The clinical implications of reduced viral fitness

Viral fitness, defined as the extent of viral adaptation to the host environment, arises from tissue tropism, immune system evasion, drug resistance, and viral replication capacity. The fitness of wild-type and drug-resistant HIV-1 varies widely, associating with plasma viremia, CD4+ T-cell count, and clinical progression. HIV-1 fitness may be measured in competitive culture assays, single cycle assays, or single cycle assays based on a subgenomic fragment of HIV-1, which has been standardized as the replication capacity assay (pol RC). During virologic failure of antiretroviral therapy, CD4 T-cell counts remain elevated while pol RC declines and remains durably lower because of drug-selected changes in the gag and pol genes. CD4 T-cell sparing also is observed among patients without evidence of drug resistance who carry a low pol RC virus. Reduced HIV-1 replication capacity and virulence may occur because of drug resistance or viral escape from host immune responses.     

Continuous absence of metaphase-defined cytogenetic abnormalities,especially of chromosome 13 and hypodiploidy,ensures long-term survival in multiple myeloma treated with Total Therapy I: interpretation in the context of global gene expression

Metaphase cytogenetic abnormalities (CAs), especially of chromosome 13 (CA 13), confer a grave prognosis in multiple myeloma even with tandem autotransplantations as applied in Total Therapy I, which enrolled 231 patients between 1989 and 1994. With a median follow-up of almost 9 years, the prognostic implications of all individual CAs, detected prior to treatment and at relapse, were investigated. Among all CAs and standard prognostic factors examined prior to therapy, only hypodiploidy and CA 13 (hypo-13 CA), alone or in combination, were associated with shortest event-free survival and overall survival (OS). The shortest postrelapse OS was observed with hypo-13 CA, which was newly detected in 18 of all 28 patients presenting with this abnormality at relapse. Superior prognosis was associated with the absence of any CA at both diagnosis and relapse (10-year OS, 40%). The lack of independent prognostic implications of other CAs points to a uniquely aggressive behavior of hypo-13 CA (present in 16% of patients at diagnosis). With the use of microarray data in 146 patients enrolled in Total Therapy II, overexpression of cell cycle genes distinguished CA from no CA, especially in cases of del(13) detected by interphase fluorescence in situ hybridization (FISH). FISH 13, resulting in a haploinsufficiency of RB1 and other genes mapping to chromosome 13, as well as activation of IGF1R, appears to have an amplifying effect on cell cycle gene expression, thus providing a molecular explanation for the dire outcome of patients with CA 13 compared with those with other CAs.     

2018 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation

The Canadian Cardiovascular Society (CCS) Atrial Fibrillation Guidelines Committee provides periodic reviews of new data to produce focused updates that address clinically important advances in atrial fibrillation (AF) management. This 2018 Focused Update addresses: (1) anticoagulation in the context of cardioversion of AF; (2) the management of antithrombotic therapy for patients with AF in the context of coronary artery disease; (3) investigation and management of subclinical AF; (4) the use of antidotes for the reversal of non-vitamin K antagonist oral anticoagulants; (5) acute pharmacological cardioversion of AF; (6) catheter ablation for AF, including patients with concomitant AF and heart failure; and (7) an integrated approach to the patient with AF and modifiable cardiovascular risk factors. The recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) standards. Individual studies and literature were reviewed for quality and bias; the literature review process and evidence tables are included as Supplementary Material and are available on the CCS Web site. Details of the updated recommendations are presented, along with their background and rationale. This document is linked to an updated summary of all CCS AF guidelines recommendations, from 2010 to the present 2018 Focused Update, which is provided in the Supplementary Material.     

Ancient plant DNA reveals High Arctic greening during the Last Interglacial

Summer warming is driving a greening trend across the Arctic, with the potential for large-scale amplification of climate change due to vegetation-related feedbacks [Pearson et al., Nat. Clim. Chang. (3), 673–677 (2013)]. Because observational records are sparse and temporally limited, past episodes of Arctic warming can help elucidate the magnitude of vegetation response to temperature change. The Last Interglacial ([LIG], 129,000 to 116,000 y ago) was the most recent episode of Arctic warming on par with predicted 21st century temperature change [Otto-Bliesner et al., Philos. Trans. A Math. Phys. Eng. Sci. (371), 20130097 (2013) and Post et al., Sci. Adv. (5), eaaw9883 (2019)]. However, high-latitude terrestrial records from this period are rare, so LIG vegetation distributions are incompletely known. Pollen-based vegetation reconstructions can be biased by long-distance pollen transport, further obscuring the paleoenvironmental record. Here, we present a LIG vegetation record based on ancient DNA in lake sediment and compare it with fossil pollen. Comprehensive plant community reconstructions through the last and current interglacial (the Holocene) on Baffin Island, Arctic Canada, reveal coherent climate-driven community shifts across both interglacials. Peak LIG warmth featured a ∼400-km northward range shift of dwarf birch, a key woody shrub that is again expanding northward. Greening of the High Arctic—documented here by multiple proxies—likely represented a strong positive feedback on high-latitude LIG warming. Authenticated ancient DNA from this lake sediment also extends the useful preservation window for the technique and highlights the utility of combining traditional and molecular approaches for gleaning paleoenvironmental insights to better anticipate a warmer future.

The Arctic is greening as shrub biomass increases and vegetation ranges shift north in response to summer warming (1, 2). This process—one of the clearest terrestrial manifestations of climate change thus far—has major implications both for local ecosystems and for global energy balance and biogeochemical systems (3–5). In particular, taller shrubs darken otherwise snow-covered surfaces, contributing to the albedo feedback (6, 7), and enhanced evapotranspiration is expected to result in a positive greenhouse feedback (8). Shrub cover also impacts soil thermal regime, which may impact permafrost vulnerability (9–11). Because feedbacks related to Arctic greening are complex and potentially large in magnitude, estimating the extent and rate of northward shrub migration is a vital component of predicting future warming.Past warm periods serve as valuable analogs for understanding the extent of Arctic greening under well-constrained climate conditions. The Last Interglacial (LIG; Marine Isotope Stage [MIS] 5e, 129 to 116 ka [thousands of years before present]) was ∼1 °C warmer than the preindustrial period globally, but the Arctic experienced amplified warming due to higher summer insolation anomalies and positive feedbacks at high latitudes (12, 13). The Eastern Canadian Arctic and Greenland, in particular, were likely ∼4 to 8 °C warmer in summer than present (Fig. 1) (14–18). LIG sediment records from this region thus provide an archive of the vegetation response to Arctic warming at levels comparable to predicted 21^st-century climate change (19).Open in a separate windowFig. 1.Map of Baffin Island and Lake CF8 study area. The symbols represent maximum LIG temperature anomalies based on terrestrial proxy records (shape indicates proxy type) from Baffin Island and Greenland (see SI Appendix, Table S1 for metadata). The shaded regions indicate Arctic bioclimate subzones delineations (29), including modern Betula range in subzones D and E. We note that a small outlier population of Betula occurs east of the D/E boundary on Baffin Island (not captured by vegetation map resolution) (38).While most High Arctic lake basins were scraped clean by ice sheet erosion during the last glaciation and thus only contain postglacial sediments, lakes with small, low-relief catchments within regions of cold-based, slow-flowing ice were protected from erosion. Several such sites have been discovered on eastern Baffin Island, Arctic Canada and contain stratified records of multiple interglacials (20–22). Previous work from Lake CF8 on northeastern Baffin Island (Fig. 1 and SI Appendix, Fig. S1) demonstrates that its sediment record spans at least three interglacials (∼200 ka), including a substantially warmer-than-present LIG as indicated by chironomids, diatoms, and geochemical proxies (15, 23).We targeted the multi-interglacial record from Lake CF8 to assess the vegetation response to pronounced warmth during the LIG and moderate warmth during the Holocene. Pollen produced by some key shrubs and trees, including Betula (birch), is efficiently wind-transported and thus present in lake sediments far north of their ranges (24, 25). We therefore analyzed both sedimentary ancient DNA (sedaDNA), which is sourced locally from within the lake catchment and does not include pollen-derived DNA (26), and fossil pollen to generate a robust vegetation record spanning the last ∼130 ka. Taken together, DNA-inferred plant communities and pollen-inferred July air temperatures provide insight into Arctic plant range shifts under strong summer warming.     

Suppressor screen in Mpl-/- mice: c-Myb mutation causes supraphysiological production of platelets in the absence of thrombopoietin signaling

Genetic screens in lower organisms, particularly those that identify modifiers of preexisting genetic defects, have been used successfully to order components of complex signaling pathways. To date, similar suppressor screens have not been used in vertebrates. To define the molecular pathways regulating platelet production, we have executed a large-scale modifier screen with genetically thrombocytopenic Mpl(-/-) mice by using N-ethyl-N-nitrosourea mutagenesis. Here we show that mutations in the c-Myb gene cause a myeloproliferative syndrome and supraphysiological expansion of megakaryocyte and platelet production in the absence of thrombopoietin signaling. This screen demonstrates the utility of large-scale N-ethyl-N-nitrosourea mutagenesis suppressor screens in mice for the simultaneous discovery and in vivo validation of targets for therapeutic discovery in diseases for which mouse models are available.     

Effect of Interferon-α Treatment of Chronic Hepatitis C on Health-Related Quality of Life

Studies of interferon- (IFN-)therapy for chronic hepatitis C have focused on viralclearance; however, few have evaluated patient'shealth-related quality of life during therapy. Thisstudy evaluates health-related quality of life and theprevalence of anxiety and depression in patients withchronic hepatitis C before, during, and followingIFN- therapy. Patients undergoing IFN-therapy for chronic hepatitis C were asked to completehealth status measures as well as anxiety and depressioninventories before, during, and following IFN-therapy. These measures were compared to the results of healthy adults in the general US population.Thirty-eight of forty-eight eligible patients (79%) withchronic hepatitis C completed the questionnaires.Respondents demonstrated a significant increase in depression during the sixth month ofinterferon therapy in comparison to pretreatmentresults. Anxiety scores improved significantly after onemonth of IFN- in comparison to pretreatmentresults. Scores on the health status measures did notvary with IFN- therapy. Patient responses wereanalyzed with respect to biochemical response(normalized transaminases) to IFN-. IFN-responders, who were aware of their transaminase results,exhibited lower scores on anxiety subscales during andafter therapy (P = 0.02-0.04). Scores on the healthstatus subscale, role emotional, improved in IFN- responders compared to nonresponders during thesixth month of therapy (P = 0.02). Response toIFN- therapy was not associated with any otherdifferences on subscale analysis. Patients with chronichepatitis C exhibited health perceptions similar to thegeneral US population, and these were unchanged duringIFN- therapy. However, the incidence ofdepression significantly increased during the sixthmonth of IFN- therapy. IFN- respondersexhibited fewer emotional problems as well as a lowerincidence of anxiety during and followingtherapy.     

Household-Level Spatiotemporal Patterns of Incidence of Cholera,Haiti, 2011

A cholera outbreak began in Haiti during October, 2010. Spatiotemporal patterns of household-level cholera in Ouest Department showed that the initial clusters tended to follow major roadways; subsequent clusters occurred further inland. Our data highlight transmission pathway complexities and the need for case and household-level analysis to understand disease spread and optimize interventions.