4Ph)16(pBBT)2 is presented. The crystallized compound resulted from ligand exchange of Au25(SC2H4Ph)18 with pBBT as the incoming ligand, and for the first time, ligand exchange is structurally resolved on the widely studied Au25(SR)18 compound. A single ligand in the asymmetric unit is observed to exchange, corresponding to two ligands in the molecule because of the crystallographic symmetry. The ligand-exchanged Au25 is bonded to the most solvent-exposed Au atom in the structure, making the exchange event consistent with an associative mechanism. The apparent nonexchange of other ligands is rationalized through possible selective crystallization of the observed product and differential bond lengths.

Recovery in a family context: experiences of mothers with serious mental illnesses.

OBJECTIVE: Adults with mental illness are as likely as those without mental illness to be parents. Yet parenting and family life have received considerably less attention than employment, housing, and community integration in psychiatric rehabilitation and mental health services research. This ethnographic pilot study aimed to understand the lived experiences of urban low-income African American mothers diagnosed with serious mental illnesses. METHOD: Ethnographic observations and informal interviews were conducted over 12 months with three mothers diagnosed with serious mental illnesses and their children. Data were analyzed using a case study approach to distill prominent themes, perspectives, and experiences within and across participating families. RESULTS: Five themes emerged to characterize the lived experiences of African American mothers with serious mental illnesses: (a) mental illness and mental health services are not a prominent focus in everyday life; (b) families live in a context of ubiquitous violence, loss, and everyday stress; (c) family life is the main focus for mothers as they strive for a better life; (d) mothers have limited social support; and (e) religion is a source of meaning and a resource for the everyday work of recovery. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Findings from this exploratory pilot study suggest that rehabilitative efforts tailored for this population should not focus on, or reside in, professional mental health services. Meaningful rehabilitative strategies for families might include supported employment, social support, youth mentoring, faith-based supports, and community-based antiviolence efforts. Peer-based approaches may be a promising way to provide supports within this population.

Treating prepartum depression to improve infant developmental outcomes: a study of diabetes in pregnancy.

Whether and how the co-occurrence of depression and diabetes in pregnancy may worsen infant development has not been reported. Pregnant women with diabetes and with (n = 34) or without (n = 34) major depressive disorder (MDD) were followed during pregnancy and 6-months postpartum. The MDD subset received randomly assigned treatment with cognitive behavior therapy (CBT) or supportive counseling (SC). Depression severity was measured with the Beck Depression Inventory (BDI); infant developmental outcomes were measured with the Bayley Scales of Infant Development (BSID) and its Behavior Rating Scale (BRS). Infants of women with MDD had lower BRS scores (p = .02). Reduction in depression scores was associated with better infant outcomes on the BSID and BRS (p values <.03). These preliminary findings suggest depression occurring in pregnant women with diabetes is associated with poorer infant development and improvement in prepartum depression is associated with improvement in measures of infant development.

Role of Toll-like receptor (TLR) 2 in experimental Bacillus cereus endophthalmitis.

Bacillus cereus causes a uniquely rapid and blinding intraocular infection, endophthalmitis. B. cereus replicates in the eye, synthesizes numerous toxins, and incites explosive intraocular inflammation. The mechanisms involved in the rapid and explosive intraocular immune response have not been addressed. Because Toll-like receptors (TLRs) are integral to the initial recognition of organisms during infection, we hypothesized that the uniquely explosive immune response observed during B. cereus endophthalmitis is directly influenced by the presence of TLR2, a known gram-positive pathogen recognition receptor. To address this hypothesis, we compared the courses of experimental B. cereus endophthalmitis in wild type C57BL/6J mice to that of age-matched homozygous TLR2(-/-) mice. Output parameters included analysis of bacterial growth, inflammatory cell (PMN) infiltration, cytokine/chemokine kinetics, retinal function testing, and histology, with N≥4 eyes/assay/time point/mouse strain. B. cereus grew at similar rates to10(8) CFU/eye by 12 h, regardless of the mouse strain. Retinal function was preserved to a greater degree in infected TLR2(-/-) eyes compared to that of infected wild type eyes, but infected eyes of both mouse strains lost significant function. Retinal architecture was preserved in infected TLR2(-/-) eyes, with limited retinal and vitreal cellular infiltration compared to that of infected wild type eyes. Ocular myeloperoxidase activities corroborated these results. In general, TNFα, IFNγ, IL6, and KC were detected in greater concentrations in infected wild type eyes than in infected TLR2(-/-) eyes. The absence of TLR2 resulted in decreased intraocular proinflammatory cytokine/chemokine levels and altered recruitment of inflammatory cells into the eye, resulting in less intraocular inflammation and preservation of retinal architecture, and a slightly greater degree of retinal function. These results demonstrate TLR2 is an important component of the initial ocular response to B. cereus endophthalmitis.