Eosinophilic inflammation in COPD: from an inflammatory marker to a treatable trait

The heterogeneity of chronic obstructive pulmonary disease (COPD) creates many diagnostic, prognostic, treatment and management challenges, as the pathogenesis of COPD is highly complex and the underlying cellular and molecular mechanisms remain poorly understood. A reliable, easy-to-measure, clinically relevant biomarker would be invaluable for improving outcomes for patients. International and national guidance for COPD suggests using blood eosinophil counts as a biomarker to help estimate likely responsiveness to inhaled corticosteroids (ICS) and, potentially, to aid effective management strategies. However, with the mechanism underlying the association between higher eosinophil levels and ICS effect unknown, use of the blood eosinophil count in COPD continues to be widely debated by the respiratory community.Two international meetings involving respiratory medicine specialists, immunologists and primary and secondary care clinicians were held in November 2018 and March 2019, facilitated and funded by GlaxoSmithKline plc. The aims of these meetings were to explore the role of eosinophils in the disease processes of COPD and as prognostic and diagnostic markers, and to identify areas of deficient knowledge that warrant further research. The consensus views of the attendees on key topics, contextualised with current literature, are summarised in this review article, with the aim of aiding ongoing research into the disease processes of COPD and the development of biomarkers to aid clinical management.Under certain conditions, eosinophils can be recruited to the lung, and increasing evidence supports a role for eosinophilic inflammation in some patients with COPD. Infiltration of eosinophils across the bronchial vascular epithelium into the airways is promoted by the actions of immunoregulatory cells, cytokines and chemokines, where eosinophil-mediated inflammation is driven by the release of proinflammatory mediators.Multiple studies and two meta-analyses suggest peripheral blood eosinophils may correlate positively with an increased likelihood of exacerbation reduction benefits of ICS in COPD. The studies, however, vary in design and duration and by which eosinophil levels are viewed as predictive of an ICS response. Generally, the response was seen when eosinophil levels were 100-300 cells/µL (or higher), levels which are traditionally viewed within the normal range. Some success with interleukin-5-targeted therapy suggests that the eosinophilic phenotype may be a treatable trait.The use of biomarkers could help to stratify treatment for COPD-the goal of which is to improve patient outcomes. Some evidence supports eosinophils as a potential biomarker of a treatable trait in COPD, though it is still lacking and research is ongoing. A unified consensus and a practical, accessible and affordable method of utilising any biomarker for COPD was thought to be of most importance. Challenges around its utilisation may include presenting a clear and pragmatic rationale for biomarker-driven therapy, guidance on ICS withdrawal between primary and secondary care and a lack of financial incentives supporting broad application in clinical practice. Future treatments should, perhaps, be more targeted rather than assuming the primary disease label (COPD or asthma) will define treatment response

PENGARUH MOTIVASI DAN LINGKUNGAN KERJA TERHADAP KINERJA KARYAWAN DI PT. MADUBARU

Penelitian ini bertujuan untuk mengetahui tingkat motivasi karyawan, bagaimana penilaian karyawan pada lingkungan kerja perusahaan, tingkat kinerja karyawan dan bagaimana pengaruh motivasi dan lingkungan kerja terhadap kinerja karyawan di perusahaan PT. Madubaru. Penelitian ini menggunakan data primer dengan cara menyebarkan kuesioner sebanyak 80 kepada responden. Penelitian ini menggunakan dua alat analisis yaitu One sample t Test dan Regresi Linier Berganda. Pada alat analisis One Sample t Test memberikan hasil bahwa tingkat motivasi karyawan di PT. Madubaru masuk dalam kategori tinggi, kedua penilaian xiv karyawan pada lingkungan kerja di perusahaan PT. Madubaru masuk dalam kategori tinggi, dan tingkat kinerja karyawan di perusahaan PT. Madubaru juga masuk dalam kategori tinggi. Pada uji Regresi Linier Berganda memberikan hasil yang berbeda. Secara simultan motivasi dan lingkungan kerja berpengaruh signifikan terhadap kinerja karyawan di perusahaan PT. Madubaru. Tetapi secara parsial memberikan dua hasil yaitu motivasi berpengaruh siginifikan terhadap kinerja karyawan dan lingkungan kerja tidak berpengaruh signifikan terhadap kinerja karyawan

Whole-genome sequencing of patients with rare diseases in a national health system

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare