Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations

A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 x 10(-7), 4.3 x 10(-9)) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.publishedVersio

Methotrexate safety and efficacy in combination therapies in patients with early rheumatoid arthritis : a post-hoc analysis of a randomized controlled trial (NORD-STAR)

This article is protected by copyright. All rights reserved.OBJECTIVE: To investigate methotrexate safety and influence of dose on efficacy outcomes in combination with three different biological treatments and with active conventional treatment (ACT) in early rheumatoid arthritis (RA). METHODS: This post-hoc analysis included 812 treatment-naïve early RA patients who were randomized (1:1:1:1) in the NORD-STAR trial (NCT01491815) to receive methotrexate in combination with ACT, certolizumab-pegol, abatacept, or tocilizumab. Methotrexate safety, doses, and dose effects on Clinical Disease Activity Index (CDAI) remission were assessed after 24 weeks of treatment. RESULTS: Compared with ACT, the prevalence of methotrexate-associated side effects was higher when methotrexate was combined with tocilizumab (HR 1.48 [95% CI 1.20 to 1.84]), but not with certolizumab-pegol (HR 0.99 [0.79 to 1.23]) or with abatacept (HR 0.93 [0.75 to 1.16]). With ACT as the reference, methotrexate dose was significantly lower when used in combination with tocilizumab (β -4.65 [95% CI -5.83 to -3.46], p<0.001), with abatacept (β -1.15 [-2.27 to -0.03], p=0.04), and numerically lower in combination with certolizumab-pegol (β -1.07 [-2.21 to 0.07], p=0.07). Methotrexate dose reductions were not associated with decreased CDAI remission rates within any of the treatment combinations. CONCLUSION: Methotrexate was generally well tolerated in combination therapies, but adverse events were a limiting factor in receiving the target dose of 25 mg/week, and these were more frequent in combination with tocilizumab versus active conventional treatment. On the other hand, methotrexate dose reductions were not associated with decreased CDAI remission rates within any of the four treatment combinations at 24 weeks. This article is protected by copyright. All rights reserved.Peer reviewe

John Steinbeck's Wrath. Human Behavior During Desperate Times

This essay examines John Steinbeck’s novel The Grapes of Wrath and how he, as a writer, approached the subject of human behavior during desperate times. Steinbeck’s The Grapes of Wrath was well received and immediately became a bestseller. In his novel Steinbeck explores the effects the Great Depression on human life, having researched intimately the life and situations of the economic refugees of the period. Some of most effective scenes in the novel deal with the harsh reality these people lived in. As a journalist, Steinbeck wanted to enlighten the public about the poverty and desperation people were facing. However, Steinbeck had difficulty getting his articles published so he saw that the only way to get his message across was to write a novel based on actual research and observations. This essay commences with historical background about the major events that eventually led to the Great Depression. The Great Depression had devastating effects not only on the economy in the United States but also worldwide. Other factors such as the droughts that plagued the Midwest for a number of years did not make the situation any easier for the small farmer. The combined effects of the economic troubles, the drought, and technical advances changed the rules for small farmers and soon they were at the mercy of the open road. The historical contextualization of this essay concludes by sketching out how Steinbeck gathered first-hand information and facts for this novel. The third and final chapter demonstrates how Steinbeck created the Joad family essentially to give the reader a chance to follow one family through the whole process that made and kept a family migrant. Steinbeck shows the importance of hope; for the Joad family, hope is the motivation that keeps the family going in the face of often insurmountable obstacles