Empirical antifungal therapy is frequently used in allogeneic transplant patients who have persistent febrile neutropenia and can be associated with high cost, toxicity and breakthrough infections. ...There are limited reports of strategies for early diagnosis of invasive fungal infection (IFI) and, to our knowledge, no reports of treatment strategies based only on high-resolution computerized tomography (HRCT) scans. We used an early treatment strategy for IFI in 99 consecutive patients undergoing allogeneic transplantation. Patients received caspofungin if they had antibiotic-resistant neutropenic fever for more than 72 h and a positive HRCT scan. Fifty-three of 99 patients (54%) had antibiotic-resistant neutropenic fever at 72 h and would have received parenteral antifungal treatment if an empirical approach had been used. The HRCT-based strategy reduced the use of parenteral antifungal agents to 17/99 patients (17%), a 68% reduction. No subsequent diagnoses of IFI occurred within 100 days in patients with a negative HRCT. Only one patient died from IFI within 100 days. These data suggest that this non-empirical strategy may be feasible and that caspofungin may be effective in this setting. A randomized controlled trial is warranted to further assess these results.
To describe risk factors for the development of acute renal failure (ARF) in a population of intensive care unit (ICU) patients, and the association of ARF with multiple organ failure (MOF) and ...outcome using the sequential organ failure assessment (SOFA) score.
Prospective, multicenter, observational cohort analysis.
Forty ICUs in 16 countries.
All patients admitted to one of the participating ICUs in May 1995, except those who stayed in the ICU for less than 48 h after uncomplicated surgery, were included. After the exclusion of 38 patients with a history of chronic renal failure requiring renal replacement therapy, a total of 1411 patients were studied.
Of the patients, 348 (24.7%) developed ARF, as diagnosed by a serum creatinine of 300 micromol/l (3.5 mg/dl) or more and/or a urine output of less than 500 ml/day. The most important risk factors for the development of ARF present on admission were acute circulatory or respiratory failure; age more than 65 years, presence of infection, past history of chronic heart failure (CHF), lymphoma or leukemia, or cirrhosis. ARF patients developed MOF earlier than non-ARF patients (median 24 vs 48 h after ICU admission, p < 0.05). ARF patients older than 65 years with a past history of CHF or with any organ failure on admission were most likely to develop MOF. ICU mortality was 3 times higher in ARF than in other patients (42.8% vs 14.0%, p < 0.01). Oliguric ARF was an independent risk factor for overall mortality as determined by a multivariate regression analysis (OR = 1.59 CI 95%: 1.23-2.06, p < 0.01). Infection increased the risk of death associated with all factors. Factors that increased the ICU mortality of ARF patients were a past history of hematologic malignancy, age more than 65 years, the number of failing organs on admission and the presence of acute cardiovascular failure.
In ICU patients, the most important risk factors for ARF or mortality from ARF are often present on admission. During the ICU stay, other organ failures (especially cardiovascular) are important risk factors. Oliguric ARF was an independent risk factor for ICU mortality, and infection increased the contribution to mortality by other factors. The severity of circulatory shock was the most important factor influencing outcome in ARF patients.
The lethal factor in stonefish venom is stonustoxin (SNTX), a heterodimeric cytolytic protein that induces cardiovascular collapse in humans and native predators. Here, using X-ray crystallography, ...we make the unexpected finding that SNTX is a pore-forming member of an ancient branch of the Membrane Attack Complex-Perforin/Cholesterol-Dependent Cytolysin (MACPF/CDC) superfamily. SNTX comprises two homologous subunits (α and β), each of which comprises an N-terminal pore-forming MACPF/CDC domain, a central focal adhesion-targeting domain, a thioredoxin domain, and a C-terminal tripartite motif family-like PRY SPla and the RYanodine Receptor immune recognition domain. Crucially, the structure reveals that the two MACPF domains are in complex with one another and arranged into a stable early prepore-like assembly. These data provide long sought after near-atomic resolution insights into how MACPF/CDC proteins assemble into prepores on the surface of membranes. Furthermore, our analyses reveal that SNTX-like MACPF/CDCs are distributed throughout eukaryotic life and play a broader, possibly immune-related function outside venom.
Genome-wide association studies (GWAS) of chronic lymphocytic leukemia (CLL) have shown that common genetic variation contributes to the heritable risk of CLL. To identify additional CLL ...susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1,739 individuals with CLL (cases) and 5,199 controls with validation in an additional 1,144 cases and 3,151 controls. A combined analysis identified new susceptibility loci mapping to 3q26.2 (rs10936599, P = 1.74 × 10(-9)), 4q26 (rs6858698, P = 3.07 × 10(-9)), 6q25.2 (IPCEF1, rs2236256, P = 1.50 × 10(-10)) and 7q31.33 (POT1, rs17246404, P = 3.40 × 10(-8)). Additionally, we identified a promising association at 5p15.33 (CLPTM1L, rs31490, P = 1.72 × 10(-7)) and validated recently reported putative associations at 5p15.33 (TERT, rs10069690, P = 1.12 × 10(-10)) and 8q22.3 (rs2511714, P = 2.90 × 10(-9)). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CLL.
The global lockdown to mitigate COVID-19 pandemic health risks has altered human interactions with nature. Here, we report immediate impacts of changes in human activities on wildlife and ...environmental threats during the early lockdown months of 2020, based on 877 qualitative reports and 332 quantitative assessments from 89 different studies. Hundreds of reports of unusual species observations from around the world suggest that animals quickly responded to the reductions in human presence. However, negative effects of lockdown on conservation also emerged, as confinement resulted in some park officials being unable to perform conservation, restoration and enforcement tasks, resulting in local increases in illegal activities such as hunting. Overall, there is a complex mixture of positive and negative effects of the pandemic lockdown on nature, all of which have the potential to lead to cascading responses which in turn impact wildlife and nature conservation. While the net effect of the lockdown will need to be assessed over years as data becomes available and persistent effects emerge, immediate responses were detected across the world. Thus, initial qualitative and quantitative data arising from this serendipitous global quasi-experimental perturbation highlights the dual role that humans play in threatening and protecting species and ecosystems. Pathways to favorably tilt this delicate balance include reducing impacts and increasing conservation effectiveness.
•The global COVID-19 lockdown has impacted nature and conservation programs.•Immediate effects are documented across the world and in all ecosystems.•Initial responses are biased towards established monitoring programs and networks.•Complex positive and negative effects were detected, some with cascading impacts.•Humans are important custodians of species and ecosystems.
Modified, agricultural landscapes are susceptible to damage by insect pests. Biological control of pests is typically successful once a control agent has established, but this depends on the agent’s ...capacity to co-evolve with the host. Theoretical studies have shown that different levels of genetic variation between the host and the control agent will lead to rapid evolution of resistance in the host. Although this has been reported in one instance, the underlying genetics have not been studied. To address this, we measured the genetic variation in New Zealand populations of the pasture pest, Argentine stem weevil (Listronotus bonariensis), which is controlled with declining effectiveness by a parasitoid wasp, Microctonus hyperodae. We constructed a draft reference genome of the weevil, collected samples from a geographical survey of 10 sites around New Zealand, and genotyped them using a modified genotyping-by-sequencing approach. New Zealand populations of Argentine stem weevil have high levels of heterozygosity and low population structure, consistent with a large effective population size and frequent gene flow. This implies that Argentine stem weevils were able to evolve more rapidly than their biocontrol agent, which reproduces asexually. These findings show that monitoring genetic diversity in biocontrol agents and their targets is critical for long-term success of biological control.
We describe the HadGEM2 family of climate configurations of the Met Office Unified Model, MetUM. The concept of a model "family" comprises a range of specific model configurations incorporating ...different levels of complexity but with a common physical framework. The HadGEM2 family of configurations includes atmosphere and ocean components, with and without a vertical extension to include a well-resolved stratosphere, and an Earth-System (ES) component which includes dynamic vegetation, ocean biology and atmospheric chemistry. The HadGEM2 physical model includes improvements designed to address specific systematic errors encountered in the previous climate configuration, HadGEM1, namely Northern Hemisphere continental temperature biases and tropical sea surface temperature biases and poor variability. Targeting these biases was crucial in order that the ES configuration could represent important biogeochemical climate feedbacks. Detailed descriptions and evaluations of particular HadGEM2 family members are included in a number of other publications, and the discussion here is limited to a summary of the overall performance using a set of model metrics which compare the way in which the various configurations simulate present-day climate and its variability.
The absence of a full pedigree can hinder selective breeding efforts. In honeybees, definitive maternity and especially paternity of queens is difficult to determine, even under managed mating ...schemes (e.g. using artificial insemination) due to the negative effects of single-drone mating on colony fitness. Here we genotyped 388 living queens from two beekeeping operations using Genotyping-by-Sequencing (GBS). We evaluate two methods to call single-nucleotide polymorphism (SNPs), Tassel 5 and Stacks, for their ability to supply SNPs that can recover known relationships. While Stacks discovered more SNPs (29,433), SNPs called with Tassel 5 (16,757) were found to be more accurate for the derivation of relationships. This methodology presents a low-cost genotyping approach and can be used to support commercial honeybee breeding schemes.
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