Long-term Prolonged-release Tacrolimus-based Immunosuppression in De Novo Kidney Transplant Recipients: 5-Y Prospective Follow-up of Patients in the ADVANCE Study.

Although prolonged-release tacrolimus (PR-T) is widely approved for posttransplantation immunosuppression in kidney recipients, large-scale studies are required to assess long-term outcomes. We present follow-up data from the Advagraf-based Immunosuppression Regimen Examining New Onset Diabetes Mellitus in Kidney Transplant Recipients (ADVANCE) trial, in which kidney transplant patients (KTPs) received corticosteroid minimization with PR-T. Methods: ADVANCE was a 24-wk, randomized, open-label, phase-4 study. De novo KTPs received PR-T with basiliximab and mycophenolate mofetil and were randomized to receive an intraoperative corticosteroid bolus plus tapered corticosteroids until day 10 (arm 1) or an intraoperative corticosteroid bolus (arm 2). In this 5-y, noninterventional follow-up, patients received maintenance immunosuppression according to standard practice. The primary endpoint was graft survival (Kaplan-Meier). Secondary endpoints included patient survival, biopsy-confirmed acute rejection-free survival, and estimated glomerular filtration rate (4-variable modification of diet in renal disease). Results: Follow-up study included 1125 patients. Overall graft survival at 1 and 5 y posttransplantation was 93.8% and 88.1%, respectively, and was similar between treatment arms. At 1 and 5 y, patient survival was 97.8% and 94.4%, respectively. Five-year graft and patient survival rates in KTPs who remained on PR-T were 91.5% and 98.2%, respectively. Cox proportional hazards analysis demonstrated similar risk of graft loss and death between treatment arms. Five-year biopsy-confirmed acute rejection-free survival was 84.1%. Mean ± standard deviation values of estimated glomerular filtration rate were 52.7 ± 19.5 and 51.1 ± 22.4 mL/min/1.73 m2 at 1 and 5 y, respectively. Fifty adverse drug reactions were recorded, probably tacrolimus-related in 12 patients (1.5%). Conclusions: Graft survival and patient survival (overall and for KTPs who remained on PR-T) were numerically high and similar between treatment arms at 5 y posttransplantation.

Sea-level rise will likely accelerate rock coast cliff retreat rates.

Coastal response to anthropogenic climate change is of central importance to the infrastructure and inhabitants in these areas. Despite being globally ubiquitous, the stability of rock coasts has been largely neglected, and the expected acceleration of cliff erosion following sea-level rise has not been tested with empirical data, until now. We have optimised a coastal evolution model to topographic and cosmogenic radionuclide data to quantify cliff retreat rates for the past 8000 years and forecast rates for the next century. Here we show that rates of cliff retreat will increase by up to an order of magnitude by 2100 according to current predictions of sea-level rise: an increase much greater than previously predicted. This study challenges conventional coastal management practices by revealing that even historically stable rock coasts are highly sensitive to sea-level rise and should be included in future planning for global climate change response.

Long-term, Prolonged-release Tacrolimus-based Immunosuppression in De Novo Liver Transplant Recipients: 5-year Prospective Follow-up of Patients in the DIAMOND Study.

BACKGROUND: Immunosuppression with calcineurin inhibitors (CNIs) is reportedly associated with risk of renal impairment in liver transplant recipients. It is believed that this can be mitigated by decreasing initial exposure to CNIs or delaying CNI introduction until 3-4 d posttransplantation. The ADVAGRAF studied in combination with mycophenolate mofetil and basiliximab in liver transplantation (DIAMOND) trial evaluated different administration strategies for prolonged-release tacrolimus (PR-T). METHODS: DIAMOND was a 24-wk, open-label, phase 3b trial in de novo liver transplant recipients randomized to: PR-T 0.2 mg/kg/d (Arm 1); PR-T 0.15-0.175 mg/kg/d plus basiliximab (Arm 2); or PR-T 0.2 mg/kg/d delayed until day 5 posttransplant plus basiliximab (Arm 3). In a 5-y follow-up, patients were maintained on an immunosuppressive regimen according to standard clinical practice (NCT02057484). Primary endpoint: graft survival (Kaplan-Meier analysis). RESULTS: Follow-up study included 856 patients. Overall graft survival was 84.6% and 73.5% at 1 and 5 y post transplant, respectively. Five-year rates for Arms 1, 2, and 3 were 74.7%, 71.5%, and 74.5%, respectively. At 5 y, death-censored graft survival in the entire cohort was 74.7%. Overall graft survival in patients remaining on PR-T for ≥30 d was 79.1%. Graft survival in patients who remained on PR-T at 5 y was 87.3%. Patient survival was 86.6% at 1 y and 76.3% at 5 y, with survival rates similar in the 3 treatment arms at 5 y. Estimated glomerular filtration rate at the end of the 24-wk initial study and 5 y posttransplant was 62.1 and 61.5 mL/min/1.73 m2, respectively, and was similar between the 3 treatment arms at 5 y. Overall, 18 (2.9%) patients had ≥1 adverse drug reaction, considered possibly related to PR-T in 6 patients. CONCLUSIONS: In the DIAMOND study patient cohort, renal function, graft survival, and patient survival were similar between treatment arms at 5 y posttransplant.

Publisher Correction: Cosmogenic exposure dating reveals limited long-term variability in erosion of a rocky coastline.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cosmogenic exposure dating reveals limited long-term variability in erosion of a rocky coastline.

Predicted sea-level rise and increased storminess are anticipated to lead to increases in coastal erosion. However, assessing if and how rocky coasts will respond to changes in marine conditions is difficult due to current limitations of monitoring and modelling. Here, we measured cosmogenic 10Be concentrations across a sandstone shore platform in North Yorkshire, UK, to model the changes in coastal erosion within the last 7 kyr and for the first time quantify the relative long-term erosive contribution of landward cliff retreat, and down-wearing and stripping of rock from the shore platform. The results suggest that the cliff has been retreating at a steady rate of 4.5 ± 0.63 cm yr-1, whilst maintaining a similar profile form. Our results imply a lack of a direct relationship between relative sea level over centennial to millennial timescales and the erosion response of the coast, highlighting a need to more fully characterise the spatial variability in, and controls on, rocky coast erosion under changing conditions.

Long-term, prolonged-release tacrolimus-based immunosuppression in de novo kidney transplant recipients: 5-year prospective follow-up of the ADHERE study patients.

The objectives of this study were to assess long-term graft survival, patient survival, renal function, and acute rejections in de novo kidney transplant recipients, treated with once-daily prolonged-release tacrolimus-based therapy. The study was a 5-year non-interventional prospective follow-up of patients from the ADHERE study, a Phase IV 12-month open-label assessment of patients randomized to receive prolonged-release tacrolimus in combination with mycophenolate mofetil (MMF) (Arm 1) or sirolimus (Arm 2). From 838 patients in the randomized study, 587 were included in the long-term follow-up, of whom 510 completed the study at year 5. At 1 year post-transplant, graft and patient survival rates were 93.0% and 97.8%, respectively, and at 5 years were 84.0% and 90.8%, respectively. Cox proportional hazards analysis showed no association between graft loss, initial randomized treatment arm, donor age, donor type, or sex. The 5-year acute rejection-free survival rate was 77.4%, and biopsy-confirmed acute rejection-free survival rate was 86.0%. Renal function remained stable over the follow-up period: mean ± SD eGFR 4-variable modification diet in renal disease formula (MDRD4) was 52.3 ± 21.6 ml/min/1.73 m2 at 6 months and 52.5 ± 23.0 ml/min/1.73 m2 at 5 years post-transplant. These findings support the role of long-term once-daily prolonged-release tacrolimus-based immunosuppression, in combination with sirolimus or MMF, for renal transplant recipients in routine clinical practice.

Recent acceleration in coastal cliff retreat rates on the south coast of Great Britain.

Rising sea levels and increased storminess are expected to accelerate the erosion of soft-cliff coastlines, threatening coastal infrastructure and livelihoods. To develop predictive models of future coastal change we need fundamentally to know how rapidly coasts have been eroding in the past, and to understand the driving mechanisms of coastal change. Direct observations of cliff retreat rarely extend beyond 150 y, during which humans have significantly modified the coastal system. Cliff retreat rates are unknown in prior centuries and millennia. In this study, we derived retreat rates of chalk cliffs on the south coast of Great Britain over millennial time scales by coupling high-precision cosmogenic radionuclide geochronology and rigorous numerical modeling. Measured 10Be concentrations on rocky coastal platforms were compared with simulations of coastal evolution using a Monte Carlo approach to determine the most likely history of cliff retreat. The 10Be concentrations are consistent with retreat rates of chalk cliffs that were relatively slow (2-6 cm⋅y-1) until a few hundred years ago. Historical observations reveal that retreat rates have subsequently accelerated by an order of magnitude (22-32 cm⋅y-1). We suggest that acceleration is the result of thinning of cliff-front beaches, exacerbated by regional storminess and anthropogenic modification of the coast.

The effectiveness of beach mega-nourishment, assessed over three management epochs.

Resilient coastal protection requires adaptive management strategies that build with nature to maintain long-term sustainability. With increasing pressures on shorelines from urbanisation, industrial growth, sea-level rise and changing storm climates soft approaches to coastal management are implemented to support natural habitats and maintain healthy coastal ecosystems. The impact of a beach mega-nourishment along a frontage of interactive natural and engineered systems that incorporate soft and hard defences is explored. A coastal evolution model is applied to simulate the impact of different hypothetical mega-nourishment interventions to assess their impacts' over 3 shoreline management planning epochs: present-day (0-20 years), medium-term (20-50 years) and long-term (50-100 years). The impacts of the smaller interventions when appropriately positioned are found to be as effective as larger schemes, thus making them more cost-effective for present-day management. Over time the benefit from larger interventions becomes more noticeable, with multi-location schemes requiring a smaller initial nourishment to achieve at least the same benefit as that of a single-location scheme. While the longer-term impact of larger schemes reduces erosion across a frontage the short-term impact down drift of the scheme can lead to an increase in erosion as the natural sediment drift becomes interrupted. This research presents a transferable modelling tool to assess the impact of nourishment schemes for a variety of sedimentary shorelines and highlights both the positive and negative impact of beach mega-nourishment.

Hillslopes record the growth and decay of landscapes.

Earth's surface archives the combined history of tectonics and erosion, which tend to roughen landscapes, and sediment transport and deposition, which smooth them. We analyzed hillslope morphology in the tectonically active Dragon's Back Pressure Ridge in California, United States, to assess whether tectonic uplift history can be reconstructed using measurable attributes of hillslope features within landscapes. Hilltop curvature and hillslope relief mirror measured rates of vertical displacement caused by tectonic forcing, and their relationships are consistent with those expected when idealizing hillslope transport as a nonlinear diffusion process. Hilltop curvature lags behind relief in its response to changing erosion rates, allowing growing landscapes to be distinguished from decaying landscapes. Numerical modeling demonstrates that hillslope morphology may be used to infer changes in tectonic rates.

The use of long acting ß2-agonists, alone or in combination with inhaled corticosteroids, in chronic obstructive pulmonary disease (COPD): a risk-benefit analysis.

Chronic obstructive pulmonary disease (COPD) is a slowly progressive, largely non-reversible pulmonary disease which is characterised by airflow limitation. It is one of the few diseases with an increasing mortality rate and by 2020 it is predicted to be the third leading cause of death. The mainstays of current treatment are long acting ß2 agonists (LABAs) coupled with an increasing reliance on inhaled corticosteroids (ICS). Two LABAs (salmeterol and formoterol) are currently licensed for COPD both as monotherapy and in combination with ICS (fluticasone propionate (FP) and budesonide respectively). A comprehensive review of the risk-benefit of these medicines in COPD is provided here which concludes that there is limited efficacy for LABAs in COPD either alone or in combination with ICS and no overall modification of the disease process. However, where directly compared, combination therapy usually provides an advantage over monotherapy. Importantly the apparent effectiveness of treatment may significantly depend upon the outcome measure chosen with some measures possibly underestimating the extent of benefit. ICS benefit may also be greater in those patients who respond to treatment. Set against this benefit are recent concerns that a number of issues related to the clinical trial design such as prior use of ICS and different withdrawal rates between groups may be significantly influencing results. Furthermore there is no evidence of a dose response relationship with regard to ICS dose. A key issue with combination therapy is the excess risk of pneumonia conferred by the use of an ICS in this patient population. This risk does not appear to be proportional to the ICS dose but may differ between FP and budesonide. We conclude that further studies are required to identify the optimal dose of ICS, in terms of both risk and benefit, and to confirm their benefit in steroid naïve patients. Furthermore it will be important to determine whether the risk of pneumonia is apparent with both FP and budesonide and to identify factors which may predict steroid responsiveness in COPD.

Prolonged calcium transients and myocardial remodelling in early experimental uraemia.

BACKGROUND: Cardiovascular disease is the most common cause of premature death in patients with end-stage renal disease, possibly due to a specific 'uraemic cardiomyopathy'. This study was designed to investigate the cardiac changes induced by a moderate impairment of renal function in a model of uraemia. METHODS: Male Wistar rats (n=11) were rendered uraemic by 5/6 nephrectomy or sham operated (n=11). After 4 weeks, cardiac dimensions were measured from fixed tissue sections using a digital image analysis technique. In parallel groups of animals, cardiac myocytes were isolated and studied for evidence of functional changes attributable to uraemia. After steady-state field stimulation at 0.5 Hz, intracellular Ca(2+) handling (using Fura-2) was investigated. Up to 20 consecutive transients were averaged as the extracellular Ca(2+) was increased. RESULTS: The 5/6 nephrectomy group had a 75% reduction in glomerular filtration rate, and a 2- to 3-fold increase in serum urea and creatinine compared with sham-operated control animals (P<0.0001). However, the blood pressure was found to be similar in each group. Histology of the intact hearts (five pairs) showed a significant increase in tissue cross-sectional area (14%; P<0.04), cross-sectional area of the left ventricle (22%; P<0.04), and a significant increase in left ventricular wall thickness (15%; P<0.03). In the single cardiac cell study, under basal conditions (1-2 mM extra-cellular Ca(2+)) no significant differences in intracellular Ca(2+) were observed, but in high extracellular Ca(2+) the uraemic cells were slower to return to diastolic intracellular Ca(2+) levels (P<0.05). CONCLUSIONS: The data provide evidence of altered myocardial structure and function in early experimental uraemia. The changes described are consistent with concentric hypertrophy of the left ventricle, which occurs in the absence of hypertension.