East Asian winter weather has altered dramatically in response to progressing climate change. However, analysis of time‐averaged atmospheric fields might obscure climate change signals that could ...relate to specific types of events. This study aimed to detect climate change signals for various background atmospheric fields by applying classification to daily surface pressure patterns. We found a pronounced trend of increase in surface air temperature over Japan since the 1980s, stronger than the seasonal mean trend, when dominating cold air advection from the Sea of Okhotsk. This cold air was warmed and humidified by the retreat of sea ice in the Sea of Okhotsk. In contrast, the warming trend was mitigated when warm air advection was dominant. These results highlight the importance of daily background atmospheric conditions in amplifying and localizing the impact of regional climate change.
Plain Language Summary
Winter weather in East Asia varies greatly depending on the daily surface pressure pattern. Hence, the impact of climate change could appear in different forms according to specific weather conditions. This study aimed to detect long‐term changes in atmospheric fields under various weather conditions. Focusing on the daily surface pressure patterns, analysis of East Asian winters showed substantial historical increase in surface air temperature when northerly cold air outbreaks brought colder air toward Japan, and the warming rate was stronger than the trend of the winter average. The retreat of sea ice in the Sea of Okhotsk, located upwind of Japan, caused this local warming and humidification. In contrast, the warming trend was weaker for days when the pressure pattern brought warmer air toward Japan. This finding indicates that winter days with cold air flowing around Japan have been warming more strongly than warm winter days. Our analysis enables assessment of the impact of global warming on specific weather conditions of interest.
Key Points
Historical changes in winter climate in Japan were decomposed based on pressure pattern classification
Northerly winter monsoon has been substantially warmed and humidified around Japan due to sea ice retreat in the upwind sea
Pressure patterns that cause stronger regional response to climate change were identified
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Standard first-line treatment of metastatic triple-negative breast cancer (mTNBC) is chemotherapy. However, outcomes are poor, and new treatment options are needed. In cohort B of the phase II ...KEYNOTE-086 study, we evaluated pembrolizumab as first-line therapy for patients with PD-L1-positive mTNBC.
Eligible patients had centrally confirmed mTNBC, no prior systemic anticancer therapy for metastatic disease, measurable disease at baseline per RECIST v1.1 by central review, no radiographic evidence of central nervous system metastases, and a tumor PD-L1 combined positive score ≥1. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. The primary end point was safety. Secondary end points included objective response rate, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), duration of response, progression-free survival and overall survival.
All 84 patients enrolled were women, and 73 (86.9%) received prior (neo)adjuvant therapy. Fifty-three (63.1%) patients had treatment-related adverse events (AEs), including 8 patients (9.5%) with grade 3 severity; no patients experienced grade 4 AEs or died because of treatment-related AEs. Four patients had a complete response and 14 had a partial response, for an objective response rate of 21.4% (95% CI 13.9–31.4). Of the 13 patients with stable disease, 2 had stable disease lasting ≥24 weeks, for a disease control rate of 23.8% (95% CI 15.9–34.0). At data cut-off, 8 of 18 (44.4%) responses were ongoing, and median duration of response was 10.4 months (range 4.2 to 19.2+). Median progression-free survival was 2.1 months (95% CI 2.0–2.2), and median overall survival was 18.0 months (95% CI 12.9–23.0).
Pembrolizumab monotherapy had a manageable safety profile and showed durable antitumor activity as first-line therapy for patients with PD-L1-positive mTNBC.
ClinicalTrials.gov, NCT02447003.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Comparative analysis of molecular sequence data is essential for reconstructing the evolutionary histories of species and inferring the nature and extent of selective forces shaping the evolution of ...genes and species. Here, we announce the release of Molecular Evolutionary Genetics Analysis version 5 (MEGA5), which is a user-friendly software for mining online databases, building sequence alignments and phylogenetic trees, and using methods of evolutionary bioinformatics in basic biology, biomedicine, and evolution. The newest addition in MEGA5 is a collection of maximum likelihood (ML) analyses for inferring evolutionary trees, selecting best-fit substitution models (nucleotide or amino acid), inferring ancestral states and sequences (along with probabilities), and estimating evolutionary rates site-by-site. In computer simulation analyses, ML tree inference algorithms in MEGA5 compared favorably with other software packages in terms of computational efficiency and the accuracy of the estimates of phylogenetic trees, substitution parameters, and rate variation among sites. The MEGA user interface has now been enhanced to be activity driven to make it easier for the use of both beginners and experienced scientists. This version of MEGA is intended for the Windows platform, and it has been configured for effective use on Mac OS X and Linux desktops. It is available free of charge from http://www.megasoftware.net.
Drosophila melanogaster has been a canonical model organism to study genetics, development, behavior, physiology, evolution, and population genetics for nearly a century. Despite this emphasis and ...the completion of its nuclear genome sequence, the timing of major speciation events leading to the origin of this fruit fly remain elusive because of the paucity of extensive fossil records and biogeographic data. Use of molecular clocks as an alternative has been fraught with non-clock-like accumulation of nucleotide and amino-acid substitutions. Here we present a novel methodology in which genomic mutation distances are used to overcome these limitations and to make use of all available gene sequence data for constructing a fruit fly molecular time scale. Our analysis of 2977 pairwise sequence comparisons from 176 nuclear genes reveals a long-term fruit fly mutation clock ticking at a rate of 11.1 mutations per kilobase pair per Myr. Genomic mutation clock-based timings of the landmark speciation events leading to the evolution of D. melanogaster show that it shared most recent common ancestry 5.4 MYA with D. simulans, 12.6 MYA with D. erecta+D. orena, 12.8 MYA with D. yakuba+D. teisseri, 35.6 MYA with the takahashii subgroup, 41.3 MYA with the montium subgroup, 44.2 MYA with the ananassae subgroup, 54.9 MYA with the obscura group, 62.2 MYA with the willistoni group, and 62.9 MYA with the subgenus Drosophila. These and other estimates are compatible with those known from limited biogeographic and fossil records. The inferred temporal pattern of fruit fly evolution shows correspondence with the cooling patterns of paleoclimate changes and habitat fragmentation in the Cenozoic.
Abstract Background Frailty is common in the elderly and in persons with chronic diseases. Few studies have examined the association of frailty with chronic kidney disease. Methods We used data from ...the Third National Health and Nutrition Examination Survey to estimate the prevalence of frailty among persons with chronic kidney disease. We created a definition of frailty based on established validated criteria, modified to accommodate available data. We used logistic regression to determine whether and to what degree stages of chronic kidney disease were associated with frailty. We also examined factors that might mediate the association between frailty and chronic kidney disease. Results The overall prevalence of frailty was 2.8%. However, among persons with moderate to severe chronic kidney disease (estimated glomerular filtration rate < 45 mL/min/1.73 m2 ), 20.9% were frail. The odds of frailty were significantly increased among all stages of chronic kidney disease, even after adjustment for the residual effects of age, sex, race, and prevalent chronic diseases. The odds of frailty associated with chronic kidney disease were only marginally attenuated with additional adjustment for sarcopenia, anemia, acidosis, inflammation, vitamin D deficiency, hypertension, and cardiovascular disease. Frailty and chronic kidney disease were independently associated with mortality. Conclusion Frailty is significantly associated with all stages of chronic kidney disease and particularly with moderate to severe chronic kidney disease. Potential mechanisms underlying the chronic kidney disease and frailty connection remain elusive.
We announce the release of the fourth version of MEGA software, which expands on the existing facilities for editing DNA sequence data from autosequencers, mining Web-databases, performing automatic ...and manual sequence alignment, analyzing sequence alignments to estimate evolutionary distances, inferring phylogenetic trees, and testing evolutionary hypotheses. Version 4 includes a unique facility to generate captions, written in figure legend format, in order to provide natural language descriptions of the models and methods used in the analyses. This facility aims to promote a better understanding of the underlying assumptions used in analyses, and of the results generated. Another new feature is the Maximum Composite Likelihood (MCL) method for estimating evolutionary distances between all pairs of sequences simultaneously, with and without incorporating rate variation among sites and substitution pattern heterogeneities among lineages. This MCL method also can be used to estimate transition/transversion bias and nucleotide substitution pattern without knowledge of the phylogenetic tree. This new version is a native 32-bit Windows application with multi-threading and multi-user supports, and it is also available to run in a Linux desktop environment (via the Wine compatibility layer) and on Intel-based Macintosh computers under the Parallels program. The current version of MEGA is available free of charge at http://www.megasoftware.net.
The Molecular Evolutionary Genetics Analysis (MEGA) software is a desktop application designed for comparative analysis of homologous gene sequences either from multigene families or from different ...species with a special emphasis on inferring evolutionary relationships and patterns of DNA and protein evolution. In addition to the tools for statistical analysis of data, MEGA provides many convenient facilities for the assembly of sequence data sets from files or web-based repositories, and it includes tools for visual presentation of the results obtained in the form of interactive phylogenetic trees and evolutionary distance matrices. Here we discuss the motivation, design principles and priorities that have shaped the development of MEGA. We also discuss how MEGA might evolve in the future to assist researchers in their growing need to analyze large data set using new computational methods.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aims
Primary central nervous system lymphoma (PCNSL) manifest aggressive clinical behaviour and have poor prognosis. Although constitutive activation of the nuclear factor‐κB (NF‐κB) pathway has been ...documented, knowledge about the genetic alterations leading to the impairment of the NF‐κB pathway in PCNSLs is still limited. This study was aimed to unravel the underlying genetic profiles of PCNSL.
Methods
We conducted the systematic sequencing of 21 genes relevant to the NF‐κB signalling network for 71 PCNSLs as well as the pyrosequencing of CD79B and MYD88 mutation hotspots in a further 35 PCNSLs and 46 glioblastomas (GBMs) for validation.
Results
The results showed that 68 out of 71 PCNSLs had mutations in the NF‐κB gene network, most commonly affecting CD79B (83%), MYD88 (76%), TBL1XR1 (23%), PRDM1 (20%) and CREBBP1 (20%). These mutations, particularly CD79B and MYD88, frequently coincided within each tumour in various combinations, simultaneously affecting diverse pathways within the network. No GBMs had hotspot mutation of CD79B Y196 and MYD88 L265.
Conclusions
The prevalence of CD79B and MYD88 mutations in PCNSLs was considerably higher than reported in systemic diffuse large B‐cell lymphomas. This observation could reflect the paucity of antigen stimuli from the immune system in the central nervous system (CNS) and the necessity to substitute them by the constitutive activation of CD79B and MYD88 that would initiate the signalling cascades. These hotspot mutations may serve as a genetic hallmark for PCNSL serving as a genetic marker for diagnose and potential targets for molecular therapy.
Mutations involving the NF‐κB gene network are common and have a unique profile in primary central nervous system lymphomas.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
•Short-term efficacy of IV and IN ketamine/esketamine is established for TRD.•Interpretation the efficacy of oral ketamine in TRD is limited.•Insufficient data on disparate formulations and routes of ...delivery of ketamine.
Ketamine is established as a rapid and effective treatment in adults with treatment-resistant depression (TRD). The availability of different formulations and routes of delivery invites the need for evaluating relative effect sizes.
Effect size with respect to depression symptom reduction for each formulation and route of delivery was compared at discrete time-points (i.e., 24 h, 2–6 days, 7–20 days, 21–28 days) in adults with TRD. A random-effects meta-analysis was conducted to evaluate the effect size across intravenous, intranasal and oral routes of administration. Analysis was also conducted evaluating the effect size of racemic ketamine to esketamine.
The pooled effect size for intranasal ketamine/esketamine at 24 h was g = 1.247 (n = 5, 95% CI: 0.591–1.903, p < 0.01). At 2–6 days, the pooled effect size for intravenous ketamine/esketamine was g = 0.949 (n = 14, 95% CI: −0.308–2.206, p = 0.139). At 7–20 days, intranasal ketamine had a pooled effect size of g = 1.018 (n = 4, 95% CI: 0.499–1.538, p < 0.01). At 21–28 days, oral ketamine had a pooled effect size of g = 0.633 (n = 2, 95% CI: 0.368–0.898, p < 0.01).
Additional comparative studies are needed with regards to the efficacy of different formulations and routes of delivery.
The short-term efficacy of intravenous and intranasal ketamine/esketamine for adults with TRD was established. Interpreting the efficacy of oral ketamine was limited by the need for studies with larger samples across independent sites. No conclusions regarding comparative efficacy of the disparate formulations and routes of delivery can be derived from this analysis. Direct comparative studies are needed to further inform treatment options for TRD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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