Invasive pulmonary aspergillosis is associated with adverse clinical outcomes in critically ill patients receiving veno-venous extracorporeal membrane oxygenation.

To identify the incidence, risk factors and impact on long-term survival of invasive pulmonary aspergillosis (IPA) and Aspergillus colonisation in patients receiving vv-extracorporeal membrane oxygenation (ECMO). A retrospective evaluation was performed of patients receiving vv-ECMO at a tertiary hospital in Manchester (UK) between January 2012 and December 2016. Data collected included epidemiological data, microbiological cultures, radiographic findings and outcomes. Cases were classified as proven IPA, putative IPA or Aspergillus colonisation according to a validated clinical algorithm. One hundred thirty-four patients were supported with vv-ECMO, median age of 45.5 years (range 16.4-73.4). Ten (7%) patients had putative IPA and nine (7%) had Aspergillus colonisation. Half of the patients with putative IPA lacked classical host risk factors for IPA. The median number of days on ECMO prior to Aspergillus isolation was 5 days. Immunosuppression and influenza A infection were significantly associated with developing IPA in a logistic regression model. Cox regression model demonstrates a three times greater hazard of death associated with IPA. Overall 6-month mortality rate was 38%. Patients with putative IPA and colonised patients had a 6-month mortality rate of 80 and 11%, respectively. Immunosuppression and influenza A infection are independent risk factors for IPA. IPA, but not Aspergillus colonisation, is associated with high long-term mortality in patients supported with vv-ECMO.

Crop Rotations and Poultry Litter Affect Dynamic Soil Chemical Properties and Soil Biota Long Term.

Dynamic soil chemical interactions with conservation agricultural practices and soil biota are largely unknown. Therefore, this study aims to quantify long-term (12-yr) impacts of cover crops, poultry litter, crop rotations, no-tillage, and their interactions on dynamic soil properties and to determine their relationships with nutrient cycling, crop yield, and soil biodiversity (soil microbial and earthworm communities). Main effects were 13 different cropping sequences of soybean [ (L.) Merr.], corn ( L.), and cotton ( L.) at the Research and Education Center at Milan, TN, and eight sequences of corn and soybean at the Middle Tennessee Research and Education Center, Spring Hill, TN. Sequences were repeated in 4-yr phases from 2002 to 2014. Split-block cover crop treatments consisted of winter wheat ( L.), hairy vetch ( Roth), poultry litter, and a fallow control. Soil C and nutrient fluxes were calculated at surface (0-5 cm) and subsurface (5-15 cm) layers during Years 0, 2, 4, 8, and 12. After 12 yr, weighted means (0-15 cm) of soil pH, P, K, Ca, Mg, total N, and C were greater under poultry litter-amended soils compared with cover crops ( < 0.05). In addition, continuous corn sequences resulted in greater soil K, N, and C concentrations than soybean-soybean-corn-corn rotations ( < 0.05). Poultry litter treatments were positively correlated with greater soil fertility levels, as well as higher crop yield and soil biodiversity. These results underscore linkages between manure additions and cropping sequences, within the nutrient cycling, soil health, and crop production continuum.

Extracorporeal membrane oxygenation: a radiologists' guide to who, what and where.

Extracorporeal membrane oxygenation (ECMO) is the short-term (days to weeks) support of patients with severe respiratory and/or cardiac failure. The use of these devices has been well established in paediatric and post-heart and lung transplantation patients; however, its use in patients with severe acute respiratory distress syndrome (ARDS) has gained acceptance as standard clinical practice over the past decade. The results of the CESAR trial (Conventional ventilation or ECMO for Severe Adult Respiratory failure) showed significant survival benefit for patients with ARDS undergoing ECMO. Substantial numbers of radiological examinations are performed in this patient group, prompting the need for general radiologists to understand the radiological appearances of these devices and associated complications. In this review, we highlight the uses, subtypes, physiology, normal appearances, and complications of ECMO. An example of the chronological radiographic images in the perioperative period demonstrates the importance of discriminating normal appearances associated with EMCO.

Reasons for palliative treatments in stage III non-small-cell lung cancer: what contribution is made by time-dependent changes in tumour or patient status?

INTRODUCTION: Stage iii lung cancer is the most advanced stage of lung cancer for which the potential of curative treatment is often discussed. However, a large proportion of patients are treated with palliative intent. An understanding of the time-dependent and -independent factors contributing to the choice of palliative-intent treatment is needed to help optimize patient outcomes. METHODS: This retrospective cohort study of patients with stage iii non-small-cell lung cancer (nsclc) newly diagnosed between 1 January 2008 and 31 December 2012 at the Cancer Centre of Southeastern Ontario collected data including patient demographics, clinical characteristics, tumour characteristics, treatment, and outcomes. RESULTS: Of 237 patients with stage iii nsclc included in the study, 130 were not treated with radical or curative intent (55%). Major time-independent variables cited for palliative-intent treatment included extreme age (5%), comorbidity (27%), patient choice (5%), and poor lung function (5%). Time-dependent variables included tumour progression on imaging (15%), weight loss (33%), performance status (32%), and the occurrence of a major complication such as hemoptysis, lung collapse, or pulmonary embolism (7%). A significant number of patients (20%) experienced a decline in performance status-to 2, 3, or 4 from 0 or 1-over the course of the diagnostic journey, and 12% experienced a transition from no weight loss to more than 10% weight loss. CONCLUSIONS: A significant proportion of patients receive palliative therapy for stage iii nsclc because of changes that occur during the diagnostic journey. Shortening or altering that pathway to avoid tumour growth or patient deterioration during care could allow for more patients to be treated with curative intent.

Causes of death and subsequent treatment after initial radical or palliative therapy of stage III non-small-cell lung cancer.

INTRODUCTION: Stage iii lung cancer is the most advanced stage of lung cancer for which radical (potentially curative) treatment is often discussed. Understanding the reasons for mortality and subsequent treatments in patients with stage iii non-small-cell lung cancer (nsclc) is important. METHODS: This retrospective cohort study extracted demographic, clinical, treatment, and outcomes data for patients with newly diagnosed stage iii nsclc diagnosed between 1 January 2008 and 31 December 2012 at a single institution. RESULTS: The study included 237 patients with stage iii nsclc, 130 of whom were not treated with radical or curative intent (55%). Median survival in the entire cohort was 14 months from diagnosis. For patients treated with radical-intent therapy, causes of death varied with the time period. The hazard rate for death was approximately 2.8 per 100 person-months of follow-up over the entire disease course and was highest between 6 months and 24 months. Over the entire time period, local causes accounted for 29% of deaths; systemic non-central nervous system metastases, for 25%; and brain metastases, for 14%. For patients treated with palliative intent, the overwhelming cause of death was local disease complications or progression (56% of deaths). Only 12% of patients in the palliative treatment group who progressed received subsequent chemotherapy; 23% of patients in the radical group who progressed received palliative chemotherapy. The most frequent subsequent treatment in both groups was radiation therapy. CONCLUSIONS: The eventual life-ending event in stage iii nsclc varied for the patients who qualified for, and were treated with, radical or curative intent and for the patients who received palliative-intent therapy. Utilization of systemic chemotherapy in patients not fit for radical therapy is low.

Combined effects of endogenous sex hormone levels and mammographic density on postmenopausal breast cancer risk: results from the Breakthrough Generations Study.

BACKGROUND: Mammographic density and sex hormone levels are strong risk factors for breast cancer, but it is unclear whether they represent the same aetiological entity or are independent risk factors. METHODS: Within the Breakthrough Generations Study cohort, we conducted a case-control study of 265 postmenopausal breast cancer cases and 343 controls with prediagnostic mammograms and blood samples. Plasma was assayed for oestradiol, testosterone and sex hormone-binding globulin (SHBG) concentrations and mammographic density assessed by Cumulus. RESULTS: Oestradiol and testosterone were negatively and SHBG positively associated with percentage density and absolute dense area, but after adjusting for body mass index the associations remained significant only for SHBG. Breast cancer risk was independently and significantly positively associated with percentage density (P=0.002), oestradiol (P=0.002) and testosterone (P=0.007) levels. Women in the highest tertile of both density and sex hormone level were at greatest risk, with an odds ratio of 7.81 (95% confidence interval (CI): 2.89-21.1) for oestradiol and 4.57 (95% CI: 1.75-11.9) for testosterone and high density compared with those who were in the lowest tertiles. The cumulative risk of breast cancer in the highest oestradiol and density tertiles, representing 8% of controls, was estimated as 12.8% at ages 50-69 years and 19.4% at ages 20-79 years, and in the lowest tertiles was 1.7% and 4.3%, respectively. Associations of breast cancer risk with tertiles of mammographic dense area were less strong than for percentage density. CONCLUSIONS: Endogenous sex hormone levels and mammographic density are independent risk factors for postmenopausal breast cancer, which in combination can identify women who might benefit from increased frequency of screening and chemoprophylaxis.

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.

BACKGROUND: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. METHODS: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. RESULTS: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. CONCLUSION: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.

Cytosine-based nucleoside analogs are selectively lethal to DNA mismatch repair-deficient tumour cells by enhancing levels of intracellular oxidative stress.

BACKGROUND: DNA mismatch repair deficiency is present in a significant proportion of a number of solid tumours and is associated with distinct clinical behaviour. METHODS: To identify the therapeutic agents that might show selectivity for mismatch repair-deficient tumour cells, we screened a pair of isogenic MLH1-deficient and MLH1-proficient tumour cell lines with a library of clinically used drugs. To test the generality of hits in the screen, selective agents were retested in cells deficient in the MSH2 mismatch repair gene. RESULTS: We identified cytarabine and other related cytosine-based nucleoside analogues as being selectively toxic to MLH1 and MSH2-deficient tumour cells. The selective cytotoxicity we observed was likely caused by increased levels of cellular oxidative stress, as it could be abrogated by antioxidants. CONCLUSION: We propose that cytarabine-based chemotherapy regimens may represent a tumour-selective treatment strategy for mismatch repair-deficient cancers.

Male breast cancer, age and sex chromosome aneuploidy.

BACKGROUND: In cultured, dividing transformed T lymphocytes and in dividing bone marrow cells from normal men and those with a haematological malignancy, sex chromosome aneuploidy has been found to increase in prevalence and degree with age. This has rarely been investigated in non-dividing uncultured blood samples. The loss and gain of the X chromosome in dividing transformed lymphocytes in women with age is much more frequent than that of the Y chromosome in males. However, paradoxically X chromosome aneuploidy is rarely seen in the dividing cells of bone marrow of females. METHODS: In blood samples from 565 men with breast cancer and 54 control men from the England and Wales general population, 80 cell nuclei per sample were scored for presence of X and Y chromosomes using fluorescent centromeric probes. RESULTS: Sex chromosome aneuploidy, largely Y chromosome loss, was present in 63% of cases and 57% of controls, with the prevalence and degree of aneuploidy increasingly sharply and highly significantly with age. At ages 65-80 years, 71% of cases and 85% of controls showed aneuploidy and 15% and 25%, respectively, had ≥ 10% of cells aneuploid. Allowing for age, aneuploidy was less prevalent (P=0.03) in cases than controls. CONCLUSION: Sex chromosome aneuploidy in non-dividing nuclei of peripheral blood cells is frequent in adult men, the prevalence and degree increasing sharply with age. The possible relation of sex chromosome aneuploidy to breast cancer risk in men, and to cancer risk generally, needs further investigation, ideally in cohort studies.

Microarray and histopathological analysis of tumours: the future and the past?

The excitement surrounding the development of DNA microarray analysis and proteomics has raised questions about the role of these techniques in clinical practice and patient management. But how did the traditional methods of cancer diagnosis and prognosis develop, and how can high-throughput techniques contribute?

A contravention of Ohno's law in mice.

The chloride channel gene, CLCN4, has been previously mapped to the X chromosome in humans. We isolated a cDNA clone for mouse Clcn4 and used this to map the gene in an interspecific backcross. This revealed the surprising finding that the gene maps to the X chromosome in Mus spretus but to chromosome 7 in C57BL/6 mice. This is the first example of a gene that contravenes Ohno's law--it is a gene unique to the X chromosome in one eutherian species but autosomal in another. The consequence of this chromosomal rearrangement is that the gene is lost by mendelian segregation in a subset of the male progeny of a (C57BL/6 x Mus spretus) x Mus spretus backcross.

Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation.

Germline mutation of the BRCA2 gene carries a high risk of developing breast cancer. To study the function of this gene, we generated a mutation in Brca2 in mice. Unlike other mutations in the Brca2 gene, which are lethal early in embryogenesis when homozygous, some of our homozygous mutant mice survive to adulthood. These animals have a wide range of defects, including small size, improper differentiation of tissues, absence of germ cells and the development of lethal thymic lymphomas. Fibroblasts cultured from BrcaZ-/-embryos have a defect in proliferation that may be mediated by over-expression of p53 and p21Waf1/CIP1. We show that Brca2 is required for efficient DNA repair, and our results suggest that loss of the p53 checkpoint may be essential for tumour progression triggered by mutations in BRCA2.

BRCA2 mutations in primary breast and ovarian cancers.

The second hereditary breast cancer gene, BRCA2, was recently isolated. Germline mutations of this gene predispose carriers to breast cancer, and, to a lesser extent, ovarian cancer. Loss of heterozygosity (LOH) at the BRCA2 locus has been observed in 30-40% of sporadic breast and ovarian tumours, implying that BRCA2 may act as a tumour suppressor gene in a proportion of sporadic cases. To define the role of BRCA2 in sporadic breast and ovarian cancer, we screened the entire gene for mutations using a combination of techniques in 70 primary breast carcinomas and in 55 primary epithelial ovarian carcinomas. Our analysis revealed alterations in 2/70 breast tumours and none of the ovarian carcinomas. One alteration found in the breast cancers was a 2-basepair (bp) deletion (4710delAG) which was subsequently shown to be a germline mutation, the other was a somatic missense mutation (Asp3095Glu) of unknown significance. Our results suggest that BRCA2 is a very infrequent target for somatic inactivation in breast and ovarian carcinomas, similar to the results obtained for BRCA1.

Characterization of nutrient runoff from perennial and annual forages following broiler litter application.

Information on how forage species influence sediment and nutrient transport in runoff is required for limiting non-point source pollution from broiler litter applications. In this study, we examined the effects of five forage species (eastern gamagrass [Tripsacum dactyloides (L.) L.], Kernza [Thinopyrum intermedium (Host) Barkworth & D.R. Dewey], silphium [Silphium integrifolium Michx.], switchgrass [Panicum virgatum L.], and winter wheat [Triticum aestivum L.]) on runoff nutrient losses from broiler litter-amended (5.6 Mg ha-1 ) and non-amended plots (control) following four simulated rainfall (5 cm h-1 ) events that were applied to these plots in late spring and early fall of 2019 and 2021. Runoff collected for 30 min was analyzed for total suspended solids (TSS) and nutrients (total organic carbon [TOC], soluble reactive phosphorus [SRP], total dissolved phosphorus [TDP], total phosphorus [TP], total nitrogen [TN], ammonium-nitrogen [NH4 -N], and nitrate-nitrogen [NO3 -N]). Total sediment and nutrient losses increased 5- to 19-fold following litter application for all species, which reduced to background levels during fall rainfall events. Across the four simulated rainfall events, switchgrass resulted in lower cumulative losses of TSS, TOC, SRP, TDP, TP, and NO3 -N than gamagrass and wheat but did not differ from Kernza and silphium for litter-amended treatments. The performance of newly introduced perennial crops (Kernza and silphium) was similar or better than that of gamagrass in terms of cumulative runoff sediment and nutrient losses. Results show high potential for Kernza, silphium, and switchgrass to improve water quality when used in forage-vegetative filter strip systems.

Multivariate evaluation of watershed health based on longitudinal pasture management.

Watershed and pasture health is a transdisciplinary concern and crucial to promoting sustainable practices. The aim of this study is to identify effective systems-level conservation pasture management practices in a longitudinal study following 14 years of consistent management by i) teasing apart complex relationships between multivariate water and soil quality using principal component analysis (PCA); and ii) identifying interactions among variables that contribute most to watershed health within catchments using partial least squares-path modeling (PLS-PM) based on five treatments: hayed (H), continuously grazed (CG), rotationally grazed (R), rotationally grazed with an unfertilized buffer strip (RB), and rotationally grazed with an unfertilized fenced riparian buffer (RBR). Over 14 years, H and RBR systems had greater watershed health based on runoff water quality parameters. Therefore, management systems that keep forage heights >10-cm, have less frequent vegetative removal, and riparian filter strips promote watershed health. Of the over 20 runoff variables measured over 14 study years, only electrical conductivity and annual total suspended solid loads constructed a significant water quality PLS-PM model. Water quality was positively influenced by pasture management and precipitation, with long-term pasture management driving runoff parameters and water quality. Overall, animal grazing days was not only related to grazing intensity, but to animal manure inputs and soil compaction, and adversely related to watershed health. Study results denote that best management strategies such as rotational grazing and riparian buffer strips prevent pasture system degradation and maintain carrying capacity while reducing anthropogenic pressure on soil and water systems.