Triple antithrombotic therapy with warfarin plus two antiplatelet agents is the standard of care after percutaneous coronary intervention (PCI) for patients with atrial fibrillation, but this therapy ...is associated with a high risk of bleeding.
In this multicenter trial, we randomly assigned 2725 patients with atrial fibrillation who had undergone PCI to triple therapy with warfarin plus a P2Y
inhibitor (clopidogrel or ticagrelor) and aspirin (for 1 to 3 months) (triple-therapy group) or dual therapy with dabigatran (110 mg or 150 mg twice daily) plus a P2Y
inhibitor (clopidogrel or ticagrelor) and no aspirin (110-mg and 150-mg dual-therapy groups). Outside the United States, elderly patients (≥80 years of age; ≥70 years of age in Japan) were randomly assigned to the 110-mg dual-therapy group or the triple-therapy group. The primary end point was a major or clinically relevant nonmajor bleeding event during follow-up (mean follow-up, 14 months). The trial also tested for the noninferiority of dual therapy with dabigatran (both doses combined) to triple therapy with warfarin with respect to the incidence of a composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization.
The incidence of the primary end point was 15.4% in the 110-mg dual-therapy group as compared with 26.9% in the triple-therapy group (hazard ratio, 0.52; 95% confidence interval CI, 0.42 to 0.63; P<0.001 for noninferiority; P<0.001 for superiority) and 20.2% in the 150-mg dual-therapy group as compared with 25.7% in the corresponding triple-therapy group, which did not include elderly patients outside the United States (hazard ratio, 0.72; 95% CI, 0.58 to 0.88; P<0.001 for noninferiority). The incidence of the composite efficacy end point was 13.7% in the two dual-therapy groups combined as compared with 13.4% in the triple-therapy group (hazard ratio, 1.04; 95% CI, 0.84 to 1.29; P=0.005 for noninferiority). The rate of serious adverse events did not differ significantly among the groups.
Among patients with atrial fibrillation who had undergone PCI, the risk of bleeding was lower among those who received dual therapy with dabigatran and a P2Y
inhibitor than among those who received triple therapy with warfarin, a P2Y
inhibitor, and aspirin. Dual therapy was noninferior to triple therapy with respect to the risk of thromboembolic events. (Funded by Boehringer Ingelheim; RE-DUAL PCI ClinicalTrials.gov number, NCT02164864 .).
Patients with albuminuria and CKD frequently have vascular dysfunction but the underlying mechanisms remain unclear. Because the endothelial surface layer, a meshwork of surface-bound and loosely ...adherent glycosaminoglycans and proteoglycans, modulates vascular function, its loss could contribute to both renal and systemic vascular dysfunction in proteinuric CKD. Using Munich-Wistar-Fromter (MWF) rats as a model of spontaneous albuminuric CKD, multiphoton fluorescence imaging and single-vessel physiology measurements revealed that old MWF rats exhibited widespread loss of the endothelial surface layer in parallel with defects in microvascular permeability to both water and albumin, in both continuous mesenteric microvessels and fenestrated glomerular microvessels. In contrast to young MWF rats, enzymatic disruption of the endothelial surface layer in old MWF rats resulted in neither additional loss of the layer nor additional changes in permeability. Intravenous injection of wheat germ agglutinin lectin and its adsorption onto the endothelial surface layer significantly improved glomerular albumin permeability. Taken together, these results suggest that widespread loss of the endothelial surface layer links albuminuric kidney disease with systemic vascular dysfunction, providing a potential therapeutic target for proteinuric kidney disease.
Abstract
Afforestation and reforestation to meet ‘Net Zero’ emissions targets are considered a necessary policy by many countries. Their potential benefits are usually assessed through forest carbon ...and growth models. The implementation of vegetation demography gives scope to represent forest management and other size-dependent processes within land surface models (LSMs). In this paper, we evaluate the impact of including management within an LSM that represents demography, using both in-situ and reanalysis climate drivers at a mature, upland Sitka spruce plantation in Northumberland, UK. We compare historical simulations with fixed and variable CO
2
concentrations, and with and without tree thinning implemented. Simulations are evaluated against the observed vegetation structure and carbon fluxes. Including thinning and the impact of increasing CO
2
concentration (‘CO
2
fertilisation’) gave more realistic estimates of stand-structure and physical characteristics. Historical CO
2
fertilisation had a noticeable effect on the Gross Primary Productivity seasonal–diurnal cycle and contributed to approximately 7% higher stand biomass by 2018. The net effect of both processes resulted in a decrease of tree density and biomass, but an increase in tree height and leaf area index.
MAGE A3, which belongs to the family of cancer-testis antigens, is an attractive target for adoptive therapy given its reactivation in various tumors and limited expression in normal tissues. We ...developed an affinity-enhanced T cell receptor (TCR) directed to a human leukocyte antigen (HLA)-A*01-restricted MAGE A3 antigen (EVDPIGHLY) for use in adoptive therapy. Extensive preclinical investigations revealed no off-target antigen recognition concerns; nonetheless, administration to patients of T cells expressing the affinity-enhanced MAGE A3 TCR resulted in a serious adverse event (SAE) and fatal toxicity against cardiac tissue. We present a description of the preclinical in vitro functional analysis of the MAGE A3 TCR, which failed to reveal any evidence of off-target activity, and a full analysis of the post-SAE in vitro investigations, which reveal cross-recognition of an off-target peptide. Using an amino acid scanning approach, a peptide from the muscle protein Titin (ESDPIVAQY) was identified as an alternative target for the MAGE A3 TCR and the most likely cause of in vivo toxicity. These results demonstrate that affinity-enhanced TCRs have considerable effector functions in vivo and highlight the potential safety concerns for TCR-engineered T cells. Strategies such as peptide scanning and the use of more complex cell cultures are recommended in preclinical studies to mitigate the risk of off-target toxicity in future clinical investigations.
Abstract
The influence of climate change on civil conflict and societal instability in the premodern world is a subject of much debate, in part because of the limited temporal or disciplinary scope ...of case studies. We present a transdisciplinary case study that combines archeological, historical, and paleoclimate datasets to explore the dynamic, shifting relationships among climate change, civil conflict, and political collapse at Mayapan, the largest Postclassic Maya capital of the Yucatán Peninsula in the thirteenth and fourteenth centuries CE. Multiple data sources indicate that civil conflict increased significantly and generalized linear modeling correlates strife in the city with drought conditions between 1400 and 1450 cal. CE. We argue that prolonged drought escalated rival factional tensions, but subsequent adaptations reveal regional-scale resiliency, ensuring that Maya political and economic structures endured until European contact in the early sixteenth century CE.
Established populations of Asian longhorned ticks (ALT), Haemaphysalis longicornis, were first identified in the United States (US) in 2017 by sequencing the mitochondrial cytochrome c oxidase ...subunit I (cox1) ‘barcoding’ locus followed by morphological confirmation. Subsequent investigations detected ALT infestations in 12, mostly eastern, US states. To gain information on the origin and spread of US ALT, we (1) sequenced cox1 from ALT populations across 9 US states and (2) obtained cox1 sequences from potential source populations China, Japan and Republic of Korea (ROK) as well as Australia, New Zealand and the Kingdom of Tonga (KOT) both by sequencing and by downloading publicly available sequences in NCBI GenBank. Additionally, we conducted epidemiological investigations of properties near its initial detection locale in Hunterdon County, NJ, as well as a broader risk analysis for importation of ectoparasites into the area. In eastern Asian populations (China/Japan/ROK), we detected 35 cox1 haplotypes that neatly clustered into two clades with known bisexual versus parthenogenetic phenotypes. In Australia/New Zealand/KOT, we detected 10 cox1 haplotypes all falling within the parthenogenetic cluster. In the United States, we detected three differentially distributed cox1 haplotypes from the parthenogenetic cluster, supporting phenotypic evidence that US ALT are parthenogenetic. While none of the source populations examined had all three US cox1 haplotypes, a phylogeographic network analysis supports a northeast Asian source for the US populations. Within the United States, epidemiological investigations indicate ALT can be moved long distances by human transport of animals, such as horses and dogs, with smaller scale movements on wildlife. These results have relevant implications for efforts aimed at minimizing the spread of ALT in the United States and preventing additional exotic tick introductions.
The purpose of the study was to determine the effects of two nights of sleep deprivation with or without energy restriction on immune indices at rest and in response to cold exposure. On three ...randomised occasions ten males slept normally mean (SD): 436 (21) min night
−1
; CON, were totally sleep-deprived (SDEP), or were totally sleep-deprived and 90% energy-restricted (SDEP + ER) for 53 h. After 53 h (1200 h) participants performed a seated cold air test (CAT) at 0.0°C until
T
re
decreased to 36.0°C. Circulating leucocyte counts, neutrophil degranulation, stress hormones and saliva secretory IgA (S-IgA) were determined at 0 h, 24 h, 48 h, pre-CAT, post-CAT, 1-h and 2-h post-CAT. One night on SDEP increased bacterially stimulated neutrophil degranulation (21%,
P
< 0.05), and two nights on SDEP and SDEP + ER increased S-IgA concentration (40 and 44%;
P
< 0.01). No other significant effects were observed for immuno-endocrine measures prior to CAT. CAT duration was not different between trials mean (SD): 133 (53) min and
T
re
decreased to 35.9 (0.3)°C. Modest whole-body cooling decreased circulating lymphocyte counts (25%;
P
< 0.01), S-IgA concentration (36%;
P
< 0.01) and secretion rate (24%;
P
< 0.05). A neutrophilia occurred post-CAT on CON and SDEP and 2-h post-CAT on SDEP + ER (
P
< 0.01). Modest whole-body cooling also decreased neutrophil degranulation on CON (22%) and SDEP (18%;
P
< 0.05). Plasma cortisol and norepinephrine increased post-CAT (31 and 346%,
P
< 0.05), but modest whole-body cooling did not alter plasma epinephrine. In conclusion, two nights of SDEP or SDEP + ER did not compromise resting immune indices. However, modest whole-body cooling (
T
re
35.9°C) decreased circulating lymphocytes, neutrophil degranulation and S-IgA, but responses were not amplified by prior SDEP or SDEP + ER.
Purpose
In persons completing exhaustive daily exercise, sleep and energy restriction have been highlighted as risk factors for hypothermia in cold environments. The present study therefore sought to ...determine the effect of sleep deprivation (SDEP), with and without energy restriction, on the thermal response to cold.
Methods
In a random order, ten recreationally active men (mean ± SD: age 25 ± 6 years, body fat 17 ± 5 %) completed three 53 h trials: a control (CON: 436 min/night sleep), SDEP (0 min sleep), and sleep deprivation and energy restriction (SDEP + ER: 0 min sleep and 10 % daily energy requirements). Exhaustive exercise was completed after 5 and 29 h. After 53 h participants completed a semi-nude seated cold air test (CAT, 0 °C), for 4 h or until rectal core temperature (
T
re
) reached 36 °C.
Results
Two nights of sleep and energy restriction did not impair the thermal response to cold (
T
re
, CON 36.15 ± 0.20 °C, SDEP 36.30 ± 0.15 °C, SDEP + ER 36.25 ± 0.20 °C,
P
= 0.25). Rewarming was also similar as indicated by 1 h post-CAT
T
re
(
P
= 0.78). In contrast, perceived thermal discomfort during the initial hour of the CAT tended to be greater after SDEP and SDEP + ER (
P
≤ 0.1).
Conclusion
Sleep and energy restriction, at least as evaluated within this experiment, should be considered minimal risk factors for hypothermia. The greater perception of cold discomfort at the same body temperature suggests that sleep and energy restriction may actually reduce cold injury risk, as people are likely to engage earlier in normal behavioral cold adaptation.
This phase III randomized trial compared two chemotherapy regimens, gemcitabine plus carboplatin and mitomycin, ifosfamide, and cisplatin, in chemotherapy-naive patients with advanced non-small-cell ...lung cancer (NSCLC). The regimens were compared with regard to effects on survival, response rates, toxicity, and quality of life.
Eligible patients had previously untreated stage IIIB or IV NSCLC suitable for cisplatin-based chemotherapy. Randomly assigned patients were to receive four cycles, each at 3-week intervals, of carboplatin area under the curve of 5 on day 1 plus gemcitabine 1,200 mg/m(2) on days 1 and 8 (GCa) or mitomycin 6 mg/m(2), ifosfamide 3g/m(2), and cisplatin 50 mg/m(2) on day 1 (MIC).
Between February 1999 and August 2001, 422 patients (GCa, n = 212; MIC, n = 210) were randomly assigned in the United Kingdom. The majority of patients received the intended four cycles (GCa, 64%; MIC, 61%). There was a significant survival advantage for GCa compared with MIC (hazard ratio, 0.76; 95% CI, 0.61 to 0. 93; P = .008). Median survival was 10 months with GCa and 7.6 months with MIC (difference, 2.4 months; 95% CI, 1.0 to 4.0), and 1-year survival was 40% with GCa and 30% with MIC (difference, 10%; 95% CI, 3% to 18%). Overall response rates were similar (42% for GCa v 41% for MIC; P = .84). More thrombocytopenia occurred with GCa (P = .03), but this was not associated with increased hospital admission or fatality. GCa caused less nausea, vomiting, constipation, and alopecia and was associated with fewer admissions for administration and better quality of life.
In patients with advanced NSCLC, GCa chemotherapy was shown to be a better-tolerated treatment that conferred a survival advantage over MIC.
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