Anti-citrullinated peptide autoantibodies, human leukocyte antigen shared epitope and risk of future rheumatoid arthritis: a nested case–control study

Introduction: The aim of this study was to characterize anti-citrullinated peptide antibody (ACPA) serostatus in pre-clinical rheumatoid arthritis (RA) with and without Human Leukocyte Antigen-Shared Epitope (HLA-SE) alleles. Methods: We identified 192 women in the Nurses’ Health Study cohorts with blood samples obtained 4 months to 17 years prior to medical record-confirmed RA diagnosis. Three controls were selected matched on age, cohort, menopausal status and post-menopausal hormone use. Reactivities to 18 ACPAs were measured using a custom BioPlex platform. We used conditional logistic regression to calculate the relative risk (RR) of RA for any ACPA-positive and peptide-specific ACPA-positive and examined RRs by time between blood draw and RA onset. Measures of multiplicative and additive interaction between any ACPA-positive and HLA-SE were calculated. Results: All ACPAs by peptide groups were significantly associated with RA risk, RRs ranged from 4.7 to 11.7. The association between ACPA and RA varied over time with the strongest association in those with blood draw less than 5 years before onset (RR 17.0 [95% CI 5.8 to 53.7]) and no association 10 or more years prior to onset (RR 1.4 [95% CI 0.5 to 4.3]). Individuals with both HLA-SE and any ACPA-positive had the highest risk of RA. HLA-SE-positive RA cases showed reactivity to more ACPA types than HLA-SE negative (χ2 test for trend, P = 0.01). Conclusions: There is increasing ACPA reactivity up to 10 years before RA onset with the strongest association within 5 years of RA onset. The magnitude of the response to ACPAs, in combination with the presence of HLA-SE, is most important for identifying those individuals with the highest risk of RA

Psychological outcomes in advanced cancer patients after receiving genomic tumor profiling results

Background: Comprehensive tumor genomic profiling (CGP) offers hope for personalized treatment for cancer patients when other treatment options have been exhausted. However, receipt of nonactionable or ambiguous results could be an ongoing source of distress. We investigated patterns of hope, anxiety, depression, and CGP-specific anxiety in advanced cancer patients after receiving CGP results and 2–3months later. Method: Participants were enrolled in a longitudinal psychosocial substudy, embedded in the Molecular Screening and Therapeutics Program, and had advanced solid cancers of any histological type with sufficient and accessible tissue for CGP. At T0 (before receiving CGP results), 1,431 participants completed sociodemographic, disease and psychosocial measures. At T1 (1–4 weeks after receiving CGP results) and T2 (2–3 months post-T1), 374 participants completed psychological outcome measures. Predictors of outcomes at T2 were identified using multinomial logistic regression. Results: Approximately 75% of participants did not experience significant hopelessness or distress at T1 and T2.Hope decreased by T2, yet general anxiety and CGP-specific anxiety also decreased. Receiving actionable results did not impact psychological outcomes at T2. At T2, lower hope, and higher anxiety, depression and CGP-specific anxiety were associated with lower self-efficacy. Psychological and demo-graphic factors (age, socioeconomic status, language, medical occupation, urban living, family history of cancer) independently predicted one or more psychological trajectories. Worse health status and perceived susceptibility to cancer progression predicted hope and anxiety trajectories. Conclusion: Further research on interventions to best support patients undergoing CGP with high anxiety, hopelessness, fear of cancer progression, and poorer health is urgently needed

Prevalence of variations in melanoma susceptibility genes among Slovenian melanoma families

<p>Abstract</p> <p>Background</p> <p>Two high-risk genes have been implicated in the development of CM (cutaneous melanoma). Germline mutations of the CDKN2A gene are found in < 25% of melanoma-prone families and there are only seven families with mutation of the <it>CDK4 </it>gene reported to date. Beside those high penetrance genes, certain allelic variants of the <it>MC1R </it>gene modify the risk of developing the disease.</p> <p>The aims of our study were: to determine the prevalence of germline <it>CDKN2A </it>mutations and variants in members of families with familial CM and in patients with multiple primary CM; to search for possible <it>CDK4 </it>mutations, and to determine the frequency of variations in the <it>MC1R </it>gene.</p> <p>Methods</p> <p>From January 2001 until January 2007, 64 individuals were included in the study. The group included 28 patients and 7 healthy relatives belonging to 25 families, 26 patients with multiple primary tumors and 3 children with CM. Additionally 54 healthy individuals were included as a control group. Mutations and variants of the melanoma susceptibility genes were identified by direct sequencing.</p> <p>Results</p> <p>Seven families with CDKN2A mutations were discovered (7/25 or 28.0%). The L94Q mutation found in one family had not been previously reported in other populations. The D84N variant, with possible biological impact, was discovered in the case of patient without family history but with multiple primary CM. Only one mutation carrier was found in the control group. Further analysis revealed that c.540C>T heterozygous carriers were more common in the group of CM patients and their healthy relatives (11/64 vs. 2/54). One p14ARF variant was discovered in the control group and no mutations of the <it>CDK4 </it>gene were found.</p> <p>Most frequently found variants of the <it>MC1R </it>gene were T314T, V60L, V92M, R151C, R160W and R163Q with frequencies slightly higher in the group of patients and their relatives than in the group of controls, but the difference was statistically insignificant.</p> <p>Conclusion</p> <p>The present study has shown high prevalence of p16INK4A mutations in Slovenian population of familial melanoma patients (37%) and an absence of p14ARF or <it>CDK4 </it>mutations.</p

Decision making in advanced heart failure: A scientific statement from the american heart association

Shared decision making for advanced heart failure has become both more challenging and more crucial as duration of disease and treatment options have increased. High-quality decisions are chosen from medically reasonable options and are aligned with values, goals, and preferences of an informed patient. The top 10 things to know about decision making in advanced heart failure care are listed in Table 1

Energy Partitioning Constraints at Kinetic Scales in Low- Turbulence

Turbulence is a fundamental physical process through which energy injected into a system at large scales cascades to smaller scales. In collisionless plasmas, turbulence provides a critical mechanism for dissipating electromagnetic energy. Here we present observations of plasma fluctuations in low- turbulence using data from NASAs Magnetospheric Multiscale mission in Earths magnetosheath. We provide constraints on the partitioning of turbulent energy density in the fluid, ion-kinetic, and electron-kinetic ranges. Magnetic field fluctuations dominated the energy density spectrum throughout the fluid and ion-kinetic ranges, consistent with previous observations of turbulence in similar plasma regimes. However, at scales shorter than the electron inertial length, fluctuation power in electron kinetic energy significantly exceeded that of the magnetic field, resulting in an electron-motion-regulated cascade at small scales. This dominance should be highly relevant for the study of turbulence in highly magnetized laboratory and astrophysical plasmas

The Arecibo Legacy Fast ALFA Survey: III. HI Source Catalog of the Northern Virgo Cluster Region

We present the first installment of HI sources extracted from the Arecibo Legacy Fast ALFA (ALFALFA) extragalactic survey, initiated in 2005. Sources have been extracted from 3-D spectral data cubes and then examined interactively to yield global HI parameters. A total of 730 HI detections are catalogued within the solid angle 11h44m < R.A.(J2000) < 14h00m and +12deg < Dec.(J2000) < +16deg, and redshift range -1600 \kms < cz < 18000 \kms. In comparison, the HI Parkes All-Sky Survey (HIPASS) detected 40 HI signals in the same region. Optical counterparts are assigned via examination of digital optical imaging databases. ALFALFA HI detections are reported for three distinct classes of signals: (a) detections, typically with S/N > 6.5; (b) high velocity clouds in the Milky Way or its periphery; and (c) signals of lower S/N (to ~ 4.5) which coincide spatially with an optical object of known similar redshift. Although this region of the sky has been heavily surveyed by previous targeted observations based on optical flux-- or size-- limited samples, 69% of the extracted sources are newly reported HI detections. The resultant positional accuracy of HI sources is 20" (median). The median redshift of the sample is ~7000 \kms and its distribution reflects the known local large scale structure including the Virgo cluster. Several extended HI features are found in the vicinity of the Virgo cluster. A small percentage (6%) of HI detections have no identifiable optical counterpart, more than half of which are high velocity clouds in the Milky Way vicinity; the remaining 17 objects do not appear connected to or associated with any known galaxy.Comment: Astronomical Journal, in pres

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Decision Making in Advanced Heart Failure: A Scientific Statement From the American Heart Association

Shared decision making for advanced heart failure has become both more challenging and more crucial as duration of disease and treatment options have increased. High-quality decisions are chosen from medically reasonable options and are aligned with values, goals, and preferences of an informed patient

Origin of Polar Order in Dense Suspensions of Phototactic Micro-Swimmers

A main question for the study of collective motion in living organisms is the origin of orientational polar order, i.e., how organisms align and what are the benefits of such collective behaviour. In the case of micro-organisms swimming at a low Reynolds number, steric repulsion and long-range hydrodynamic interactions are not sufficient to explain a homogeneous polar order state in which the direction of motion is aligned. An external symmetry-breaking guiding field such as a mechanism of taxis appears necessary to understand this phonemonon. We have investigated the onset of polar order in the velocity field induced by phototaxis in a suspension of a motile micro-organism, the algae Chlamydomonas reinhardtii, for density values above the limit provided by the hydrodynamic approximation of a force dipole model. We show that polar order originates from a combination of both the external guiding field intensity and the population density. In particular, we show evidence for a linear dependence of a phototactic guiding field on cell density to determine the polar order for dense suspensions and demonstrate the existence of a density threshold for the origin of polar order. This threshold represents the density value below which cells undergoing phototaxis are not able to maintain a homogeneous polar order state and marks the transition to ordered collective motion. Such a transition is driven by a noise dominated phototactic reorientation where the noise is modelled as a normal distribution with a variance that is inversely proportional to the guiding field strength. Finally, we discuss the role of density in dense suspensions of phototactic micro-swimmers