When silage is exposed to air on opening the silo, or after its removal from the silo, fermentation acids and other substrates are oxidized by aerobic bacteria, yeasts and moulds. The aerobic ...stability of silage is a key factor in ensuring that silage provides well‐preserved nutrients to the animal with minimal amounts of mould spores and toxins. In this paper, key findings and recent developments are reviewed, and findings of recent research are integrated in terms of four themes: (i) the most significant biochemical and microbiological factors, (ii) physical and management factors, (iii) type of additive and (iv) silo sealing. The development of yeasts and moulds during plant growth, and during field wilting or storage, and the concentration of undissociated acetic acid in silage are important microbiological and biochemical factors affecting aerobic stability. Silage density and porosity are key physical factors that affect the rate of ingress of oxygen into the silage mass during the feed‐out period. A target for potential silage aerobic stability is 7 d including time in the feed trough. To achieve this target, speed of harvest should be coordinated with packing tractor weight to achieve a minimum silage density by the time of feed‐out of 210 kg DM m−3, maximum proportional porosity of 0·4 and a rate of silage removal, which matches or exceeds the depth of air penetration into the silo. The use of additives to increase aerobic stability is advisable when there is the risk of these objectives not being met. Novel microbial approaches to solving the problem of silage aerobic deterioration are needed.
Purpose
To critically analyze physician-related variability in end-of-life decision-making in intensive care.
Methods
An ethical analysis of factors contributing to physician-related variability in ...end-of-life decision-making.
Results
There is variability in decision-making about life support, both within and between intensive care units. Physician age, race, religion, attitude to risk, and personality factors have been associated with decisions to provide or limit life-sustaining treatment, though it is unclear how much these factors affect patient outcome. Inconsistency in decision-making appears worryingly arbitrary, and may mean that patients’ values are sometimes being ignored or overridden. However, physician influence on decisions may also sometimes be appropriate and unavoidable, particularly where patient values are unclear.
Conclusions
We argue that, although physician-related variability in end-of-life care can never be eliminated entirely, it is potentially ethically problematic. We outline four potential strategies for reducing the “roster lottery.”
The anti-resorptive properties of bisphosphonates have been explored to manage several conditions that traditionally have required a surgical solution. In osteonecrosis, their use is predicated on ...the principle that bone collapse occurs during the revascularisation phase of the disease. If the associated resorptive activity were modulated, the resultant preserved joint architecture may improve clinical outcome and reduce the need for joint replacement. Pre-clinical and small-scale clinical studies have given non-conclusive support for this principle. Adequately powered clinical trials with relevant long-term endpoints are still required to firmly clarify the clinical efficacy of this treatment. Several clinical studies have shown that bisphosphonates can reduce periprosthetic bone loss and, in some situations, enhance implant fixation in the early period after joint replacement. This may be advantageous in settings where osseointegration is problematic. However, the ultimate goals of their use in joint replacement has been to reduce the incidence of late periprosthetic inflammatory osteolysis, the main cause of prosthesis failure. Population-based observational studies have associated bisphosphonate use with a lower incidence of revision surgery, supported by pre-clinical data. However, clinical trials have, to date, failed to demonstrate any efficacy for the human disease. The timing of bisphosphonate administration for secondary prevention after acute osteoporotic fracture has been subject to extensive investigation, with pre-clinical studies showing increased callus formation but decreased remodelling and no effect on the restoration of mechanical integrity of bone. Meta-analysis of clinical trial data indicates that early administration of bisphosphonate after acute fracture does not adversely affect fracture union, pain or functional outcomes. Finally, bisphosphonates have also been explored as a treatment for complex regional pain syndrome type-I. A recent meta-analysis has shown a beneficial effect on visual analogue scale pain scores, but an increase in mild adverse events.
•In osteonecrosis, bisphosphonates may preserve bone architecture and reduce the incidence of secondary osteoarthritis· In joint replacement, bisphosphonates reduce bone loss and can enhance early osseointegration.•A causal role in reducing implant wear-induced osteolysis and implant loosening has not been shown.•Bisphosphonate initiation after acute fracture does not adversely affect union rate, pain or functional outcomes.•Bisphosphonate use can improve pain scores in complex regional pain syndrome type-I.
The deformation around a 500-nm deep Berkovich indent in a large grained Fe sample has been studied using high resolution electron back scatter diffraction (EBSD). EBSD patterns were obtained in a ...two-dimensional map around the indent on the free surface. A cross-correlation-based analysis of small shifts in many sub-regions of the EBSD patterns was used to determine the variation of elastic strain and lattice rotations across the map at a sensitivity of ∼±10
−4
. Elastic strains were smaller than lattice rotations, with radial strains found to be compressive and hoop strains tensile as expected. Several analyses based on Nye's dislocation tensor were used to estimate the distribution of geometrically necessary dislocations (GNDs) around the indent. The results obtained using different assumed dislocation geometries, optimisation routines and different contributions from the measured lattice rotation and strain fields are compared. Our favoured approach is to seek a combination of GND types which support the six measurable (of a possible nine) gradients of the lattice rotations after correction for the 10 measurable elastic strain gradients, and minimise the total GND line energy using an L
1
optimisation method. A lower bound estimate for the noise on the GND density determination is ∼±10
12
m
−2
for a 200-nm step size, and near the indent densities as high as 10
15
m
−2
were measured. For comparison, a Hough-based analysis of the EBSD patterns has a much higher noise level of ∼±10
14
m
−2
for the GND density.
Highlights of progress in the production of silage over the past 50 years include the introduction of improved hybrids of maize (Zea mays L.), the forage harvester, the big baler, polyethylene ...covering for horizontal silos, stretch‐wrap film for bales and novel additives designed to improve the fermentation and aerobic stability of silage. The key biochemical pathways in the silage fermentation have been described together with the effects of microbial and chemical additives on fermentation and aerobic stability during the feed‐out phase. The significance of oxygen and water in silage fermentation has been quantified and efficacy of covering silos has been established, with recent progress in the development of oxygen barrier film. Future perspectives include improving food safety and animal health by increasing the hygienic quality of silage, reducing the environmental impact of silage by decreasing loss of nitrogen to soil and atmosphere, reducing methanogenesis in the rumen and increasing methane yield from silage as biofuel, and the use of silages as feedstocks for multiple end uses in biorefineries.
Silage may contain several agents that are potentially hazardous to animal health, the safety of milk or other animal food products, or both. This paper reviews published literature about microbial ...hazards, plant toxins, and chemical hazards. Microbial hazards include Clostridium botulinum, Bacillus cereus, Listeria monocytogenes, Shiga toxin-producing Escherichia coli, Mycobacterium bovis, and various mold species. High concentrations of C. botulinum in silage have been associated with cattle botulism. A high initial concentration of C. botulinum spores in forage in combination with poor silage fermentation conditions can promote the growth of C. botulinum in silage. The elevated pH level that is generally associated with aerobic deterioration of silage is a major factor influencing concentrations of L. monocytogenes, Shiga toxin-producing E. coli, and molds in silage and may also encourage survival and growth of M. bovis, the bacterium that causes bovine tuberculosis. Soil is a major source of B. cereus spores in silage; growth of this bacterium in silage appears to be limited. Hazards from plant toxins include pyrrolizidine, tropane and tropolone alkaloids, phytoestrogens, prussic acid, and mimosine, compounds that exist naturally in certain plant species that may contaminate forages at harvesting. Another group of toxins belonging to this category are ergot alkaloids, which are produced by endophytic fungal species in forages such as tall fescue grass, sorghum, and ryegrass. Varying effects of ensiling on the degradation of these plant toxins have been reported. Chemical hazards include nitrate, nitrite, and toxic oxide gases of nitrogen produced from nitrate and high levels of butyric acid, biogenic amines, and ammonia. Chemical and microbiological hazards are associated with poorly fermented silages, which can be avoided by using proper silage-making practices and creating conditions that promote a rapid and sufficient reduction of the silage pH and prevent aerobic deterioration.
As bona fide p53 transcriptional targets, miR-34 microRNAs (miRNAs) exhibit frequent alterations in many human tumor types and elicit multiple p53 downstream effects upon overexpression. ...Unexpectedly, miR-34 deletion alone fails to impair multiple p53-mediated tumor suppressor effects in mice, possibly due to the considerable redundancy in the p53 pathway. Here, we demonstrate that miR-34a represses HDM4, a potent negative regulator of p53, creating a positive feedback loop acting on p53. In a Kras-induced mouse lung cancer model, miR-34a deficiency alone does not exhibit a strong oncogenic effect. However, miR-34a deficiency strongly promotes tumorigenesis when p53 is haploinsufficient, suggesting that the defective p53-miR-34 feedback loop can enhance oncogenesis in a specific context. The importance of the p53/miR-34/HDM4 feedback loop is further confirmed by an inverse correlation between miR-34 and full-length HDM4 in human lung adenocarcinomas. In addition, human lung adenocarcinomas generate an elevated level of a short HDM4 isoform through alternative polyadenylation. This short HDM4 isoform lacks miR-34-binding sites in the 3' untranslated region (UTR), thereby evading miR-34 regulation to disable the p53-miR-34 positive feedback. Taken together, our results elucidated the intricate cross-talk between p53 and miR-34 miRNAs and revealed an important tumor suppressor effect generated by this positive feedback loop.
Patient-reported outcome measures (PROMs) are validated questionnaires that are completed by patients. Arthroplasty registries vary in PROM collection and use. Current information about registry ...collection and use of PROMs is important to help improve methods of PROM data analysis, reporting, comparison, and use toward improving clinical practice.
To characterize PROM collection and use by registries, we asked: (1) What is the current practice of PROM collection by arthroplasty registries that are current or former members of the International Society of Arthroplasty Registries, and are there sufficient similarities in PROM collection between registries to enable useful international comparisons that could inform the improvement of arthroplasty care? (2) How do registries differ in PROM administration and demographic, clinical, and comorbidity index variables collected for case-mix adjustment in data analysis and reporting? (3) What quality assurance methods are used for PROMs, and how are PROM results reported and used by registries? (4) What recommendations to arthroplasty registries may improve PROM reporting and facilitate international comparisons?
An electronic survey was developed with questions about registry structure and collection, analysis, reporting, and use of PROM data and distributed to directors or senior administrators of 39 arthroplasty registries that were current or former members of the International Society of Arthroplasty Registries. In all, 64% (25 of 39) of registries responded and completed the survey. Missing responses from incomplete surveys were captured by contacting the registries, and up to three reminder emails were sent to nonresponding registries. Recommendations about PROM collection were drafted, revised, and approved by the International Society of Arthroplasty Registries PROMs Working Group members.
Of the 25 registries that completed the survey, 15 collected generic PROMs, most frequently the EuroQol-5 Dimension survey; 16 collected joint-specific PROMs, most frequently the Knee Injury and Osteoarthritis Outcome Score and Hip Disability and Osteoarthritis Outcome Score; and 11 registries collected a satisfaction item. Most registries administered PROM questionnaires within 3 months before and 1 year after surgery. All 16 registries that collected PROM data collected patient age, sex or gender, BMI, indication for the primary arthroplasty, reason for revision arthroplasty, and a comorbidity index, most often the American Society of Anesthesiologists classification. All 16 registries performed regular auditing and reporting of data quality, and most registries reported PROM results to hospitals and linked PROM data to other data sets such as hospital, medication, billing, and emergency care databases. Recommendations for transparent reporting of PROMs were grouped into four categories: demographic and clinical, survey administration, data analysis, and results.
Although registries differed in PROM collection and use, there were sufficient similarities that may enable useful data comparisons. The International Society of Arthroplasty Registries PROMs Working Group recommendations identify issues that may be important to most registries such as the need to make decisions about survey times and collection methods, as well as how to select generic and joint-specific surveys, handle missing data and attrition, report data, and ensure representativeness of the sample.
By collecting PROMs, registries can provide patient-centered data to surgeons, hospitals, and national entities to improve arthroplasty care.
In the thermal dark matter (DM) paradigm, primordial interactions between DM and Standard Model particles are responsible for the observed DM relic density. In Bœhm et al., we showed that ...weak-strength interactions between DM and radiation (photons or neutrinos) can erase small-scale density fluctuations, leading to a suppression of the matter power spectrum compared to the collisionless cold DM (CDM) model. This results in fewer DM subhaloes within Milky Way-like DM haloes, implying a reduction in the abundance of satellite galaxies. Here we use very high-resolution N-body simulations to measure the dynamics of these subhaloes. We find that when interactions are included, the largest subhaloes are less concentrated than their counterparts in the collisionless CDM model and have rotation curves that match observational data, providing a new solution to the ‘too big to fail’ problem.
Genome-wide analyses have identified thousands of long noncoding RNAs (lncRNAs). Malat1 (metastasis-associated lung adenocarcinoma transcript 1) is among the most abundant lncRNAs whose expression is ...altered in numerous cancers. Here we report that genetic loss or systemic knockdown of Malat1 using antisense oligonucleotides (ASOs) in the MMTV (mouse mammary tumor virus)-PyMT mouse mammary carcinoma model results in slower tumor growth accompanied by significant differentiation into cystic tumors and a reduction in metastasis. Furthermore, Malat1 loss results in a reduction of branching morphogenesis in MMTV-PyMT- and Her2/neu-amplified tumor organoids, increased cell adhesion, and loss of migration. At the molecular level, Malat1 knockdown results in alterations in gene expression and changes in splicing patterns of genes involved in differentiation and protumorigenic signaling pathways. Together, these data demonstrate for the first time a functional role of Malat1 in regulating critical processes in mammary cancer pathogenesis. Thus, Malat1 represents an exciting therapeutic target, and Malat1 ASOs represent a potential therapy for inhibiting breast cancer progression.
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