Life expectancy after surgical aortic valve replacement for low-gradient aortic stenosis with preserved ejection fraction.

INTRODUCTION AND OBJECTIVES: Surgical aortic valve replacement (SAVR) can modify the natural history of severe aortic stenosis (SAS). However, compared with the general population, these patients have a loss of life expectancy. The life expectancy of patients who undergo SAVR due to low-gradient SAS with preserved left ventricular ejection fraction (LVEF) is unknown. METHODS: We included all patients between 50 and 65 years who underwent isolated SAVR in 27 Spanish centers during an 18-year period. We analyzed observed and expected survival at 18 years in patients with low-gradient SAS with preserved LVEF and all other types of SAS. We used propensity score matching to compare the life expectancy of patients with low-gradient SAS with preserved LVEF vs those with high-gradient SAS with preserved LVEF. RESULTS: We analyzed 5084 patients, of whom 413 had low-gradient SAS with preserved LVEF. For these patients, observed survival at 10, 15 and 18 years was 86.6% (95%CI, 85.3-87.8), 75% (95%CI, 72.7-77.2), and 63.5% (95%CI, 58.8-67.8). Expected survival at 10, 15 and 18 years was 90.2%, 82.1%, and 75.7%. In the matched sample, survival of patients with low-gradient SAS with preserved LVEF was similar to that of patients with high-gradient with preserved LVEF, log-rank test, P=.95; HR=1 (95%CI, 0.7-1.4; P=.95). CONCLUSIONS: There is a loss of life expectancy in patients with all types of SAS undergoing SAVR. This loss is higher in patients with left ventricular dysfunction and lower in patients with low-gradient or high-gradient aortic stenosis with preserved LVEF. The benefit of surgery is similar between these last 2 groups.

Nitroglycerin Plus Whole Intracranial Radiation Therapy for Brain Metastases in Patients With Non-Small Cell Lung Cancer: A Randomized, Open-Label, Phase 2 Clinical Trial.

PURPOSE: Hypoxia has been associated with chemoradioresistance secondary to vascular endothelial growth factor receptor induced by hypoxia-induced factor (HIF). Nitroglycerin (NTG) can reduce HIF-1 in tissues, and this may have antiangiogenic, proapoptotic, and antiefflux effects. Particularly, epidermal growth factor-mutated (EGFRm) tumor cell lines have been shown to overexpress both vascular endothelial growth factor and HIF. In this phase 2 study, we evaluated the effect of transdermal NTG plus whole brain radiation therapy (WBRT) in patients with non-small cell lung cancer (NSCLC) with brain metastases (BM). METHODS: This was an open-label, phase 2 clinical trial with 96 patients with NSCLC and BM. Patients were randomized 1:1 to receive NTG plus WBRT (30 Gy in 10 fractions) or WBRT alone. The primary endpoint was intracranial objective response rate (iORR) evaluated 3 months posttreatment. NTG was administered using a transdermal 36-mg patch from Monday through Friday throughout WBRT administration (10 days). The protocol was retrospectively registered at ClinicalTrials.gov (NCT04338867). RESULTS: Fifty patients were allocated to the control group, and 46 were allocated to the experimental group (NTG); among these, 26 (52%) had EGFRm in the control group and 21 (45.7%) had EGFRm in the NTG arm. In terms of the iORR, patients in the NTG group had a significantly higher response compared with controls (56.5% [n = 26/46 evaluable patients] vs 32.7% [n = 16/49 evaluable patients]; relative risk, 1.73; 95% confidence interval [CI], 1.08-2.78; P = .024). Additionally, patients who received NTG + WBRT had an independently prolonged intracranial progression-free survival (ICPFS) compared with those who received WBRT alone (27.7 vs 9.6; hazard ratio [HR], 0.5; 95% CI, 0.2-0.9; P = .020); this positively affected overall progression-free survival among patients who received systemic therapy (n = 88; HR, 0.5; 95% CI, 0.2-0.9; P = .043). The benefit of ICPFS (HR, 0.4; 95% CI, 0.2-0.9; P = .030) was significant in the EGFRm patient subgroup. No differences were observed in overall survival. A significantly higher rate of vomiting presented in the NTG arm of the study (P = .016). CONCLUSIONS: The concurrent administration of NTG and radiation therapy improves iORR and ICPFS among patients with NSCLC with BM. The benefit in ICPFS is significant in the EGFRm patient subgroup.

Modelling the Mediterranean Sea ecosystem at high spatial resolution to inform the ecosystem-based management in the region.

Cumulative pressures are rapidly expanding in the Mediterranean Sea with consequences for marine biodiversity and marine resources, and the services they provide. Policy makers urge for a marine ecosystem assessment of the region in space and time. This study evaluates how the whole Mediterranean food web may have responded to historical changes in the climate, environment and fisheries, through the use of an ecosystem modelling over a long time span (decades) at high spatial resolution (8 × 8 km), to inform regional and sub-regional management. Results indicate coastal and shelf areas to be the sites with highest marine biodiversity and marine resources biomass, which decrease towards the south-eastern regions. High levels of total catches and discards are predicted to be concentrated in the Western sub-basin and the Adriatic Sea. Mean spatial-temporal changes of total and commercial biomass show increases in offshore waters of the region, while biodiversity indicators show marginal changes. Total catches and discards increase greatly in offshore waters of the Western and Eastern sub-basins. Spatial patterns and temporal mean changes of marine biodiversity, community biomasses and trophic indices, assessed in this study, aim at identifying areas and food web components that show signs of deterioration with the overall goal of assisting policy makers in designing and implementing spatial management actions for the region.

Life expectancy after aortic valve replacement in young patients.

INTRODUCTION AND OBJECTIVES: In young patients with severe aortic stenosis, it is unknown whether their life expectancy restored after aortic valve replacement (AVR) is unknown. METHODS: We analyzed all patients aged between 50 and 65 years who underwent isolated AVR in 27 Spanish centers during an 18-year period. We compared observed and expected survival at 15 years of follow-up. We repeated all analyses for patients without complications in the postoperative period. RESULTS: A total of 5084 patients were analyzed. For the overall sample, observed survival at 10 and 15 years was 85.3% (95%CI, 84.1%-86.4%) and 73.7% (95%CI, 71.6%-75.6%), respectively. Expected survival was 90.1% and 82.1%. Cumulative relative survival for 1, 5, 10 and 15 years of follow-up was 97.4% (95%CI, 96.9%-97.9%), 96.5% (95%CI, 95.7%-97.3%), 94.7% (95%CI, 93.3%-95.9%), and 89.8% (95%CI, 87.3%-92.1%). For patients without complications, cumulative relative survival for 1, 5, 10 and 15 years was 100.3% (95%CI, 99.8%-100.5%), 98.9% (95%CI 97.6% -99.9%), 97.3% (95%CI, 94.9%-99.4%), and 91.9% (95%CI, 86.5%-96.8%). CONCLUSIONS: Life expectancy in young patients who have severe aortic stenosis and undergo AVR is lower than that of the general population. Life expectancy of individuals without complications during the postoperative period is also reduced. Therefore, baseline characteristics are likely the main factors that explain the reduction in life expectancy.

Model based estimate of transboundary litter pollution on Mediterranean coasts.

Plastic litter pollution is one of the major concerns for the health of marine ecosystems worldwide. This pervasive form of pollution affects all oceans and seas and it's interacting with multiple levels of the marine food webs. In the European context, several pieces of legislation try to fight against this pervasive and ubiquitous form of pollution. Recently, EU Member States have agreed to a maximum threshold of litter items per coast length (20 items/100 m coastline). One major concern among stakeholders to reach this consensus was the transboundary litter, as measures need to be implemented in the country of origin. Henceforth, a solid method to estimate the amounts of the transboundary litter to a given Member State's coasts is needed. In this contribution, we use a combination of hydrodynamic and Lagrangian models for the Mediterranean Sea in order to understand the origin of coastal litter. Simulations show that the amount of transboundary litter in Mediterranean countries could be as large as 30% although both regional and seasonal differences could be significant.

Making spatial-temporal marine ecosystem modelling better - A perspective.

Marine Ecosystem Models (MEMs) provide a deeper understanding of marine ecosystem dynamics. The United Nations Decade of Ocean Science for Sustainable Development has highlighted the need to deploy these complex mechanistic spatial-temporal models to engage policy makers and society into dialogues towards sustainably managed oceans. From our shared perspective, MEMs remain underutilized because they still lack formal validation, calibration, and uncertainty quantifications that undermines their credibility and uptake in policy arenas. We explore why these shortcomings exist and how to enable the global modelling community to increase MEMs' usefulness. We identify a clear gap between proposed solutions to assess model skills, uncertainty, and confidence and their actual systematic deployment. We attribute this gap to an underlying factor that the ecosystem modelling literature largely ignores: technical issues. We conclude by proposing a conceptual solution that is cost-effective, scalable and simple, because complex spatial-temporal marine ecosystem modelling is already complicated enough.

Differences in life expectancy between men and women after aortic valve replacement.

OBJECTIVES: Some researchers have observed an increased number of deaths during the follow-up of young patients who undergo aortic valve replacement due to severe aortic stenosis, suggesting that this procedure does not restore their life expectancy. Our goal was to confirm these findings and explore sex-based differences. METHODS: All patients between 50 and 65 years of age who underwent isolated aortic valve replacement in 27 Spanish centres during an 18-year period were included. We compared observed and expected survival at 15 years of follow-up and estimated the cumulative incidence of death from a competing risks point of view. We stratified by sex and analysed if being a woman was an independent risk factor for death. RESULTS: For men, the observed survival at 10 and 15 years of follow-up was 85% [95% confidence interval (CI) 83.6%-86.4%] and 72.3% (95% CI 69.7%-74.7%), respectively whereas the expected survival was 88.1% and 78.8%. For women, the observed survival at 10 and 15 years was 85% (95% CI 82.8%-86.9%) and 73% (95% CI 69.1%-76.4%), whereas the expected survival was 94.6% and 89.4%. At 15 years of follow-up, the cumulative incidence of death due to the disease in men and women was 8.2% and 16.7%, respectively. In addition, being a woman was an independent risk factor for death (hazard ratio = 1.23 (95% CI 1.02-1.48; P = 0.03). CONCLUSIONS: After the aortic valve replacement, men and women do not have their life expectancy restored, but this loss is much higher in women than in men. In addition, being a woman is a risk factor for long-term death. Reasons for these findings are unknown and must be investigated.

Biological or mechanical prostheses for isolated aortic valve replacement in patients aged 50-65 years: the ANDALVALVE study.

OBJECTIVES: The decision about whether to use a biological or a mechanical prosthesis for aortic valve replacement remains controversial in patients between 50 and 65 years of age and has yet to be addressed in a Mediterranean population. This research aimed to analyse long-term survival and major morbidity rates (30-day mortality, stroke, any prosthetic reoperation and major bleeding) within this population. METHODS: Our multicentre observational retrospective study included all subjects aged 50-65 years who had a primary isolated aortic valve replacement due to severe aortic stenosis at 7 public hospitals from Andalusia (Spain) between 2000 and 2015. Concomitant surgery, reoperations and endocarditis were the exclusion criteria. A total of 1443 patients were enrolled in the study (272 with biological and 1171 with mechanical valves). Multivariate analyses including a 2:1 propensity score matching (506 mechanical and 257 biological prostheses) were conducted. RESULTS: Bioprostheses were implanted in 18.8% (n = 272): 35% were women; the mean EuroSCORE-I was 3%. The mean follow-up was 8.1 ± 4.9 years in a matched sample: 8.8 ± 4.9 years in those receiving a mechanical vs 7.1 ± 4.5 years in those receiving a biological prosthesis (P = 0.001). In the paired sample, the 15-year survival rate was 73% in those who had a biological vs 76% in those who had a mechanical valve [hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.54-1.20; P = 0.159]. No significant differences were observed in patients ≥55 years old (74% of 15-year survival in both groups: HR 0.88, 95% CI 0.56-1.34; P = 0.527). A higher rate of major bleeding was found in patients with a mechanical prosthesis (P = 0.004), whereas reoperation was more frequent among those with a biological prosthesis (P = 0.01). CONCLUSIONS: Long-term survival was comparable in patients above 55 years of age. Mechanical prostheses were associated with more major bleeding and bioprostheses, with more reoperations. A bioprosthesis in patients above 55 years old is a reasonable choice. CLINICAL TRIAL REGISTRATION NUMBER: NCT03239509.

Non-Redfieldian dynamics driven by phytoplankton phosphate frugality explain nutrient and chlorophyll patterns in model simulations for the Mediterranean Sea.

The relative abundance of nitrate (N) over phosphate (P) measured as a molar ratio (N:P) is typically considered to determine the macronutrient limiting marine primary production. In low-complexity biogeochemical models, a simple threshold value is usually applied based on the canonical Redfield ratio (N:P = 16). However, the N:P ratio is not constant in many oceanic areas, especially marginal, semi-enclosed seas, such as the Mediterranean basin. In this work, a flexible definition of the N:P ratio based on the capacity of phytoplankton to modulate phosphate uptake according to its availability in seawater, the so-called Line of Frugality, is incorporated into the biogeochemical model MedERGOM. This modification allows the acquisition of a more realistic representation of the stoichiometry of nutrients in the Mediterranean basin and allows to better reproduce the observed phytoplankton biomass in productive areas such as the Gulf of Gabes and the Adriatic Sea. This approach is, thus, especially suitable for coastal areas in which basin-scale biogeochemical models fail to reproduce patterns observed by remote sensing or in situ measurements. Our results show that implementation of the stoichiometric flexibility of phytoplankton in a low-complexity biogeochemical model enhances the reproducibility of ecosystem dynamics without increasing the computational demand, representing a simple approximation easily implemented in models aiming to describe regions with a Non-Redfieldian stoichiometry.

Deep winter convection and phytoplankton dynamics in the NW Mediterranean Sea under present climate and future (horizon 2030) scenarios.

Deep water convection (DC) in winter is one of the major processes driving open-ocean primary productivity in the Northwestern Mediterranean Sea. DC is highly variable in time, depending on the specific conditions (stratification, circulation and ocean-atmosphere interactions) of each specific winter. This variability also drives the interannual oscillations of open-ocean primary productivity in this important region for many commercially-important fish species. We use a coupled model system to 1) understand to what extent DC impacts phytoplankton seasonality in the present-day and 2) to explore potential changes in future scenarios (~2030). Our model represents quite accurately the present-day characteristics of DC and its importance for open-ocean phytoplankton blooms. However, for the future scenarios the importance of deep nutrients in fertilizing the euphotic layer of the NW Mediterranean decreases. The model simulates changes in surface density and on the levels of kinetic energy that make mesoscale activity associated with horizontal currents to become a more important fertilization mechanism, inducing subsequently phenological changes in seasonal plankton cycles. Because of our focus on the open-sea, an exact quantification of the impact of those changes on the overall biological production of the NW Mediterranean cannot be made at the moment.

Hydrological and biogeochemical response of the Mediterranean Sea to freshwater flow changes for the end of the 21st century.

We evaluate the changes on the hydrological (temperature and salinity) and biogeochemical (phytoplankton biomass) characteristics of the Mediterranean Sea induced by freshwater flow modifications under two different scenarios for the end of the 21st century. An ensemble of four regional climate model realizations using different global circulation models at the boundary and different emission scenarios are used to force a single ocean model for the Mediterranean Sea. Freshwater flow is modified according to the simulated changes in the precipitation rates for the different rivers' catchment regions. To isolate the effect resulting from a change in freshwater flow, model results are evaluated against a 'baseline' simulation realized assuming a constant inflow equivalent to climatologic values. Our model results indicate that sea surface salinity could be significantly altered by freshwater flow modification in specific regions and that the affected area and the sign of the anomaly are highly dependent on the used climate model and emission scenario. Sea surface temperature and phytoplankton biomass, on the contrary, show no coherent spatial pattern but a rather widespread scattered response. We found in open-water regions a significant negative relationship between sea surface temperature anomalies and phytoplankton biomass anomalies. This indicates that freshwater flow modification could alter the vertical stability of the water column throughout the Mediterranean Sea, by changing the strength of vertical mixing and consequently upper water fertilization. In coastal regions, however, the correlation between sea temperature anomalies and phytoplankton biomass is positive, indicating a larger importance of the physiological control of growth rates by temperature.

Historical changes of the Mediterranean Sea ecosystem: modelling the role and impact of primary productivity and fisheries changes over time.

The Mediterranean Sea has been defined "under siege" because of intense pressures from multiple human activities; yet there is still insufficient information on the cumulative impact of these stressors on the ecosystem and its resources. We evaluate how the historical (1950-2011) trends of various ecosystems groups/species have been impacted by changes in primary productivity (PP) combined with fishing pressure. We investigate the whole Mediterranean Sea using a food web modelling approach. Results indicate that both changes in PP and fishing pressure played an important role in driving species dynamics. Yet, PP was the strongest driver upon the Mediterranean Sea ecosystem. This highlights the importance of bottom-up processes in controlling the biological characteristics of the region. We observe a reduction in abundance of important fish species (~34%, including commercial and non-commercial) and top predators (~41%), and increases of the organisms at the bottom of the food web (~23%). Ecological indicators, such as community biomass, trophic levels, catch and diversity indicators, reflect such changes and show overall ecosystem degradation over time. Since climate change and fishing pressure are expected to intensify in the Mediterranean Sea, this study constitutes a baseline reference for stepping forward in assessing the future management of the basin.

Ecosystem services sustainability in the Mediterranean Sea: assessment of status and trends using multiple modelling approaches.

Mediterranean ecosystems support important processes and functions that bring direct benefits to human society. Yet, marine ecosystem services are usually overlooked due to the challenges in identifying and quantifying them. This paper proposes the application of several biophysical and ecosystem modelling approaches to assess spatially and temporally the sustainable use and supply of selected marine ecosystem services. Such services include food provision, water purification, coastal protection, lifecycle maintenance and recreation, focusing on the Mediterranean region. Overall, our study found a higher number of decreasing than increasing trends in the natural capacity of the ecosystems to provide marine and coastal services, while in contrast the opposite was observed to be true for the realised flow of services to humans. Such a study paves the way towards an effective support for Blue Growth and the European maritime policies, although little attention is paid to the quantification of marine ecosystem services in this context. We identify a key challenge of integrating biophysical and socio-economic models as a necessary step to further this research.

On the causal structure between CO2 and global temperature.

We use a newly developed technique that is based on the information flow concept to investigate the causal structure between the global radiative forcing and the annual global mean surface temperature anomalies (GMTA) since 1850. Our study unambiguously shows one-way causality between the total Greenhouse Gases and GMTA. Specifically, it is confirmed that the former, especially CO2, are the main causal drivers of the recent warming. A significant but smaller information flow comes from aerosol direct and indirect forcing, and on short time periods, volcanic forcings. In contrast the causality contribution from natural forcings (solar irradiance and volcanic forcing) to the long term trend is not significant. The spatial explicit analysis reveals that the anthropogenic forcing fingerprint is significantly regionally varying in both hemispheres. On paleoclimate time scales, however, the cause-effect direction is reversed: temperature changes cause subsequent CO2/CH4 changes.

The Psychological Impact of Prostate Biopsy: Anxiety and Depression Associated with a Positive Biopsy Result.

INTRODUCTION: We evaluated the psychological impact on patients caused by transrectal prostate biopsy and the emotional stress in those with a positive prostate cancer finding. METHODS: We performed a psychological evaluation of 328 men who underwent transrectal prostate biopsy using HADS (Hospital Anxiety and Depression Scale) at 3 time points. In addition we analyzed events related to the procedure, compared anxiety and depression levels in men with a negative result vs those diagnosed with prostate cancer, and evaluated anxiety and depression associated with events related to the procedure. RESULTS: Of the 328 men 99.08% completed the evaluation, including 51.2% with a biopsy positive for prostate cancer and 48.8% with a negative prostate cancer result. The group with a positive biopsy scored an average of 6.85 in the anxiety category and 3.48 for depressive symptoms with a 2.02 point difference in respect to the original evaluation (p = 0.01). Prostate cancer with prostate specific antigen greater than 20 ng/ml was associated with significant anxiety (p = 0.03). CONCLUSIONS: Biopsy positive for prostate cancer with prostate specific antigen greater than 20 ng/ml is associated with significant anxiety. However, events related to the procedure and marital status are not associated with significant anxiety.

Nutritional Status, Body Surface, and Low Lean Body Mass/Body Mass Index Are Related to Dose Reduction and Severe Gastrointestinal Toxicity Induced by Afatinib in Patients With Non-Small Cell Lung Cancer.

BACKGROUND: The main reason for dose reduction of afatinib is gastrointestinal toxicity (GT). In a phase II study, we analyzed anthropometrical, nutritional, and biochemical factors associated with GT induced by afatinib. MATERIALS AND METHODS: Patients diagnosed with non-small cell lung cancer who progressed to prior chemotherapy received 40 mg of afatinib. Malnutrition was determined by Subjective Global Assessment, and lean body mass (LBM) was determined by computed tomography scan analysis using a pre-established Hounsfield unit threshold. Toxicity was obtained during four cycles by Common Terminology Criteria for Adverse Events. RESULTS: Eighty-four patients were enrolled. Afatinib was administered as the second, third, and fourth line of treatment in 54.8%, 38.1%, and 7.12% of patients, respectively. Severe diarrhea, mucositis, and overall severe GT were present in 38.9%, 28.8%, and 57.5%, respectively. Of the patients, 50% developed dose-limiting toxicity (DLT). Patients with malnutrition have higher risk for severe GT. Patients with lower LBM and body mass index developed more DLT (71.4% vs. 18.8%). CONCLUSION: Malnutrition is associated with a higher risk of severe GT induced by afatinib. Determination of nutritional status and body composition are helpful in identifying patients at higher risk of severe GT and could allow initiating treatment with lower doses according to tolerance.

Ageostrophic Frontal Processes Controlling Phytoplankton Production in the Catalano-Balearic Sea (Western Mediterranean).

Buoyancy-induced unstable boundary currents and the accompanying retrograde density fronts are often the sites of pronounced mesoscale activity, ageostrophic frontal processes, and associated high biological production in marginal seas. Biophysical model simulations of the Catalano-Balearic Sea (Western Mediterranean) illustrated that the unstable and nonlinear southward frontal boundary current along the Spanish coast resulted in a strain-driven frontogenesis mechanism. High upwelling velocities of up to 80 m d(-1) injected nutrients into the photic layer and promoted enhanced production on the less dense, onshore side of the front characterized by negative relative vorticity. Additional down-front wind stress and heat flux (cooling) intensified boundary current instabilities and thus ageostrophic cross-frontal circulation and augmented production. Specifically, entrainment of nutrients by relatively strong buoyancy-induced vertical mixing gave rise to a more widespread phytoplankton biomass distribution within the onshore side of the front. Mesoscale cyclonic eddies contributed to production through an eddy pumping mechanism, but it was less effective and more limited regionally than the frontal processes. The model was configured for the Catalano-Balearic Sea, but the mechanisms and model findings apply to other marginal seas with similar unstable frontal boundary current systems.

Randomized, open-label trial evaluating the preventive effect of tetracycline on afatinib induced-skin toxicities in non-small cell lung cancer patients.

BACKGROUND: Afatinib has shown long progression free survival and improvement in quality of life in advanced Non-Small Cell Lung Cancer (NSCLC) patients. Although afatinib causes acneiform rash, it can be manageable. Tetracyclines are usually used to treat it; nonetheless, there is no trial that evaluates their prophylactic efficacy on afatinib induced-skin toxicities (AIST). PATIENTS AND METHODS: This open-label, randomized, controlled trial assessed the preventive effect of tetracycline for reducing afatinib-skin toxicities in NSCLC patients receiving afatinib 40 mg/day. Patients were randomly assigned to receive pre-emptive treatment with tetracycline 250 mg every 12h for 4 weeks or not. Reactive treatment in both groups included general dermatological recommendations such as use of skin moisturizers, sunscreen and topical steroids, according to toxicity severity. All patients were blindly monitored for skin toxicities by an expert dermatologist at the start of treatment with afatinib (day 0), weeks 2 and 4 of treatment. The protocol is registered on clinicaltrials.gov (NCT01880515). RESULTS: We included 90 patients, no differences were found in clinical and dermatological baseline characteristics. Rash incidence of any grade, and grade ≥2 was less frequent in the pre-emptive arm vs. the control arm (44.5 vs. 75.6%, RR 0.4 [95% CI 0.17-0.99], p=0.046 and 15.6 vs. 35.6%, RR 0.35 [95% CI, 0.12-0.91], p=0.030, respectively). No difference was found in paronychia, xerosis, mucositis, folliculitis, and skin fissure. No adverse event was associated with tetracycline. Neither rash nor pre-emptive tetracycline impacted on response rate, progression-free or overall survivals. CONCLUSION: Pre-emptive tetracycline was well tolerated and reduced the rash incidence and severity associated with afatinib in more than 60%.

Fueling plankton production by a meandering frontal jet: a case study for the Alboran Sea (Western Mediterranean).

A three dimensional biophysical model was employed to illustrate the biological impacts of a meandering frontal jet, in terms of efficiency and persistency of the autotrophic frontal production, in marginal and semi-enclosed seas. We used the Alboran Sea of the Western Mediterranean as a case study. Here, a frontal jet with a width of 15-20 km, characterized by the relatively low density Atlantic water mass, flows eastward within the upper 100 m as a marked meandering current around the western and the eastern anticyclonic gyres prior to its attachment to the North African shelf/slope topography of the Algerian basin. Its inherent nonlinearity leads to the development of a strong ageostrophic cross-frontal circulation that supplies nutrients into the nutrient-starved euphotic layer and stimulates phytoplankton growth along the jet. Biological production is larger in the western part of the basin and decreases eastwards with the gradual weakening of the jet. The higher production at the subsurface levels suggests that the Alboran Sea is likely more productive than predicted by the satellite chlorophyll data. The Mediterranean water mass away from the jet and the interiors of the western and eastern anticyclonic gyres remain unproductive.