The Beetle Tree of Life Reveals that Coleoptera Survived End-Permium Mass Extinction to Diversify During the Cretaceous Terrestrial Revolution

Here we present a phylogeny of beetles (Insecta: Coleoptera) based on DNA sequence data from eight nuclear genes, including six single-copy nuclear protein-coding genes, for 367 species representing 172 of 183 extant families. Our results refine existing knowledge of relationships among major groups of beetles. Strepsiptera was confirmed as sister to Coleoptera and each of the suborders of Coleoptera was recovered as monophyletic. Interrelationships among the suborders, namely Polyphaga (Adephaga (Archostemata, Myxophaga)), in our study differ from previous studies. Adephaga comprised two clades corresponding to Hydradephaga and Geadephaga. The series and superfamilies of Polyphaga were mostly monophyletic. The traditional Cucujoidea were recovered in three distantly related clades. Lymexyloidea was recovered within Tenebrionoidea. Several of the series and superfamilies of Polyphaga received moderate to maximal clade support in most analyses, for example Buprestoidea, Chrysomeloidea, Coccinelloidea, Cucujiformia, Curculionoidea, Dascilloidea, Elateroidea, Histeroidea and Hydrophiloidea. However, many of the relationships within Polyphaga lacked compatible resolution under maximum-likelihood and Bayesian inference, and/or lacked consistently strong nodal support. Overall, we recovered slightly younger estimated divergence times than previous studies for most groups of beetles. The ordinal split between Coleoptera and Strepsiptera was estimated to have occurred in the Early Permian. Crown Coleoptera appeared in the Late Permian, and only one or two lineages survived the end-Permian mass extinction, with stem group representatives of all four suborders appearing by the end of the Triassic. The basal split in Polyphaga was estimated to have occurred in the Triassic, with the stem groups of most series and superfamilies originating during the Triassic or Jurassic. Most extant families of beetles were estimated to have Cretaceous origins. Overall, Coleoptera experienced an increase in diversification rate compared to the rest of Neuropteroidea. Furthermore, 10 family-level clades, all in suborder Polyphaga, were identified as having experienced significant increases in diversification rate. These include most beetle species with phytophagous habits, but also several groups not typically or primarily associated with plants. Most of these groups originated in the Cretaceous, which is also when a majority of the most species-rich beetle families first appeared. An additional 12 clades showed evidence for significant decreases in diversification rate. These clades are species-poor in the Modern fauna, but collectively exhibit diverse trophic habits. The apparent success of beetles, as measured by species numbers, may result from their associations with widespread and diverse substrates – especially plants, but also including fungi, wood and leaf litter – but what facilitated these associations in the first place or has allowed these associations to flourish likely varies within and between lineages. Our results provide a uniquely well-resolved temporal and phylogenetic framework for studying patterns of innovation and diversification in Coleoptera, and a foundation for further sampling and resolution of the beetle tree of life

The Beetle Tree of Life Reveals the Order Coleoptera Survived End Permain Mass Extinction to Diversify During the Cretaceous Terrestrial Revolution

Here we present a phylogeny of beetles (Insecta: Coleoptera) based on DNA sequence data from eight nuclear genes, including six single-copy nuclear protein-coding genes, for 367 species representing 172 of 183 extant families. Our results refine existing knowledge of relationships among major groups of beetles. Strepsiptera was confirmed as sister to Coleoptera and each of the suborders of Coleoptera was recovered as monophyletic. Interrelationships among the suborders, namely Polyphaga (Adephaga (Archostemata, Myxophaga)), in our study differ from previous studies. Adephaga comprised two clades corresponding to Hydradephaga and Geadephaga. The series and superfamilies of Polyphaga were mostly monophyletic. The traditional Cucujoidea were recovered in three distantly related clades. Lymexyloidea was recovered within Tenebrionoidea. Several of the series and superfamilies of Polyphaga received moderate to maximal clade support in most analyses, for example Buprestoidea, Chrysomeloidea, Coccinelloidea, Cucujiformia, Curculionoidea, Dascilloidea, Elateroidea, Histeroidea and Hydrophiloidea. However, many of the relationships within Polyphaga lacked compatible resolution under maximum-likelihood and Bayesian inference, and/or lacked consistently strong nodal support. Overall, we recovered slightly younger estimated divergence times than previous studies for most groups of beetles. The ordinal split between Coleoptera and Strepsiptera was estimated to have occurred in the Early Permian. Crown Coleoptera appeared in the Late Permian, and only one or two lineages survived the end-Permian mass extinction, with stem group representatives of all four suborders appearing by the end of the Triassic. The basal split in Polyphaga was estimated to have occurred in the Triassic, with the stem groups of most series and superfamilies originating during the Triassic or Jurassic. Most extant families of beetles were estimated to have Cretaceous origins. Overall, Coleoptera experienced an increase in diversification rate compared to the rest of Neuropteroidea. Furthermore, 10 family-level clades, all in suborder Polyphaga, were identified as having experienced significant increases in diversification rate. These include most beetle species with phytophagous habits, but also several groups not typically or primarily associated with plants. Most of these groups originated in the Cretaceous, which is also when a majority of the most species-rich beetle families first appeared. An additional 12 clades showed evidence for significant decreases in diversification rate. These clades are species-poor in the Modern fauna, but collectively exhibit diverse trophic habits. The apparent success of beetles, as measured by species numbers, may result from their associations with widespread and diverse substrates - especially plants, but also including fungi, wood and leaf litter - but what facilitated these associations in the first place or has allowed these associations to flourish likely varies within and between lineages. Our results provide a uniquely well-resolved temporal and phylogenetic framework for studying patterns of innovation and diversification in Coleoptera, and a foundation for further sampling and resolution of the beetle tree of life.Facultad de Ciencias Naturales y Muse

Health-related quality of life in patients with locally recurrent or metastatic breast cancer treated with etirinotecan pegol versus treatment of physician’s choice: Results from the randomised phase III BEACON trial

Background: Health-related quality of life (HRQoL) enhances understanding of treatment effects that impact clinical decision-making. Although the primary end-point was not achieved, the BEACON (BrEAst Cancer Outcomes with NKTR-102) trial established etirinotecan pegol, a long-acting topoisomerase-1 (TOP1) inhibitor, as a promising therapeutic for patients with advanced/metastatic breast cancer (MBC) achieving clinically meaningful benefits in median overall survival (OS) for patients with stable brain metastases, with liver metastases or ≥ 2 sites of metastatic disease compared to treatment of physician’s choice (TPC). Reported herein are the findings from the preplanned secondary end-point of HRQoL. Patients and methods: HRQoL, assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) (version 3.0) supplemented by the breast cancer-specific Quality of Life Questionnaire (QLQ-BR23), was evaluated post randomisation in 733 of 852 patients with either anthracycline-, taxane- and capecitabine-pretreated locally recurrent or MBC randomised to etirinotecan pegol (n = 378; 145 mg/m2 every 3 weeks (q3wk)) or single-agent TPC (n = 355). Patients completed assessments at screening, every 8 weeks (q8wk) during treatment, and end-of-treatment. Changes from baseline were analysed, and the proportions of patients achieving differences (≥5 points) in HRQoL scores were compared. Results: Differences were seen favouring etirinotecan pegol up to 32 weeks for global health status (GHS) and physical functioning scales (P < 0.02); numerical improvement was reported in other functional scales. The findings from HRQoL symptom scales were consistent with adverse event profiles; etirinotecan pegol was associated with worsening gastrointestinal symptoms whereas TPC was associated with worsened dyspnoea and other systemic side-effects. Analysis of GHS and physical functioning at disease progression showed a decline in HRQoL in both treatment arms, with a mean change from baseline of −9.4 and −10.8 points, respectively. Conclusion: There was evidence of benefit associated with etirinotecan pegol compared with current standard of care agents in multiple HRQoL measurements, including global health status and physical functioning, despite worse gastrointestinal symptoms (e.g. diarrhoea). Patients in both arms had a decline in HRQoL at disease progression. Study number: NCT01492101

Synopsis of the pelidnotine scarabs (Coleoptera, Scarabaeidae, Rutelinae, Rutelini) and annotated catalog of the species and subspecies

The pelidnotine scarabs (Scarabaeidae: Rutelinae: Rutelini) are a speciose, paraphyletic assemblage of beetles that includes spectacular metallic species (“jewel scarabs”) as well as species that are ecologically important as herbivores, pollinators, and bioindicators. These beetles suffer from a complicated nomenclatural history, due primarily to 20th century taxonomic and nomenclatural errors. We review the taxonomic history of the pelidnotine scarabs, present a provisional key to genera with overviews of all genera, and synthesize a catalog of all taxa with synonyms, distributional data, type specimen information, and 107 images of exemplar species. As a result of our research, the pelidnotine leaf chafers (a paraphyletic group) include 27 (26 extant and 1 extinct) genera and 420 valid species and subspecies (419 extant and 1 extinct). Our research makes biodiversity research on this group tractable and accessible, thus setting the stage for future studies that address evolutionary and ecological trends. Based on our research, 1 new species is described, 1 new generic synonym and 12 new species synonyms are proposed, 11 new lectotypes and 1 new neotype are designated, many new or revised nomenclatural combinations, and many unavailable names are presented. The following taxonomic changes are made: New generic synonym: The genus Heteropelidnota Ohaus, 1912 is a new junior synonym of Pelidnota MacLeay, 1819. New species synonyms: Plusiotis adelaida pavonacea Casey, 1915 is a syn. n. of Chrysina adelaida (Hope, 1841); Odontognathus gounellei Ohaus, 1908 is a revised synonym of Pelidnota ebenina (Blanchard, 1842); Pelidnota francoisgenieri Moore & Jameson, 2013 is a syn. n. of Pelidnota punctata (Linnaeus, 1758); Pelidnota genieri Soula, 2009 is a syn. n. of Pelidnota punctata (Linnaeus, 1758); Pelidnota lutea (Olivier, 1758) is a revised synonym of Pelidnota punctata (Linnaeus, 1758); Pelidnota (Pelidnota) texensis Casey, 1915 is a revised synonym of Pelidnota punctata (Linnaeus, 1758); Pelidnota (Strigidia) zikani (Ohaus, 1922) is a revised synonym of Pelidnota tibialis tibialis Burmeister, 1844; Pelidnota ludovici Ohaus, 1905 is a syn. n. of Pelidnota burmeisteri tricolor Nonfried, 1894; Rutela fulvipennis Germar, 1824 is syn. n. of Pelidnota cuprea (Germar, 1824); Pelidnota pulchella blanda Burmeister, 1844 is a syn. n. of Pelidnota pulchella pulchella (Kirby, 1819); Pelidnota pulchella scapularis Burmeister, 1844 is a syn. n. of Pelidnota pulchella pulchella (Kirby, 1819); Pelidnota xanthogramma Perty, 1830 is a syn. n. of Pelidnota pulchella pulchella (Kirby, 1819). New or revised statuses: Pelidnota fabricelavalettei Soula, 2009, revised status, is considered a species; Pelidnota rioensis Soula, 2009, stat. n., is considered a species; Pelidnota semiaurata semiaurata Burmeister, 1844, stat. rev., is considered a subspecies. New or comb. rev. and revised status: Plusiotis guaymi Curoe, 2001 is formally transferred to the genus Chrysina (C. guaymi (Curoe, 2001), comb. n.); Plusiotis transvolcanica Morón & Nogueira, 2016 is transferred to the genus Chrysina (C. transvolcanica (Morón & Nogueira, 2016), comb. n.). Heteropelidnota kuhnti Ohaus, 1912 is transferred to the genus Pelidnota (P. kuhnti (Ohaus, 1912), comb. n.); Odontognathus riedeli Ohaus, 1905 is considered a subspecies of Pelidnota rubripennis Burmeister, 1844 (Pelidnota rubripennis riedeli (Ohaus, 1905), revised status and comb. rev.); Pelidnota (Strigidia) acutipennis (F. Bates, 1904) is transferred to the genus Sorocha (Sorocha acutipennis (F. Bates, 1904), comb. rev.); Pelidnota (Odontognathus) nadiae Martínez, 1978 is transferred to the genus Sorocha (Sorocha nadiae (Martínez, 1978), comb. rev.); Pelidnota (Ganonota) plicipennis Ohaus, 1934 is transferred to the genus Sorocha (Sorocha plicipennis (Ohaus, 1934), comb. rev.); Pelidnota similis Ohaus, 1908 is transferred to the genus Sorocha (Sorocha similis (Ohaus, 1908), comb. rev.); Pelidnota (Ganonota) yungana Ohaus, 1934 is transferred to Sorocha (Sorocha yungana (Ohaus, 1934), comb. rev.); Pelidnota malyi Soula, 2010: 58, revised status; Xenopelidnota anomala porioni Chalumeau, 1985, revised subspecies status. To stabilize the classification of the group, a neotype is designated for the following species: Pelidnota thiliezi Soula, 2009. Lectotypes are designated for the following names (given in their original combinations): Pelidnota brevicollis Casey, 1915, Pelidnota brevis Casey, 1915, Pelidnota debiliceps Casey, 1915, Pelidnota hudsonica Casey, 1915, Pelidnota oblonga Casey, 1915, Pelidnota pallidipes Casey, 1915, Pelidnota ponderella Casey, 1915, Pelidnota strenua Casey, 1915, Pelidnota tarsalis Casey, 1915, Pelidnota texensis Casey, 1915, and Scarabaeus punctatus Linnaeus, 1758. The following published infrasubspecific names are unavailable per ICZN Article 45.6.1: Pelidnota (Odontognathus) cuprea var. coerulea Ohaus, 1913; Pelidnota (Odontognathus) cuprea var. rufoviolacea Ohaus, 1913; Pelidnota (Odontognathus) cuprea var. nigrocoerulea Ohaus, 1913; Pelidnota pulchella var. fulvopunctata Ohaus, 1913; Pelidnota pulchella var. sellata Ohaus, 1913; Pelidnota pulchella var. reducta Ohaus, 1913; Pelidnota unicolor var. infuscata Ohaus, 1913. The following published species name is unavailable per ICZN Article 11.5: Neopatatra synonyma Moore & Jameson, 2013. The following published species name is unavailable per application of ICZN Article 16.1: Parhoplognathus rubripennis Soula, 2008. Synopsis of the pelidnotine scarabs (Coleoptera, Scarabaeidae, Rutelinae, Rutelini) 3 The following published species name is unavailable per application of ICZN Article 16.4.1: Strigidia testaceovirens argentinica Soula, 2006, Pelidnota (Strigidia) testaceovirens argentinica (Soula, 2006), and Pelidnota testaceovirens argentinica (Soula, 2006). The following published species names are unavailable per application of ICZN Article 16.4.2: Homonyx digennaroi Soula, 2010; Homonyx lecourti Soula, 2010; Homonyx mulliei Soula, 2010; Homonyx simoensi Soula, 2010; Homonyx wagneri Soula, 2010; Homonyx zovii Demez & Soula, 2011; Pelidnota arnaudi Soula, 2009; Pelidnota brusteli Soula, 2010; Pelidnota chalcothorax septentrionalis Soula, 2009; Pelidnota degallieri Soula, 2010; Pelidnota lavalettei Soula, 2008; Pelidnota lavalettei Soula, 2009; Pelidnota dieteri Soula, 2011; Strigidia gracilis decaensi Soula, 2008, Pelidnota (Strigidia) gracilis decaensi (Soula, 2008), and Pelidnota gracilis decaensi (Soula, 2008); Pelidnota halleri Demez & Soula, 2011; Pelidnota injantepalominoi Demez & Soula, 2011; Pelidnota kucerai Soula, 2009; Pelidnota malyi Soula, 2010: 36-37; Pelidnota mezai Soula, 2009; Pelidnota polita darienensis Soula, 2009; Pelidnota polita orozcoi Soula, 2009; Pelidnota polita pittieri Soula, 2009; Pelidnota punctulata decolombia Soula, 2009; Pelidnota punctulata venezolana Soula, 2009; Pelidnota raingeardi Soula, 2009; Pelidnota schneideri Soula, 2010; Pelidnota simoensi Soula, 2009; Pelidnota unicolor subandina Soula, 2009; Sorocha carloti Demez & Soula, 2011; Sorocha castroi Soula, 2008; Sorocha fravali Soula, 2011; Sorocha jeanmaurettei Demez & Soula, 2011; Sorocha yelamosi Soula, 2011; Xenopelidnota bolivari Soula, 2009; Xenopelidnota pittieri pittieri Soula, 2009. Due to unavailability of the name Pseudogeniates cordobaensis Soula 2009, we describe the species as intentionally new (Pseudogeniates cordobaensis Moore, Jameson, Garner, Audibert, Smith, and Seidel, sp. n.)

The beetle tree of life reveals that Coleoptera survived end-Permian mass extinction to diversify during the Cretaceous terrestrial revolution

Here we present a phylogeny of beetles (Insecta: Coleoptera) based on DNA sequence data from eight nuclear genes, including six single-copy nuclear protein-coding genes, for 367 species representing 172 of 183 extant families. Our results refine existing knowledge of relationships among major groups of beetles. Strepsiptera was confirmed as sister to Coleoptera and each of the suborders of Coleoptera was recovered as monophyletic. Interrelationships among the suborders, namely Polyphaga (Adephaga (Archostemata, Myxophaga)), in our study differ from previous studies. Adephaga comprised two clades corresponding to Hydradephaga and Geadephaga. The series and superfamilies of Polyphaga were mostly monophyletic. The traditional Cucujoidea were recovered in three distantly related clades. Lymexyloidea was recovered within Tenebrionoidea. Several of the series and superfamilies of Polyphaga received moderate to maximal clade support in most analyses, for example Buprestoidea, Chrysomeloidea, Coccinelloidea, Cucujiformia, Curculionoidea, Dascilloidea, Elateroidea, Histeroidea and Hydrophiloidea. However, many of the relationships within Polyphaga lacked compatible resolution under maximum-likelihood and Bayesian inference, and/or lacked consistently strong nodal support. Overall, we recovered slightly younger estimated divergence times than previous studies for most groups of beetles. The ordinal split between Coleoptera and Strepsiptera was estimated to have occurred in the Early Permian. Crown Coleoptera appeared in the Late Permian, and only one or two lineages survived the end-Permian mass extinction, with stem group representatives of all four suborders appearing by the end of the Triassic. The basal split in Polyphaga was estimated to have occurred in the Triassic, with the stem groups of most series and superfamilies originating during the Triassic or Jurassic. Most extant families of beetles were estimated to have Cretaceous origins. Overall, Coleoptera experienced an increase in diversification rate compared to the rest of Neuropteroidea. Furthermore, 10 family-level clades, all in suborder Polyphaga, were identified as having experienced significant increases in diversification rate. These include most beetle species with phytophagous habits, but also several groups not typically or primarily associated with plants. Most of these groups originated in the Cretaceous, which is also when a majority of the most species-rich beetle families first appeared. An additional 12 clades showed evidence for significant decreases in diversification rate. These clades are species-poor in the Modern fauna, but collectively exhibit diverse trophic habits. The apparent success of beetles, as measured by species numbers, may result from their associations with widespread and diverse substrates – especially plants, but also including fungi, wood and leaf litter – but what facilitated these associations in the first place or has allowed these associations to flourish likely varies within and between lineages. Our results provide a uniquely well-resolved temporal and phylogenetic framework for studying patterns of innovation and diversification in Coleoptera, and a foundation for further sampling and resolution of the beetle tree of life.This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by John Wiley & Sons, Ltd on behalf of Royal Entomological Society. The published article can be found at: http://onlinelibrary.wiley.com/journal/10.1111/%28ISSN%291365-311

Environmental Barcoding Reveals Massive Dinoflagellate Diversity in Marine Environments

Rowena F. Stern is with University of British Columbia, Ales Horak is with University of British Columbia, Rose L. Andrew is with University of British Columbia, Mary-Alice Coffroth is with State University of New York at Buffalo, Robert A. Andersen is with the Bigelow Laboratory for Ocean Sciences, Frithjof C. Küpper is with the Scottish Marine Institute, Ian Jameson is with CSIRO Marine and Atmospheric Research, Mona Hoppenrath is with the German Center for Marine Biodiversity Research, Benoît Véron is with University of Caen Lower Normandy and the National Institute for Environmental Studies, Fumai Kasai is with the National Institute for Environmental Studies, Jerry Brand is with UT Austin, Erick R. James is with University of British Columbia, Patrick J. Keeling is with University of British Columbia.Background -- Dinoflagellates are an ecologically important group of protists with important functions as primary producers, coral symbionts and in toxic red tides. Although widely studied, the natural diversity of dinoflagellates is not well known. DNA barcoding has been utilized successfully for many protist groups. We used this approach to systematically sample known “species”, as a reference to measure the natural diversity in three marine environments. Methodology/Principal Findings -- In this study, we assembled a large cytochrome c oxidase 1 (COI) barcode database from 8 public algal culture collections plus 3 private collections worldwide resulting in 336 individual barcodes linked to specific cultures. We demonstrate that COI can identify to the species level in 15 dinoflagellate genera, generally in agreement with existing species names. Exceptions were found in species belonging to genera that were generally already known to be taxonomically challenging, such as Alexandrium or Symbiodinium. Using this barcode database as a baseline for cultured dinoflagellate diversity, we investigated the natural diversity in three diverse marine environments (Northeast Pacific, Northwest Atlantic, and Caribbean), including an evaluation of single-cell barcoding to identify uncultivated groups. From all three environments, the great majority of barcodes were not represented by any known cultured dinoflagellate, and we also observed an explosion in the diversity of genera that previously contained a modest number of known species, belonging to Kareniaceae. In total, 91.5% of non-identical environmental barcodes represent distinct species, but only 51 out of 603 unique environmental barcodes could be linked to cultured species using a conservative cut-off based on distances between cultured species. Conclusions/Significance -- COI barcoding was successful in identifying species from 70% of cultured genera. When applied to environmental samples, it revealed a massive amount of natural diversity in dinoflagellates. This highlights the extent to which we underestimate microbial diversity in the environment.This project was funded by Genome Canada and the Canadian Barcode of Life Network. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Biological Sciences, School o

Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Rheumatoid arthritis - treatment: 180. Utility of Body Weight Classified Low-Dose Leflunomide in Japanese Rheumatoid Arthritis

Background: In Japan, more than 20 rheumatoid arthritis (RA) patients died of interstitial pneumonia (IP) caused by leflunomide (LEF) were reported, but many of them were considered as the victims of opportunistic infection currently. In this paper, efficacy and safety of low-dose LEF classified by body weight (BW) were studied. Methods: Fifty-nine RA patients were started to administrate LEF from July 2007 to July 2009. Among them, 25 patients were excluded because of the combination with tacrolimus, and medication modification within 3 months before LEF. Remaining 34 RA patients administered 20 to 50 mg/week of LEF were followed up for 1 year and enrolled in this study. Dose of LEF was classified by BW (50 mg/week for over 50 kg, 40 mg/week for 40 to 50 kg and 20 to 30 mg/week for under 40 kg). The average age and RA duration of enrolled patients were 55.5 years old and 10.2 years. Prednisolone (PSL), methotrexate (MTX) and etanercept were used in 23, 28 and 2 patients, respectively. In case of insufficient response or adverse effect, dosage change or discontinuance of LEF were considered. Failure was defined as dosages up of PSL and MTX, or dosages down or discontinuance of LEF. Last observation carried forward method was used for the evaluation of failed patients at 1 year. Results: At 1 year after LEF start, good/ moderate/ no response assessed by the European League Against Rheumatism (EULAR) response criteria using Disease Activity Score, including a 28-joint count (DAS28)-C reactive protein (CRP) were showed in 14/ 10/ 10 patients, respectively. The dosage changes of LEF at 1 year were dosage up: 10, same dosage: 5, dosage down: 8 and discontinuance: 11 patients. The survival rate of patients in this study was 23.5% (24 patients failed) but actual LEF continuous rate was 67.6% (11 patients discontinued) at 1 year. The major reason of failure was liver dysfunction, and pneumocystis pneumonia was occurred in 1 patient resulted in full recovery. One patient died of sepsis caused by decubitus ulcer infection. DAS28-CRP score was decreased from 3.9 to 2.7 significantly. Although CRP was decreased from 1.50 to 0.93 mg/dl, it wasn't significant. Matrix metalloproteinase (MMP)-3 was decreased from 220.0 to 174.2 ng/ml significantly. Glutamate pyruvate transaminase (GPT) was increased from 19 to 35 U/l and number of leukocyte was decreased from 7832 to 6271 significantly. DAS28-CRP, CRP, and MMP-3 were improved significantly with MTX, although they weren't without MTX. Increase of GPT and leukopenia were seen significantly with MTX, although they weren't without MTX. Conclusions: It was reported that the risks of IP caused by LEF in Japanese RA patients were past IP history, loading dose administration and low BW. Addition of low-dose LEF is a potent safe alternative for the patients showing unsatisfactory response to current medicines, but need to pay attention for liver function and infection caused by leukopenia, especially with MTX. Disclosure statement: The authors have declared no conflicts of interes

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms