Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups

Objectives: Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies. Methods: We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups. Results: We report associations with eight autoantibodies reaching our study-wide significance level of p<2.9x10(-5). Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28x10(-53) and HLA-DRB1*03:01, p=3.25x10(-9)), anti-PM/Scl (HLA-DQB1*02:01, p=1.47x10(-26)) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40x10(-11)). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92x10(-13)) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09x10(-6)). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47x10(-64)) and position 9 of HLA-B (p=7.03x10(-11)). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies. Conclusions: These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research

Populations and Interventions for Palliative and End-of-Life Care: A Systematic Review

ImportanceEvidence supports palliative care effectiveness. Given workforce constraints and the costs of new services, payers and providers need help to prioritize their investments. They need to know which patients to target, which personnel to hire, and which services best improve outcomes.ObjectiveTo inform how payers and providers should identify patients with "advanced illness" and the specific interventions they should implement, we reviewed the evidence to identify (1) individuals appropriate for palliative care and (2) elements of health service interventions (personnel involved, use of multidisciplinary teams, and settings of care) effective in achieving better outcomes for patients, caregivers, and the healthcare system.Evidence reviewSystematic searches of MEDLINE, EMBASE, PsycINFO, Web of Science, and Cochrane Database of Systematic Reviews databases (1/1/2001-1/8/2015).ResultsRandomized controlled trials (124) met inclusion criteria. The majority of studies in cancer (49%, 38 of 77 studies) demonstrated statistically significant patient or caregiver outcomes (e.g., p &lt; 0.05), as did those in congestive heart failure (CHF) (62%, 13 of 21), chronic obstructive pulmonary disease (COPD; 58%, 11 of 19), and dementia (60%, 15 of 25). Most prognostic criteria used clinicians' judgment (73%, 22 of 30). Most interventions included a nurse (70%, 69 of 98), and many were nurse-only (39%, 27 of 69). Social workers were well represented, and home-based approaches were common (56%, 70 of 124). Home interventions with visits were more effective than those without (64%, 28 of 44; vs. 46%, 12 of 26). Interventions improved communication and care planning (70%, 12 of 18), psychosocial health (36%, 12 of 33, for depressive symptoms; 41%, 9 of 22, for anxiety), and patient (40%, 8 of 20) and caregiver experiences (63%, 5 of 8). Many interventions reduced hospital use (65%, 11 of 17), but most other economic outcomes, including costs, were poorly characterized. Palliative care teams did not reliably lower healthcare costs (20%, 2 of 10).ConclusionsPalliative care improves cancer, CHF, COPD, and dementia outcomes. Effective models include nurses, social workers, and home-based components, and a focus on communication, psychosocial support, and the patient or caregiver experience. High-quality research on intervention costs and cost outcomes in palliative care is limited

Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups

OBJECTIVES: Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies. METHODS: We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups. RESULTS: We report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10 -5. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10 -53  and HLA-DRB1*03:01, p=3.25×10 -9), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10 -26) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10 -11). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10 -13) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10 -6). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10 -64) and position 9 of HLA-B (p=7.03×10 -11). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies. CONCLUSIONS: These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research

Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010:a systematic analysis for the Global Burden of Disease Study 2010

BACKGROUND: Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease (GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs).METHODS: Of the 291 diseases and injuries in the GBD cause list, 289 cause disability. For 1160 sequelae of the 289 diseases and injuries, we undertook a systematic analysis of prevalence, incidence, remission, duration, and excess mortality. Sources included published studies, case notification, population-based cancer registries, other disease registries, antenatal clinic serosurveillance, hospital discharge data, ambulatory care data, household surveys, other surveys, and cohort studies. For most sequelae, we used a Bayesian meta-regression method, DisMod-MR, designed to address key limitations in descriptive epidemiological data, including missing data, inconsistency, and large methodological variation between data sources. For some disorders, we used natural history models, geospatial models, back-calculation models (models calculating incidence from population mortality rates and case fatality), or registration completeness models (models adjusting for incomplete registration with health-system access and other covariates). Disability weights for 220 unique health states were used to capture the severity of health loss. YLDs by cause at age, sex, country, and year levels were adjusted for comorbidity with simulation methods. We included uncertainty estimates at all stages of the analysis.FINDINGS: Global prevalence for all ages combined in 2010 across the 1160 sequelae ranged from fewer than one case per 1 million people to 350,000 cases per 1 million people. Prevalence and severity of health loss were weakly correlated (correlation coefficient -0·37). In 2010, there were 777 million YLDs from all causes, up from 583 million in 1990. The main contributors to global YLDs were mental and behavioural disorders, musculoskeletal disorders, and diabetes or endocrine diseases. The leading specific causes of YLDs were much the same in 2010 as they were in 1990: low back pain, major depressive disorder, iron-deficiency anaemia, neck pain, chronic obstructive pulmonary disease, anxiety disorders, migraine, diabetes, and falls. Age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010. Regional patterns of the leading causes of YLDs were more similar compared with years of life lost due to premature mortality. Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria, and anaemia were important causes of YLDs in sub-Saharan Africa.INTERPRETATION: Rates of YLDs per 100,000 people have remained largely constant over time but rise steadily with age. Population growth and ageing have increased YLD numbers and crude rates over the past two decades. Prevalences of the most common causes of YLDs, such as mental and behavioural disorders and musculoskeletal disorders, have not decreased. Health systems will need to address the needs of the rising numbers of individuals with a range of disorders that largely cause disability but not mortality. Quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Effective and affordable strategies to deal with this rising burden are an urgent priority for health systems in most parts of the world.FUNDING: Bill &amp; Melinda Gates Foundation.</p

Simultaneous determination of CKM angle γ\gamma and charm mixing parameters

A combination of measurements sensitive to the CP violation angle γ of the Cabibbo-Kobayashi-Maskawa unitarity triangle and to the charm mixing parameters that describe oscillations between D$^{0}$ and $\overline{D} ^{0}$ mesons is performed. Results from the charm and beauty sectors, based on data collected with the LHCb detector at CERN’s Large Hadron Collider, are combined for the first time. This method provides an improvement on the precision of the charm mixing parameter y by a factor of two with respect to the current world average. The charm mixing parameters are determined to be $x=\left({0.400}_{-0.053}^{+0.052}\right)\%$ and y = $\left({0.630}_{-0.030}^{+0.033}\right)\%$. The angle γ is found to be γ = $\left({65.4}_{-4.2}^{+3.8}\right){}^{\circ}$ and is the most precise determination from a single experiment.[graphic not available: see fulltext

Observation of the suppressed Λb0→DpK- decay with D→K+π- and measurement of its CP asymmetry

International audienceA study of Λb0 baryon decays to the DpK- final state is presented based on a proton-proton collision data sample corresponding to an integrated luminosity of 9  fb-1 collected with the LHCb detector. Two Λb0 decays are considered, Λb0→DpK- with D→K-π+ and D→K+π-, where D represents a superposition of D0 and D¯0 states. The latter process is expected to be suppressed relative to the former, and is observed for the first time. The ratio of branching fractions of the two decays is measured, and the CP asymmetry of the suppressed mode, which is sensitive to the Cabibbo-Kobayashi-Maskawa angle γ, is also reported

Angular analysis of the rare decay Bs0 {B}_s^0 → ϕμ+^{+}μ−^{−}

An angular analysis of the rare decay ${B}_s^0$→ ϕμ$^{+}$μ$^{−}$ is presented, using proton-proton collision data collected by the LHCb experiment at centre-of-mass energies of 7, 8 and 13 TeV, corresponding to an integrated luminosity of 8.4 fb$^{−1}$. The observables describing the angular distributions of the decay ${B}_s^0$→ ϕμ$^{+}$μ$^{−}$ are determined in regions of q$^{2}$, the square of the dimuon invariant mass. The results are consistent with Standard Model predictions.[graphic not available: see fulltext

Simultaneous determination of CKM angle γ\gamma and charm mixing parameters

International audienceA combination of measurements sensitive to the CP violation angle γ of the Cabibbo-Kobayashi-Maskawa unitarity triangle and to the charm mixing parameters that describe oscillations between D$^{0}$ and $\overline{D} ^{0}$ mesons is performed. Results from the charm and beauty sectors, based on data collected with the LHCb detector at CERN’s Large Hadron Collider, are combined for the first time. This method provides an improvement on the precision of the charm mixing parameter y by a factor of two with respect to the current world average. The charm mixing parameters are determined to be $x=\left({0.400}_{-0.053}^{+0.052}\right)\%$ and y = $\left({0.630}_{-0.030}^{+0.033}\right)\%$. The angle γ is found to be γ = $\left({65.4}_{-4.2}^{+3.8}\right){}^{\circ}$ and is the most precise determination from a single experiment.[graphic not available: see fulltext

Observation of excited Ωc0\Omega_c^0 baryons in Ωb−→Ξc+K−π−\Omega_b^- \to \Xi_c^+ K^-\pi^-decays

The first observation of the $Ω_b^- → Ξ_c^+ K^- π^-$ decay is reported using p p collision data at center of mass energies of 7, 8, and 13 TeV collected by the LHCb experiment, corresponding to an integrated luminosity of 9 fb$^{-1}$. Four excited $Ω_c^0$ baryons are observed in the $Ξ_c^+ K^-$ mass projection of the $Ω_b^-→ Ξ_c^+ K^- π^-$ decays with the significance of each exceeding five standard deviations. They coincide with the states previously observed in prompt pp and $e^+ e^-$ production. Relative production rates, masses, and natural widths of the states are measured, and a test of spin hypotheses is performed. Moreover, the branching ratio of $Ω_b^- → Ξ_c^+ K^- π^-$ is measured relative to the $Ω_b^- → Ω_c^0 π^-$ decay mode and a precise measurement of the $Ω_b^-$ mass of $6044.3±1.2±1.1_{-0.22}^{+0.19}$ MeV is obtained