We conducted an open‐label, prospective, randomized trial to assess the efficacy and safety of RANKL inhibition with denosumab to prevent the loss of bone mineral density (BMD) in the first year ...after kidney transplantation. Ninety kidney transplant recipients were randomized 1:1 2 weeks after surgery to receive denosumab (60 mg at baseline and 6 months) or no treatment. After 12 months, total lumbar spine areal BMD (aBMD) increased by 4.6% (95% confidence interval CI 3.3–5.9%) in 46 patients in the denosumab group and decreased by −0.5% (95% CI −1.8% to 0.9%) in 44 patients in the control group (between‐group difference 5.1% 95% CI 3.1–7.0%, p < 0.0001). Denosumab also increased aBMD at the total hip by 1.9% (95% CI, 0.1–3.7%; p = 0.035) over that in the control group at 12 months. High‐resolution peripheral quantitative computed tomography in a subgroup of 24 patients showed that denosumab increased volumetric BMD at the distal tibia and radius (all p < 0.05). Biomarkers of bone turnover (C‐terminal telopeptide of type I collagen, procollagen type I N‐terminal propeptide) markedly decreased with denosumab (all p < 0.0001). Episodes of cystitis and asymptomatic hypocalcemia occurred more often with denosumab, whereas graft function, rate of rejections, and incidence of opportunistic infections were similar. In conclusion, denosumab increased BMD in the first year after kidney transplantation but was associated with more frequent episodes of urinary tract infection.
This study demonstrates that denosumab, a receptor activator of nuclear factor kB ligand inhibiting monoclonal antibody, effectively increases bone mineral density at vertebral and nonvertebral sites in de novo kidney transplant recipients.
We assessed the impact of antiviral prophylaxis and preemptive therapy on the incidence and outcomes of cytomegalovirus (CMV) disease in a nationwide prospective cohort of solid organ transplant ...recipients. Risk factors associated with CMV disease and graft failure‐free survival were analyzed using Cox regression models. One thousand two hundred thirty‐nine patients transplanted from May 2008 until March 2011 were included; 466 (38%) patients received CMV prophylaxis and 522 (42%) patients were managed preemptively. Overall incidence of CMV disease was 6.05% and was linked to CMV serostatus (D+/R− vs. R+, hazard ratio HR 5.36 95% CI 3.14–9.14, p < 0.001). No difference in the incidence of CMV disease was observed in patients receiving antiviral prophylaxis as compared to the preemptive approach (HR 1.16 95% CI 0.63–2.17, p = 0.63). CMV disease was not associated with a lower graft failure‐free survival (HR 1.27 95% CI 0.64–2.53, p = 0.50). Nevertheless, patients followed by the preemptive approach had an inferior graft failure‐free survival after a median of 1.05 years of follow‐up (HR 1.63 95% CI 1.01–2.64, p = 0.044). The incidence of CMV disease in this cohort was low and not influenced by the preventive strategy used. However, patients on CMV prophylaxis were more likely to be free from graft failure.
In this nationwide cohort of solid organ transplant recipients, the authors find that the incidence of cytomegalovirus disease is similar irrespective of the antiviral preventive strategy used (preemptive vs. prophylaxis), although patients who received antiviral prophylaxis have better graft failure‐free survival.
•Most progress in assessing agricultural impacts was made by using ensemble modelling.•Distinct crop model improvements were made in the response or cereals to heat stress.•Gaps in understanding to ...be bridged by better linking experimentation and modelling.•Integrated crop and economic modelling is needed for more practical relevance.•Research on complex tropical plant production systems to receive more attention.
Modelling is a key tool to explore agricultural impacts of and adaptations to climate change. Here we report recent progress made especially referring to the large project initiatives MACSUR and AgMIP; in particular, in modelling potential crop impacts from field to global using multi-model ensembles. We identify two main fields where further progress is necessary: a more mechanistic understanding of climate impacts and management options for adaptation and mitigation; and focusing on cropping systems and integrative multi-scale assessments instead of single season and crops, especially in complex tropical and neglected but important cropping systems. Stronger linking of experimentation with statistical and eco-physiological crop modelling could facilitate the necessary methodological advances.
Heat stress (HS) negatively affects dry matter intake (DMI), milk yield (MY), feed efficiency (FE), and free water intake (FWI) in dairy cows, with detrimental consequences to animal welfare, health, ...and profitability of dairy farms. Absolute enteric methane (CH4) emission, yield (CH4/DMI), and intensity (CH4/MY) may also be affected. Therefore, the goal of this study was to model the changes in dairy cow productivity, water intake, and absolute CH4 emissions, yield, and intensity with the progression (days of exposure) of a cyclical HS period in lactating dairy cows. Heat stress was induced by increasing the average temperature by 15°C (from 19°C in the thermoneutral period to 34°C) while keeping relative humidity constant at 20% (temperature-humidity index peaks of approximately 83) in climate-controlled chambers for up to 20 d. A database composed of individual records (n = 1,675) of DMI and MY from 82 heat-stressed lactating dairy cows housed in environmental chambers from 6 studies was used. Free water intake was also estimated based on DMI, dry matter, crude protein, sodium, and potassium content of the diets, and ambient temperature. Absolute CH4 emissions was estimated based on DMI, fatty acids, and dietary digestible neutral detergent fiber content of the diets. Generalized additive mixed-effects models were used to describe the relationships of DMI, MY, FE, and absolute CH4 emissions, yield, and intensity with HS. Dry matter intake and absolute CH4 emissions and yield reduced with the progression of HS up to 9 d, when it started to increase again up to 20 d. Milk yield and FE reduced with the progression of HS up to 20 d. Free water intake (kg/d) decreased during the exposure to HS mainly because of a reduction in DMI; however, when expressed in kg/kg of DMI it increased modestly. Methane intensity also reduced initially up to d 5 during HS exposure but then started to increase again following the DMI and MY pattern up to d 20. However, the reductions in CH4 emissions (absolute, yield, and intensity) occurred at the expense of decreases in DMI, MY, and FE, which are not desirable. This study provides quantitative predictions of the changes in animal performance (DMI, MY, FE, FWI) and CH4 emissions (absolute, yield, and intensity) with the progression of HS in lactating dairy cows. The models developed in this study could be used as a tool to help dairy nutritionists to decide when and how to adopt strategies to mitigate the negative effects of HS on animal health and performance and related environmental costs. Thus, more precise and accurate on-farm management decisions could be taken with the use of these models. However, application of the developed models outside of the ranges of temperature-humidity index and period of HS exposure included in this study is not recommended. Also, validation of predictive capacity of the models to predict CH4 emissions and FWI using data from in vivo studies where these variables are measured in heat-stressed lactating dairy cows is required before these models can be used.
Peptide receptor radionuclide therapy (PRRNT) is a molecularly targeted radiation therapy involving the systemic administration of a radiolabelled peptide designed to target with high affinity and ...specificity receptors overexpressed on tumours. PRRNT employing the radiotagged somatostatin receptor agonists
90
Y-DOTATOC (
90
Y-DOTA
0
,Tyr
3
-octreotide) or
177
Lu-DOTATATE (
177
Lu-DOTA
0
,Tyr
3
,Thr
8
-octreotide or
177
Lu-DOTA
0
,Tyr
3
-octreotate) have been successfully used for the past 15 years to target metastatic or inoperable neuroendocrine tumours expressing the somatostatin receptor subtype 2. Accumulated evidence from clinical experience indicates that these tumours can be subjected to a high absorbed dose which leads to partial or complete objective responses in up to 30 % of treated patients. Survival analyses indicate that patients presenting with high tumour receptor expression at study entry and receiving
177
Lu-DOTATATE or
90
Y-DOTATOC treatment show significantly higher objective responses, leading to longer survival and improved quality of life. Side effects of PRRNT are typically seen in the kidneys and bone marrow. These, however, are usually mild provided adequate protective measures are undertaken. Despite the large body of evidence regarding efficacy and clinical safety, PRRNT is still considered an investigational treatment and its implementation must comply with national legislation, and ethical guidelines concerning human therapeutic investigations. This guidance was formulated based on recent literature and leading experts’ opinions. It covers the rationale, indications and contraindications for PRRNT, assessment of treatment response and patient follow-up. This document is aimed at guiding nuclear medicine specialists in selecting likely candidates to receive PRRNT and to deliver the treatment in a safe and effective manner. This document is largely based on the book published through a joint international effort under the auspices of the Nuclear Medicine Section of the International Atomic Energy Agency.
The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin ...secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent β-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity.
In this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases.
Since its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders
Gentle Remediation Options (GRO) are risk management strategies or techniques for contaminated sites that result in no gross reduction in soil functionality (or a net gain) as well as risk ...management. Intelligently applied GROs can provide: (a) rapid risk management via pathway control, through containment and stabilisation, coupled with a longer term removal or immobilisation/isolation of the contaminant source term; and (b) a range of additional economic (e.g. biomass generation), social (e.g. leisure and recreation) and environmental (e.g. CO2 sequestration) benefits. In order for these benefits to be optimised or indeed realised, effective stakeholder engagement is required. This paper reviews current sector practice in stakeholder engagement and its importance when implementing GRO and other remediation options. From this, knowledge gaps are identified, and strategies to promote more effective stakeholder engagement during GRO application are outlined. Further work is required on integrating stakeholder engagement strategies into decision support systems and tools for GRO (to raise the profile of the benefits of effective stakeholder engagement and participation, particularly with sector professionals), and developing criteria for the identification of different stakeholder profiles/categories. Demonstrator sites can make a significant contribution to stakeholder engagement via providing evidence on the effectiveness of GRO under varying site contexts and conditions. Effective and sustained engagement strategies however will be required to ensure that site risk is effectively managed over the longer-term, and that full potential benefits of GRO (e.g. CO2 sequestration, economic returns from biomass generation and “leverage” of marginal land, amenity and educational value, ecosystem services) are realised and communicated to stakeholders.
•Stakeholder engagement when applying gentle remediation options (GRO) is reviewed.•A context for GRO application within sustainable remediation strategies is outlined.•Key principles of stakeholder engagement are described for GRO.•Effective long-term engagement is required to optimise potential benefits from GRO.
Poroelastic contribution to the reservoir stress path Altmann, Johannes B.; Müller, Tobias M.; Müller, Birgit I.R. ...
International journal of rock mechanics and mining sciences (Oxford, England : 1997),
10/2010, Volume:
47, Issue:
7
Journal Article
Peer reviewed
Pore pressure/stress coupling is the change in the smaller horizontal stress
σ
h
associated with changes in pore pressure
P, and has been measured in numerous reservoirs worldwide. These measurements ...suggest that the change in minimum horizontal stress Δ
σ
h
is on average ca. 64% of the change in the reservoir pore pressure Δ
P, but can be as low as 34% and as high as 118%. Conventionally it is assumed that the total vertical stress
σ
v
, given by the overburden, is not affected by changes in pore pressure, in contrast to the horizontal stresses
σ
H
and
σ
h
. We investigate analytically and numerically the spatio-temporal pore pressure and stress evolution in poroelastic media for continuous fluid injection at a point source, and calculate from the numerical modelling results the ratio Δ
σ/Δ
P. Analytically, we show that the measured average of Δ
σ
h
/Δ
P can mathematically be deduced from the long-term limit of the spatio-temporal evolution of pore pressure and horizontal stress caused by fluid injection at a point source. We compare our numerical results to the analytical solution for continuous point injection into homogeneous poroelastic media as well as to Δ
σ
h
/Δ
P values measured in the field, and show that all stress components change with a variation in
P. We use the concept of poroelasticity to explain the observed coupling between pore pressure and stress in reservoirs, and we consider different measurement locations and measurement times as one possible reason for the measured variation in Δ
σ
h
/Δ
P in different oil fields worldwide.
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