Search

Abstract Background Secondary anterior cruciate ligament (ACL) ruptures are a relevant clinical concern after surgical treatment of a primary ACL rupture. However, there is a lack of scientific evidence related to the role of muscle strength prior to revision surgery in a second ACL rupture. The aim of this study was to assess differences in knee extensor and flexor strength in patients before primary and secondary ACL reconstruction compared to healthy controls. Methods In total, n = 69 age, weight and sex matched individuals were included in the study: n = 23 patients with isolated primary ACL rupture, n = 23 with secondary ACL rupture, and n = 23 matched healthy controls. Maximal isokinetic knee extension and flexion torque normalized to body mass was assessed for both legs. Results For patients with secondary ACL ruptures, torques were reduced in the non-injured (extension: 1.94 Nm/kg vs. 2.46 Nm/kg, p

Optical satellite-derived surface water monitoring is challenging because of the spatial gaps in images caused by clouds, cloud shadows, voids, etc. Here, an efficient method for filling gaps in time-series surface water images is proposed, based on the spatiotemporal characteristics of water. This method utilises the accurately classified historical ternary (gap, water, non-water) or binary (water, non-water) water image time-series and the clear part of the ternary gap water image. Pixels with values of 0 and 1 in the same period water occurrence image are first used to correct the gap water image. The spatial neighbourhood similarity is then calculated as a quality control band for mosaicking the accurately classified historical water images. The final result is generated by replacing the gap pixels with a mosaic image. The proposed method was implemented on the Google Earth Engine, and 93 Landsat 8 top-of-atmosphere (TOA) images were used to verify its validity. Quantitative evaluations were adequate, with a mean accuracy, recall, and precision of 0.98, 0.90, and 0.85, respectively. The proposed method could improve the utilisation of optical remote sensing data and would be applicable to the production of large-area homogeneous surface water time-series and water resource monitoring.

Mohammad Arafat,1 Yunmei Song,1 Kyle Brewer,2 Paris Fouladian,1 Ankit Parikh,1 Hugo Albrecht,3 Anton Blencowe,2 Sanjay Garg1 1Pharmaceutical Innovation and Development (PIDG) Group, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia; 2Applied Chemistry and Translational Biomaterials (ACTB) Group, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia; 3Drug Discovery and Development Group, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, AustraliaCorrespondence: Sanjay GargPharmaceutical Innovation and Development (PIDG) Group, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, AustraliaEmail Sanjay.Garg@unisa.edu.auAnton BlencoweApplied Chemistry and Translational Biomaterials (ACTB) Group, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, AustraliaEmail Anton.Blencowe@unisa.edu.auBackground: Drug-eluting gastrointestinal (GI) stents are emerging as promising platforms for the treatment of GI cancers and provide the combined advantages of mechanical support to prevent lumen occlusion and as a reservoir for localized drug delivery to tumors. Therefore, in this work we present a detailed quality assurance study of 5-fluorouracil (5FU) drug-eluting stents (DESs) as potential candidates for the treatment of obstructive GI cancers.Methods: The 5FU DESs were fabricated via a simple two-step sequential dip-coating process of commercial GI self-expanding nitinol stents with a 5FU-loaded polyurethane basecoat and a drug-free protective poly(ethylene-co-vinyl acetate) topcoat. The drug loading, content uniformity and drug stability were determined using a validated high-performance liquid chromatography (HPLC) method, which is also recommended in the United States Pharmacopeia. In vitro drug release studies were performed in phosphate buffered saline to determine the drug releasing properties of the two 5FU-loaded stents. Gas chromatography (GC) and HPLC were employed to determine total residual tetrahydrofuran and N,N-dimethylformamide in the stents remaining from the manufacturing process. Sterilization of the stents was performed using gamma radiation and stability testing was carried out for 3 months.Results: The drug loading analysis revealed excellent uniformity in the distribution of 5FU between and within individual stents. Determination of drug stability in the biorelevant release media confirmed that 5FU remains stable over 100 d. In vitro drug release studies from the stents revealed sustained release of 5FU across two different time scales (161 and 30 d), and mathematical modeling of drug release profiles revealed a diffusion-controlled mechanism for the sustained 5FU release. GC and HPLC analysis revealed that the daily residual solvent leached from the stents was below the United States (US) Food and Drug Administration (FDA) guidelines, and therefore, unlikely to cause localized/systemic toxicities. Sterilization of the stents with gamma radiation and accelerated stability tests over a period of 3 months revealed no significant effect on the stability or in vitro release of 5FU.Conclusion: Our results demonstrate that the 5FU DESs meet relevant quality standards and display favourable drug release characteristics for the potential treatment of GI cancers and related obstructions.Keywords: drug-eluting stent, 5-fluorouracil, gastrointestinal cancer, self-expanding metal stents

Ensemble projections of future changes in discharge over Europe show large variation. Several methods for performance-based weighting exist that have the potential to increase the robustness of the change signal. Here we use future projections of an ensemble of three hydrological models forced with climate datasets from the Coordinated Downscaling Experiment - European Domain (EURO-CORDEX). The experiment is set-up for nine river basins spread over Europe that hold different climate and catchment characteristics. We evaluate the ensemble consistency and apply two weighting approaches; the Climate model Weighting by Independence and Performance (ClimWIP) that focuses on meteorological variables and the Reliability Ensemble Averaging (REA) in our study applied to discharge statistics per basin. For basins with a strong climate signal, in Southern and Northern Europe, the consistency in the set of projections is large. For rivers in Central Europe the differences between models become more pronounced. Both weighting approaches assign high weights to single General Circulation Models (GCMs). The ClimWIP method results in ensemble mean weighted changes that differ only slightly from the non-weighted mean. The REA method influences the weighted mean more, but the weights highly vary from basin to basin. We see that high weights obtained through past good performance can provide deviating projections for the future. It is not apparent that the GCM signal dominates the overall change signal, i.e., there is no strong intra GCM consistency. However, both weighting methods favored projections from the same GCM.

Sanjay Tripathi,1 Ashish Nikhare,2 Gaurav Sharma,3 Tim Shea,4 Helmut Albrecht5 1Department of Pulmonary Medicine, Sheth LG General Hospital & AMC MET Medical College, Ahmedabad, India; 2Department of Pulmonology, Lata Mangeshkar Hospital, Nagpur, India; 3Regional Medical Affairs (South of Asia), Reckitt Benckiser, Haryana, India; 4Global Medical - Respiratory, Reckitt Benckiser, Parsippany, NJ, USA; 5Department of Cellular Biology & Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USACorrespondence: Tim SheaReckitt Benckiser, 399 Interpace Parkway, Parsippany, NJ 07054, USATel +1 973 404 2883Fax +1 201-573-6325Email Tim.Shea@rb.comPurpose: An extended-release (ER) formulation of the expectorant guaifenesin has recently been launched in India for the treatment of productive cough accompanied by mucus (phlegm). Although the safety profile of ER guaifenesin marketed in the USA is well documented, there were limited safety data available in the Indian population. The aim of this study was to further elucidate the safety profile of ER guaifenesin in patients with acute upper respiratory tract infection (URTI).Patients and methods: A prospective, post-marketing surveillance study enrolled 552 adults with cough, thickened mucus and chest congestion due to URTI, who took ER guaifenesin 1200 mg (Mucinex®, Reckitt Benckiser; two 600 mg tablets) every 12 hrs for 7 days. Adverse events (AEs) were recorded and questionnaires administered to patients and investigators.Results: A total of 29 treatment-emergent AEs were recorded in 28/552 patients, including gastrointestinal (n = 11), nervous system (n = 8), psychiatric (n = 3), respiratory, thoracic and mediastinal (n = 2), skin and subcutaneous tissue (n = 2), and general disorders (n = 3). All AEs were mild in severity and no serious AEs or deaths occurred. The majority of both patients and investigators were either satisfied or very satisfied with improvements in treatment outcomes.Conclusion: This study found that ER guaifenesin was well tolerated and had a favorable safety profile in otherwise healthy patients suffering from symptoms of cough, thickened mucus and chest congestion associated with URTI. Registered trial NCT03725085 (ClinicalTrials.gov) and CTRI/2014/07/004730 (ctri.nic.in).Keywords: expectorant, guaifenesin, Mucinex, post-marketing surveillance, safety profile, satisfaction

Droughts can be studied from an atmospheric perspective by analysing large-scale dynamics and thermodynamics, and from a hydrological perspective by analysing interaction of precipitation, evaporation, soil moisture and temperature at the land-surface. Here, we study it from both perspectives, and assess the moisture (evaporative) sources of precipitation in the Rhine basin during the exceptionally dry summers of 2003 and 2018. We use ERA5 re-analysis data (1979–2018) and the Eulerian moisture tracking model WAM-2layers in order to determine the moisture sources of the Rhine basin. During an average summer, these evaporative sources are mostly located over the Atlantic Ocean, and there is a large contribution from continental evaporation, mostly from regions west of the Rhine basin. Both in 2003 and 2018 the absolute moisture source contribution declined over the ocean. In both years the anomalous moisture fluxes over the boundaries of the Rhine basin are mainly a result of anomalous wind and not because of anomalous moisture advection by the mean wind. Due to high pressure (blocking) over Europe, moisture is transported from the ocean with anticyclonic flow around the Rhine basin, but not into the basin. In 2018, unlike 2003, moisture is transported from the east towards the basin as a result of the anticyclonic flow around the Scandinavian blocking. The large-scale synoptic situation during the summer of 2018 was exceptional, and very favourable for dry conditions over the Rhine basin. Although blocking also occurred in 2003, the exact synoptic conditions were less favourable to dryness over the Rhine basin. In 2003 however, the recycling of moisture within the basin was much lower than the climatology and 2018, especially in August, possibly indicating the drying out of the soil resulting in the second heatwave in August 2003. To conclude, although the summer of 2003 and 2018 were both exceptionally dry, their characteristics in terms of moisture sources and recycling, and thereby their dependence on the large-scale circulation and land-atmosphere interactions, were found to be very different. It is therefore imperative that droughts are also studied as individual events to advance understanding of complex interactions between the large-scale atmospheric processes and the land surface.

Wei Zhang,1 Yunmei Song,1 Preethi Eldi,1 Xiuli Guo,2 John D Hayball,1,3 Sanjay Garg,1 Hugo Albrecht1 1Centre for Pharmaceutical Innovation and Development, Centre for Drug Discovery and Development, Experimental Therapeutics Laboratory, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia; 2Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan, China; 3Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia Abstract: Prostate cancer cells frequently overexpress the gastrin-releasing peptide receptor, and various strategies have been applied in preclinical settings to target this receptor for the specific delivery of anticancer compounds. Recently, elastin-like polypeptide (ELP)-based self-assembling micelles with tethered GRP on the surface have been suggested to actively target prostate cancer cells. Poorly soluble chemotherapeutics such as docetaxel (DTX) can be loaded into the hydrophobic cores of ELP micelles, but only limited drug retention times have been achieved. Herein, we report the generation of hybrid ELP/liposome nanoparticles which self-assembled rapidly in response to temperature change, encapsulated DTX at high concentrations with slow release, displayed the GRP ligand on the surface, and specifically bound to GRP receptor expressing PC-3 cells as demonstrated by flow cytometry. This novel type of drug nanocarrier was successfully used to reduce cell viability of prostate cancer cells in vitro through the specific delivery of DTX. Keywords: ELP-GRP, micelle, liposome, docetaxel, prostate cancer, GRPR, GPCR

Combining metamodels with data assimilation schemes allows the incorporation of up-to-date information in metamodels, offering new opportunities for operational water resources management. We developed a data assimilation scheme for the unsaturated zone metamodel MetaSWAP using OpenDA, which is an open source data assimilation framework. A twin experiment showed the feasibility of applying an Ensemble Kalman filter as a data assimilation method for updating metamodels. Furthermore, we assessed the accuracy of root zone soil moisture model estimates when assimilating the regional SMAP L3 Enhanced surface soil moisture product. The model accuracy is assessed using in situ soil moisture measurements collected at 12 locations in the Twente region, the Netherlands. Although the accuracy of the model estimates does not improve in terms of correlation coefficient, the accuracy does improve in terms of Root Mean Square Error and bias. Therefore, the assimilation of surface soil moisture observations has value for updating root zone soil moisture model estimates. In addition, the accuracy of the model estimates improves on both regional and local spatial scales. The increasing availability of remotely sensed soil moisture data will lead to new possibilities for integrating metamodelling and data assimilation in operational water resources management. However, we expect that significant investments in computational capacities are necessary for effective implementation in decision-making. Keywords: Data assimilation, Ensemble Kalman filter, Hydrological modelling, Metamodelling, Remote sensing, SMAP, Soil moisture

The EU Roadmap on climate services can be seen as a result of a convergence between the society's call for “actionable research”, and the ability of the climate research community to provide tailored data, information and knowledge. However, although weather and climate have clearly distinct definitions, a strong link between weather and climate services exists that is not explored extensively. Stakeholders being interviewed in the context of the Roadmap consider climate as a far distant long term feature that is difficult to incorporate in present-day decision taking, which is dominated by daily experience with handling extreme events. In this paper we argue that this experience is a rich source of inspiration to increase society's resilience to an unknown future.A newly started European research project, IMPREX, is built on the notion that “experience in managing current day weather extremes is the best learning school to anticipate consequences of future climate”. This paper illustrates possible ways to increase the link between information and services for the water sector, by addressing weather and climate time scales and discussing the underlying concepts of IMPREX and its expected outcome. Keywords: Climate services, Water, Sectoral climate impacts, Weather forecasting, Climate projections

IMproving PRedictions and management of hydrological EXtremes (IMPREX) was a European Union Horizon 2020 project that ran from September 2015 to September 2019. IMPREX aimed to improve society’s ability to anticipate and respond to future extreme hydrological events in Europe across a variety of uses in the water-related sectors (flood forecasting, drought risk assessment, agriculture, navigation, hydropower and water supply utilities). Through the engagement with stakeholders and continuous feedback between model outputs and water applications, progress was achieved in better understanding the way hydrological predictions can be useful to (and operationally incorporated into) problem-solving in the water sector. The work and discussions carried out during the project nurtured further reflections toward a common vision for hydrological prediction. In this article, we summarized the main findings of the IMPREX project within a broader overview of hydrological prediction, providing a vision for improving such predictions. In so doing, we first presented a synopsis of hydrological and weather forecasting, with a focus on medium-range to seasonal scales of prediction for increased preparedness. Second, the lessons learned from IMPREX were discussed. The key findings were the gaps highlighted in the global observing system of the hydrological cycle, the degree of accuracy of hydrological models and the techniques of post-processing to correct biases, the origin of seasonal hydrological skill in Europe and user requirements of hydrometeorological forecasts to ensure their appropriate use in decision-making models and practices. Last, a vision for how to improve these forecast systems/products in the future was expounded, including advancing numerical weather and hydrological models, improved earth monitoring and more frequent interaction between forecasters and users to tailor the forecasts to applications. We conclude that if these improvements can be implemented in the coming years, earth system and hydrological modelling will become more skillful, thus leading to socioeconomic benefits for the citizens of Europe and beyond.

Purpose: Previous evidence indicated that the tibiofemoral bone configuration might elevate the risk of an anterior cruciate ligament (ACL) injury. Furthermore, a low hamstring‐to‐quadriceps muscle ratio predisposes especially females to unfavourable knee kinematics. The primary objective of the present study was to investigate sex‐specific associations between tibiofemoral bone geometry and isokinetic knee flexion torque in patients with primary ACL injury followed by ACL reconstruction. Methods: N = 100 patients (72 = male, 28 = female, age = 31.3 ± 10.2, body mass index = 25.3 ± 3.6) with primary ACL rupture with isokinetic knee flexion torque assessments before and 6 months after ACL reconstruction surgery were analysed. Magnetic resonance imaging scans were analysed for medial posterior tibial slope (MPTS) and lateral posterior tibial slope, notch width index (NWI) and lateral femoral condyle index (LFCI). Additionally, isokinetic knee flexion torque (60°/s) and hamstring–quadriceps ratios were evaluated. Subsequently, functional parameters were correlated with imaging data for gender subgroups. Results: The findings showed that presurgical isokinetic knee flexion torque was not associated with any marker of femoral or tibial bone geometry. Further, while significant differences were observed between female (0.883 ± 0.31 Nm/kg) and male (1.18 ± 0.35 Nm/kg) patients regarding preoperative normalized knee flexion torque (p < 0.001), no significant sex differences were found for percentage increases in normalized knee flexion torque from presurgery to postsurgery. Generally, female patients demonstrated significantly higher MPTS magnitudes (p < 0.05) and lower LFCI values (p < 0.05) compared to men. Conclusion: The present results demonstrated no association between tibial or femoral bone geometry and muscle strength of the hamstrings in patients with ACL reconstruction, indicating an important mismatch of muscular compensation to deviations in bone geometry. There were no sex‐specific differences in tibiofemoral bone parameters. Level of Evidence: Level III. [ABSTRACT FROM AUTHOR]

In the past decades significant progress has been made in the fitting of hydrologic models to data. Most of this work has focused on simple, CPU-efficient, lumped hydrologic models using discharge, water table depth, soil moisture, or tracer data from relatively small river basins. In this paper, we focus on large-scale hydrologic modeling and analyze the effect of parameter and rainfall data uncertainty on simulated discharge dynamics with the global hydrologic model PCR-GLOBWB. We use three rainfall data products; the CFSR reanalysis, the ERA-Interim reanalysis, and a combined ERA-40 reanalysis and CRU dataset. Parameter uncertainty is derived from Latin Hypercube Sampling (LHS) using monthly discharge data from five of the largest river systems in the world. Our results demonstrate that the default parameterization of PCR-GLOBWB, derived from global datasets, can be improved by calibrating the model against monthly discharge observations. Yet, it is difficult to find a single parameterization of PCR-GLOBWB that works well for all of the five river basins considered herein and shows consistent performance during both the calibration and evaluation period. Still there may be possibilities for regionalization based on catchment similarities. Our simulations illustrate that parameter uncertainty constitutes only a minor part of predictive uncertainty. Thus, the apparent dichotomy between simulations of global-scale hydrologic behavior and actual data cannot be resolved by simply increasing the model complexity of PCR-GLOBWB and resolving sub-grid processes. Instead, it would be more productive to improve the characterization of global rainfall amounts at spatial resolutions of 0.5° and smaller.

The wflow_sbm hydrological model, recently released by Deltares, as part of the Wflow.jl (v0.7.3) modelling framework, is being used to better understand and potentially address multiple operational and water resource planning challenges from a catchment scale to national scale to continental and global scale. Wflow.jl is a free and open-source distributed hydrological modelling framework written in the Julia programming language. The development of wflow_sbm, the model structure, equations and functionalities are described in detail, including example applications of wflow_sbm. The wflow_sbm model aims to strike a balance between low-resolution, low-complexity and high-resolution, high-complexity hydrological models. Most wflow_sbm parameters are based on physical characteristics or processes, and at the same time wflow_sbm has a runtime performance well suited for large-scale high-resolution model applications. Wflow_sbm models can be set a priori for any catchment with the Python tool HydroMT-Wflow based on globally available datasets and through the use of point-scale (pedo)transfer functions and suitable upscaling rules and generally result in a satisfactory (0.4 ≥ Kling–Gupta efficiency (KGE) < 0.7) to good (KGE ≥ 0.7) performance for discharge a priori (without further tuning). Wflow_sbm includes relevant hydrological processes such as glacier and snow processes, evapotranspiration processes, unsaturated zone dynamics, (shallow) groundwater, and surface flow routing including lakes and reservoirs. Further planned developments include improvements on the computational efficiency and flexibility of the routing scheme, implementation of a water demand and allocation module for water resource modelling, the addition of a deep groundwater concept, and computational efficiency improvements through for example distributed computing and graphics processing unit (GPU) acceleration. [ABSTRACT FROM AUTHOR]