Making Decisions for Hospitalized Older Adults: Ethical Factors Considered by Family Surrogates

Background Hospitalized older adults frequently have impaired cognition and must rely on surrogates to make major medical decisions. Ethical standards for surrogate decision making are well delineated, but little is known about what factors surrogates actually consider when making decisions. Objectives To determine factors surrogate decision makers consider when making major medical decisions for hospitalized older adults, and whether or not they adhere to established ethical standards. Design Semi-structured interview study of the experience and process of decision making. Setting A public safety-net hospital and a tertiary referral hospital in a large city in the Midwest. Participants Thirty-five surrogates with a recent decision making experience for an inpatient age 65 and older. Measurements Key factors surrogates considered when making decisions. Interview transcripts were coded and analyzed using the grounded theory method of qualitative analysis. Results Surrogates considered patient-centered factors and surrogate-centered factors. Patient-centered factors included: 1) respecting the patient’s input, (2) using past knowledge of patient to infer the patient’s wishes, and (3) considering what is in the patient’s best interests. Some surrogates expressed a desire for more information about the patient’s prior wishes. Surrogate-centered factors included 1) Surrogate’s wishes as a guide, (2) The surrogate’s religious beliefs and/or spirituality, (3) The surrogate’s interests, (4) Family consensus and (5) Obligation and guilt. Conclusion These data show that surrogate decision making is more complex than the standard ethical models, which are limited to patient autonomy and beneficence. Because surrogates also imagine what they would want under the circumstances and consider their own needs and preferences, models of surrogate decision making must account for these additional considerations. Surrogates’ desire for more information about patient preferences suggests a need for greater advance care planning

A comparison of grassland vegetation from three agri-environment conservation measures

peer-reviewedSemi-natural grassland habitats have declined significantly throughout Europe. To halt the decline, grassland conservation measures have been included in most European agri-environment schemes. This is the first study to compare the botanical composition of grassland habitats managed under the Irish Agri-Environment Options Scheme (AEOS). Sixty fields on drystock pastoral farms in receipt of agri-environment payments for grassland conservation were surveyed, with 20 fields being enrolled in each of the following AEOS options: Traditional Hay Meadow (THM), Species-Rich Grassland (SRG) and Natura 2000 species-rich grassland (Natura). The vegetation quality of sites enrolled in the Natura measure was higher than the quality of those enrolled in the THM and SRG measures. Natura sites had the greatest species richness, with a mean >40 species per site, which included approximately 17 species indicative of high botanical quality. Traditional Hay Meadows sites had the lowest species richness (mean: 29 species per site) and were dominated by species associated with improved grassland. Some THM sites had good levels of botanical richness and were similar in composition to Natura sites, with some Natura sites having lower vegetation quality, more similar to that of THM sites. Species-Rich Grassland had botanical richness that was intermediate between THM and Natura sites. A thorough assessment of the effectiveness of these measures was confounded by a lack of quantitative objectives for the target community composition to be attained. We discuss limitations and potential opportunities regarding the design, targeting, implementation and cost-effectiveness of these agri-environment measures

Effects of vancomycin and ceftazidime on biofilm formation in Elizabethkingia

Elizabethkingia infections are associated with high mortality rates which is due in part to the antibiotic resistance expressed by all Gram-negative Elizabethkingia species. Biofilm formation by Elizabethkingia provides the bacteria with further defense against the action of antibiotics. Vancomycin is an unusual drug used to treat Elizabethkingia infections, but its use is controversial, since it is normally only used to treat Gram-positive infections. Our study tests the effect of vancomycin and ceftazidime on biofilm formation for all known species of Elizabethkingia. Biofilm formation was measured at 24, 48, and 72-hour timepoints using a crystal violet biofilm assay. Biofilm formation occurred in all positive control wells for all three timepoints for all species. The biofilms of Elizabethkingia meningoseptica in the presence of subinhibitory vancomycin concentrations, and Elizabethkingia ursingii in the presence of inhibitory ceftazidime concentrations, were reduced compared to the controls. This suggests that both drugs can inhibit biofilm formation in a species-specific manner.Howard Hughes Medical Institute Science Education ProgramBiochemistry and Molecular Biolog

Methods of enhancing botanical diversity within field margins of intensively managed grassland: a 7-year field experiment

P>1. Increased intensification in agricultural grasslands has led to well-documented declines in the associated flora. Manipulation of field margins for biodiversity enhancement in arable systems has been extensively investigated. However, there is a paucity of corresponding long-term research within intensively managed grasslands. 2. We investigated a combination of establishment and management methods to enhance botanical diversity of newly established field margins in intensively managed grasslands. Three methods of field margin establishment were investigated including fencing, natural regeneration by rotavation, or seeding with a wildflower mixture. Subsequent sward management by either grazing or mowing was tested at three margin widths. Success of establishment was addressed in terms of persistence of species richness, plant community composition and incidence of noxious weeds. 3. Seeding with a wildflower mixture was the most successful establishment method to enhance plant species richness and this effect persisted throughout the 7 years of the experiment ( = 16 center dot 4 +/- 0 center dot 43 SE plant species richness per 1 x 3 m2 quadrat). Mown ( = 6 center dot 01 +/- 0 center dot 30 SE) and rotavated ( = 9 center dot 7 +/- 0 center dot 34 SE) treatments contained significantly fewer plant species; grazed controls contained 9 center dot 83 +/- 0 center dot 24 species. 4. Grazing led to a significant, but modest increase in species richness in fenced and rotavated plots compared to the mowing treatment, but had no effect in seeded plots. Grazing also led to an increased frequency and cover of competitive grasses in the seeded treatment. 5. Although margin width was not found to significantly influence species richness, there was increased herb cover and reduced abundance of noxious weeds in the wider seeded margins. 6.Synthesis and applications. The choice of establishment method and subsequent management of grassland field margins significantly affected their conservation value. The botanical diversity of margins within intensively managed pasture can be enhanced by sowing wildflower seed mixtures. This diversity can be maintained over time through appropriate management, i.e. either the reduction of high grazing pressure by seasonal fencing, or annual mowing. Management approaches that involve minimal change are currently adopted in many agri-environment schemes (such as fencing and/or the cessation of nutrient inputs) but did not produce swards of conservation value in this study

Fatty acid-induced mitochondrial uncoupling in adipocytes as a key protective factor against insulin resistance and beta cell dysfunction: a new concept in the pathogenesis of obesity-associated type 2 diabetes mellitus

Type 2 diabetes is associated with excessive food intake and a sedentary lifestyle. Local inflammation of white adipose tissue induces cytokine-mediated insulin resistance of adipocytes. This results in enhanced lipolysis within these cells. The fatty acids that are released into the cytosol can be removed by mitochondrial β-oxidation. The flux through this pathway is normally limited by the rate of ADP supply, which in turn is determined by the metabolic activity of the adipocyte. It is expected that the latter does not adapt to an increased rate of lipolysis. We propose that elevated fatty acid concentrations in the cytosol of adipocytes induce mitochondrial uncoupling and thereby allow mitochondria to remove much larger amounts of fatty acids. By this, release of fatty acids out of adipocytes into the circulation is prevented. When the rate of fatty acid release into the cytosol exceeds the β-oxidation capacity, cytosolic fatty acid concentrations increase and induce mitochondrial toxicity. This results in a decrease in β-oxidation capacity and the entry of fatty acids into the circulation. Unless these released fatty acids are removed by mitochondrial oxidation in active muscles, these fatty acids result in ectopic triacylglycerol deposits, induction of insulin resistance, beta cell damage and diabetes. Thiazolidinediones improve mitochondrial function within adipocytes and may in this way alleviate the burden imposed by the excessive fat accumulation associated with the metabolic syndrome. Thus, the number and activity of mitochondria within adipocytes contribute to the threshold at which fatty acids are released into the circulation, leading to insulin resistance and type 2 diabetes

Absence of an adipogenic effect of rosiglitazone on mature 3T3-L1 adipocytes: increase of lipid catabolism and reduction of adipokine expression

Aims/hypothesis: The thiazolidinedione (TZD) rosiglitazone is a peroxisome proliferator-activated receptor-¿ agonist that induces adipocyte differentiation and, hence, lipid accumulation. This is in apparent contrast to the long-term glucose-lowering, insulin-sensitising effect of rosiglitazone. We tested whether the action of rosiglitazone involves specific effects on mature adipocytes, which are different from those on preadipocytes. Materials and methods: Differentiated mature 3T3-L1 adipocytes were used as an in vitro model. Transcriptomics, proteomics and assays of metabolism were applied to assess the effect of rosiglitazone in different insulin and glucose conditions. Results: Rosiglitazone does not induce an increase, but rather a decrease in the lipid content of mature adipocytes. Analysis of transcriptome data, confirmed by quantitative RT-PCR and measurements of lipolysis, indicates that an altered energy metabolism may underlie this change. The pathway analysis shows a consistent picture dominated by lipid catabolism. In addition, we confirmed at both mRNA level and protein level that rosiglitazone represses adipokine expression and production, except for genes encoding adiponectin and apolipoprotein E. Moreover, transcriptome changes indicate that a general repression of genes encoding secreted proteins occurs. Conclusions/ interpretation: Our findings suggest that the change of adiposity as seen in vivo reflects a shift in balance between the different effects of TZDs on preadipocytes and on mature adipocytes, while the changes in circulating adipokine levels primarily result from an effect on mature adipocyte

Thymidine Kinase 2 Deficiency-Induced Mitochondrial DNA Depletion Causes Abnormal Development of Adipose Tissues and Adipokine Levels in Mice

Mammal adipose tissues require mitochondrial activity for proper development and differentiation. The components of the mitochondrial respiratory chain/oxidative phosphorylation system (OXPHOS) are encoded by both mitochondrial and nuclear genomes. The maintenance of mitochondrial DNA (mtDNA) is a key element for a functional mitochondrial oxidative activity in mammalian cells. To ascertain the role of mtDNA levels in adipose tissue, we have analyzed the alterations in white (WAT) and brown (BAT) adipose tissues in thymidine kinase 2 (Tk2) H126N knockin mice, a model of TK2 deficiency-induced mtDNA depletion. We observed respectively severe and moderate mtDNA depletion in TK2-deficient BAT and WAT, showing both tissues moderate hypotrophy and reduced fat accumulation. Electron microscopy revealed altered mitochondrial morphology in brown but not in white adipocytes from TK2-deficient mice. Although significant reduction in mtDNA-encoded transcripts was observed both in WAT and BAT, protein levels from distinct OXPHOS complexes were significantly reduced only in TK2-deficient BAT. Accordingly, the activity of cytochrome c oxidase was significantly lowered only in BAT from TK2-deficient mice. The analysis of transcripts encoding up to fourteen components of specific adipose tissue functions revealed that, in both TK2-deficient WAT and BAT, there was a consistent reduction of thermogenesis related gene expression and a severe reduction in leptin mRNA. Reduced levels of resistin mRNA were found in BAT from TK2-deficient mice. Analysis of serum indicated a dramatic reduction in circulating levels of leptin and resistin. In summary, our present study establishes that mtDNA depletion leads to a moderate impairment in mitochondrial respiratory function, especially in BAT, causes substantial alterations in WAT and BAT development, and has a profound impact in the endocrine properties of adipose tissues

Efficacy of host cell serine protease inhibitor MM3122 against SARS-CoV-2 for treatment and prevention of COVID-19

We developed a novel class of peptidomimetic inhibitors targeting several host cell human serine proteases, including transmembrane protease serine 2 (TMPRSS2), matriptase, and hepsin. TMPRSS2 is a membrane-associated protease that is highly expressed in the upper and lower respiratory tracts and is utilized by SARS-CoV-2 and other viruses to proteolytically process their glycoproteins, enabling host cell entry, replication, and dissemination of new virus particles. We have previously shown that compound MM3122 exhibited subnanomolar potency against all three proteases and displayed potent antiviral effects against SARS-CoV-2 in a cell viability assay. Herein, we demonstrate that MM3122 potently inhibits viral replication in human lung epithelial cells and is also effective against the EG.5.1 variant of SARS-CoV-2. Furthermore, we evaluated MM3122 in a mouse model of COVID-19 and demonstrated that MM3122 administered intraperitoneally (IP) before (prophylactic) or after (therapeutic) SARS-CoV-2 infection had significant protective effects against weight loss and lung congestion and reduced pathology. Amelioration of COVID-19 disease was associated with a reduction in proinflammatory cytokine and chemokine production after SARS-CoV-2 infection. Prophylactic, but not therapeutic, administration of MM3122 also reduced virus titers in the lungs of SARS-CoV-2-infected mice. Therefore, MM3122 is a promising lead candidate small-molecule drug for the treatment and prevention of infections caused by SARS-CoV-2 and other coronaviruses

Sward composition and soil moisture conditions affect nitrous oxide emissions and soil nitrogen dynamics following urea-nitrogen application

peer-reviewedIncreased emissions of N2O, a potent greenhouse gas (GHG), from agricultural soils is a major concern for the sustainability of grassland agriculture. Emissions of N2O are closely associated with the rates and forms of N fertilisers applied as well as prevailing weather and soil conditions. Evidence suggests that multispecies swards require less fertiliser N input, and may cycle N differently, thus reducing N loss to the environment. This study used a restricted simplex-centroid experimental design to investigate N2O emissions and soil N cycling following application of urea-N (40 kg N ha−1) to eight experimental swards (7.8 m2) with differing proportions of three plant functional groups (grass, legume, herb) represented by perennial ryegrass (PRG, Lolium perenne), white clover (WC, Trifolium repens) and ribwort plantain (PLAN, Plantago lanceolata), respectively. Swards were maintained under two contrasting soil moisture conditions to examine the balance between nitrification and denitrification. Two N2O peaks coincided with fertiliser application and heavy rainfall events; 13.4 and 17.7 g N2O-N ha−1 day−1 (ambient soil moisture) and 39.8 and 86.9 g N2O-N ha−1 day−1 (wet soil moisture). Overall, cumulative N2O emissions post-fertiliser application were higher under wet soil conditions. Increasing legume (WC) proportions from 0% to 60% in multispecies swards resulted in model predicted N2O emissions increasing from 22.3 to 96.2 g N2O-N ha−1 (ambient soil conditions) and from 59.0 to 219.3 g N2O-N ha−1 (wet soil conditions), after a uniform N application rate. Soil N dynamics support denitrification as the dominant source of N2O especially under wet soil conditions. Significant interactions of PRG or WC with PLAN on soil mineral N concentrations indicated that multispecies swards containing PLAN potentially inhibit nitrification and could be a useful mitigation strategy for N loss to the environment from grassland agriculture.Teagas