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Assessing the risk of complex systems to natural hazards is an important but challenging problem. In today's intricate socio-technological world, characterized by strong urbanization and technological trends, the connections and interdependencies between exposed elements are crucial. These complex relationships call for a paradigm shift in collective risk assessments, from a reductionist approach to a holistic one. Most commonly, the risk of a system is estimated through a reductionist approach, based on the sum of the risk evaluated individually at each of its elements. In contrast, a holistic approach considers the whole system to be a unique entity of interconnected elements, where those connections are taken into account in order to assess risk more thoroughly. To support this paradigm shift, this paper proposes a holistic approach to analyse risk in complex systems based on the construction and study of a graph, the mathematical structure to model connections between elements. We demonstrate that representing a complex system such as an urban settlement by means of a graph, and using the techniques made available by the branch of mathematics called graph theory, will have at least two advantages. First, it is possible to establish analogies between certain graph metrics (e.g. authority, degree and hub values) and the risk variables (exposure, vulnerability and resilience) and leverage these analogies to obtain a deeper knowledge of the exposed system to a hazard (structure, weaknesses, etc.). Second, it is possible to use the graph as a tool to propagate the damage into the system, for not only direct but also indirect and cascading effects, and, ultimately, to better understand the risk mechanisms of natural hazards in complex systems. The feasibility of the proposed approach is illustrated by an application to a pilot study in Mexico City.

Flood loss modelling is a crucial part of risk assessments. However, it is subject to large uncertainty that is often neglected. Most models available in the literature are deterministic, providing only single point estimates of flood loss, and large disparities tend to exist among them. Adopting any one such model in a risk assessment context is likely to lead to inaccurate loss estimates and sub-optimal decision-making. In this paper, we propose the use of multi-model ensembles to address these issues. This approach, which has been applied successfully in other scientific fields, is based on the combination of different model outputs with the aim of improving the skill and usefulness of predictions. We first propose a model rating framework to support ensemble construction, based on a probability tree of model properties, which establishes relative degrees of belief between candidate models. Using 20 flood loss models in two test cases, we then construct numerous multi-model ensembles, based both on the rating framework and on a stochastic method, differing in terms of participating members, ensemble size and model weights. We evaluate the performance of ensemble means, as well as their probabilistic skill and reliability. Our results demonstrate that well-designed multi-model ensembles represent a pragmatic approach to consistently obtain more accurate flood loss estimates and reliable probability distributions of model uncertainty.

Methodologies to estimate economic flood damages are increasingly important for flood risk assessment and management. In this work, we present a new synthetic flood damage model based on a component-by-component analysis of physical damage to buildings. The damage functions are designed using an expert-based approach with the support of existing scientific and technical literature, loss adjustment studies, and damage surveys carried out for past flood events in Italy. The model structure is designed to be transparent and flexible, and therefore it can be applied in different geographical contexts and adapted to the actual knowledge of hazard and vulnerability variables. The model has been tested in a recent flood event in northern Italy. Validation results provided good estimates of post-event damages, with similar or superior performances when compared with other damage models available in the literature. In addition, a local sensitivity analysis was performed in order to identify the hazard variables that have more influence on damage assessment results.

This paper presents the application of a graph-based methodology for the assessment of flood impacts in an urban context. In this methodology, exposed elements are organized as nodes on a graph, which is used to propagate impacts from directly affected nodes to other nodes across graph links. Compared to traditional approaches, the main advantage of the adopted methodology lies in the possibility of identifying and understanding indirect impacts and cascading effects. The application case concerns floods numerically reconstructed in Mexico City in response to rainfall events of increasing return periods. The hazard reconstruction was carried out by using a simplified hydrological/hydraulic model of the urban drainage system, implemented in EPASWMM, the Storm Water Management Model developed by the United States Environmental Protection Agency. The paper shows how the impacts are propagated along different orders of the impact chain for each return period and compares the risk curves between direct and indirect impact. It also highlights the extent to which the reduction in demand of services from consumers and the loss of services from suppliers are respectively contributing to the final indirect impacts. Finally, it illustrates how different impact mitigation measures can be formulated based on systemic information provided by the analysis of graph properties and taking into account indirect impacts.

The operational measurement of discharge in medium and large rivers is mostly based on indirect approaches by converting water stages into discharge on the basis of steady-flow rating curves. Unfortunately, under unsteady flow conditions, this approach does not guarantee accurate estimation of the discharge due, on the one hand, to the underlying steady state assumptions and, on the other hand, to the required extrapolation of the rating curve beyond the range of actual measurements used for its derivation. Historically, several formulae were proposed to correct the steady-state discharge value and to approximate the unsteady-flow stage-discharge relationship. In the majority of these methods, the correction is made on the basis of water level measurements taken at a single cross section where a steady state rating curve is available, while other methods explicitly account for the water surface slope using stage measurements in two reference sections. However, most of the formulae available in literature are either over-simplified or based on approximations that prevent their generalisation. Moreover they have been rarely tested on cases where their use becomes essential, namely under unsteady-flow conditions characterised by wide loop rating curves. In the present work, an original approach, based on simultaneous stage measurements at two adjacent cross sections, is introduced and compared to the approaches described in the literature. The most relevant feature is that the proposed procedure allows for the application of the full dynamic flow equations without restrictive hypotheses. The comparison has been carried out on channels with constant or spatially variable geometry under a wide range of flood wave and river bed slope conditions. The results clearly show the improvement in the discharge estimation and the reduction of estimation errors obtainable using the proposed approach.

Operational real time flood forecasting systems generally require a hydrological model to run in real time as well as a series of hydro-informatics tools to transform the flood forecast into relatively simple and clear messages to the decision makers involved in flood defense. The scope of this paper is to set forth the possibility of providing flood warnings at given river sections based on the direct comparison of the quantitative precipitation forecast with critical rainfall threshold values, without the need of an on-line real time forecasting system. This approach leads to an extremely simplified alert system to be used by non technical stakeholders and could also be used to supplement the traditional flood forecasting systems in case of system failures. The critical rainfall threshold values, incorporating the soil moisture initial conditions, result from statistical analyses using long hydrological time series combined with a Bayesian utility function minimization. In the paper, results of an application of the proposed methodology to the Sieve river, a tributary of the Arno river in Italy, are given to exemplify its practical applicability.

TOPKAPI is a physically-based, fully distributed hydrological model with a simple and parsimonious parameterisation. The original TOPKAPI is structured around five modules that represent evapotranspiration, snowmelt, soil water, surface water and channel water, respectively. Percolation to deep soil layers was ignored in the old version of the TOPKAPI model since it was not important in the basins to which the model was originally applied. Based on published literature, this study developed a new version of the TOPKAPI model, in which the new modules of interception, infiltration, percolation, groundwater flow and lake/reservoir routing are included. This paper presents an application study that makes a first attempt to derive information from public domains through the internet on the topography, soil and land use types for a case study Chinese catchment - the Upper Xixian catchment in Huaihe River with an area of about 10000 km2, and apply a new version of TOPKAPI to the catchment for flood simulation. A model parameter value adjustment was performed using six months of the 1998 dataset. Calibration did not use a curve fitting process, but was chiefly based upon moderate variations of parameter values from those estimated on physical grounds, as is common in traditional calibration. The hydrometeorological dataset of 2002 was then used to validate the model, both against the outlet discharge as well as at an internal gauging station. Finally, to complete the model performance analysis, parameter uncertainty and its effects on predictive uncertainty were also assessed by estimating a posterior parameter probability density via Bayesian inference.

ABSTRACT Background: Autonomic dysfunction, an early manifestation of diabetic neuropathy, presents with altered sweating patterns, leading to dryness and fissuring. We conducted a study to assess the sweat function in [...]

Weather index insurance is an innovative tool in risk transfer for disasters induced by natural hazards. This paper proposes a methodology that uses machine learning algorithms for the identification of extreme flood and drought events aimed at reducing the basis risk connected to this kind of insurance mechanism. The model types selected for this study were the neural network and the support vector machine, vastly adopted for classification problems, which were built exploring thousands of possible configurations based on the combination of different model parameters. The models were developed and tested in the Dominican Republic context, based on data from multiple sources covering a time period between 2000 and 2019. Using rainfall and soil moisture data, the machine learning algorithms provided a strong improvement when compared to logistic regression models, used as a baseline for both hazards. Furthermore, increasing the amount of information provided during the training of the models proved to be beneficial to the performances, increasing their classification accuracy and confirming the ability of these algorithms to exploit big data and their potential for application within index insurance products.

Floods and droughts are the events that most threaten crop production; however, the impact of floods on crops is still not fully understood and often under-reported. Nowadays, multiple sources of information and approaches support the estimation of agricultural losses due to floods. This study aims to understand the differences in agricultural loss estimates provided by two conceptually different approaches (crop models and expert-based models), evaluating their sensitivity to flood hazard inputs. We investigated the challenges in flood agricultural loss assessments referring to a case study for which, in addition to model simulations, information from surveys and on-site inspections were available. Two crop models (APSIM and WOFOST) and the expert-based model AGRIDE-c were applied to evaluate agricultural yield losses after the flood event of the Panaro River (Emilia-Romagna, Northern Italy) that took place on the 6 December 2020. Two modelling tools were used to reproduce the event: the hydraulic model HEC-RAS and the image-based tool FwDET. Additionally, surveys among local farmers were conducted in the aftermath of the event to evaluate the flood features (water depth, extent and duration) and crop losses. The main findings of the study are that APSIM and WOFOST provide similar estimates of yield losses, while AGRIDE-c tends to underestimate yield losses when the losses over the entire study area are evaluated. The choice of the flood simulation technique does not influence the loss estimation since the difference between the yield loss estimates retrieved from the same model initialized with HEC-RAS or FwDET was always lower than 2%. Information retrieved from the surveys was not sufficient to validate the damage estimates provided by the models but could be used to derive a qualitative picture of the event. Therefore, further research is needed to understand how to effectively incorporate this kind of information in agricultural loss estimation.

In the last decades, resilience became officially the worldwide cornerstone to reduce the risk of disasters and improve preparedness, response, and recovery capacities. Although the concept of resilience is now clear, it is still under debate how to model and quantify it. The aim of this work was to quantify the resilience of a complex system, such as a densely populated and urbanized area, by modelling it with a graph, the mathematical representation of the system element and connections. We showed that the graph can account for the resilience characteristics included in its definition according to the United Nations General Assembly, considering two significant aspects of this definition in particular: (1) resilience is a property of a system and not of single entities and (2) resilience is a property of the system dynamic response. We proposed to represent the exposed elements of the system and their connections (i.e., the services they exchange) with a weighted and redundant graph. By mean of it, we assessed the systemic properties, such as authority and hub values and highlighted the centrality of some elements. Furthermore, we showed that after an external perturbation, such as a hazardous event, each element can dynamically adapt, and a new graph configuration is set up, taking advantage of the redundancy of the connections and the capacity of each element to supply lost services. Finally, we proposed a quantitative metric for resilience as the actual reduction of the impacts of events at different return periods when resilient properties of the system are activated. To illustrate step by step the proposed methodology and show its practical feasibility, we applied it to a pilot study: the city of Monza, a densely populated urban environment exposed to river and pluvial floods.

The development of strategies to adapt to and mitigate the potential adverse consequences of natural hazards requires support from risk assessment studies that quantify the impacts of hazardous events on our society. A comprehensive analysis of risk commonly evaluates the elements exposed to the hazard probabilistic scenarios and their vulnerabilities. However, while significant advances have been made in the assessment of direct losses, indirect impacts are less frequently examined. This work assesses the indirect consequences of two hydrologic hazards, i.e., pluvial and fluvial floods, in an urban context from a system perspective. It presents a methodology to estimate the services accessibility risk (SAR) that considers the accessibility of roads and the connection between providers and users of services in a city. The feasibility of the proposed approach is illustrated by an application to a pilot study in Monza city (northern Italy) considering pluvial and fluvial flood hazard with different return periods. The results in terms of the social and economic impacts are analyzed considering features of age, disability, and the different economic sectors.

Embryonic neurodevelopment, particularly neural progenitor differentiation into post-mitotic neurons, has been extensively studied. While the number and composition of post-mitotic neurons remain relatively constant from birth to adulthood, the brain undergoes significant postnatal maturation marked by major property changes frequently disrupted in neural diseases. This review first summarizes recent characterizations of the functional and molecular maturation of the postnatal nervous system. We then review regulatory mechanisms controlling the precise gene expression changes crucial for the intricate sequence of maturation events, highlighting experience-dependent versus cell-intrinsic genetic timer mechanisms. Despite significant advances in understanding of the gene-environmental regulation of postnatal neuronal maturation, many aspects remain unknown. The review concludes with our perspective on exciting future research directions in the next decade., Competing Interests: Declaration of interests The authors have declared no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The aim of the study was to evaluate the effects of GnRH administrated at day 35 after artificial insemination (AI) on the reproductive performance of buffalo cows. In ten buffalo farms in the period January−February, 481 buffalo cows were subjected to estrus synchronization protocol and fixed-time artificial insemination (Ovsynch−TAI program). Radioimmunoassays (RIA) for pregnancy-associated glycoproteins (PAGs) were used to detect pregnancy at day 28 after AI (cut-off value: ≥1 ng/mL). Among pregnant subjects, those with PAG values between 1 and 2.5 ng/mL were considered at risk of embryonic mortality (EM) and were assigned into two groups: treated (T; n = 57) control (C; n = 57). Treated buffaloes received 0.01 mg of buserelin acetate intramuscularly on day 35 after AI, whereas control buffaloes received no treatment. The pregnancy diagnosis was confirmed at day 60 through PAGs level and rectal palpation. The treatment with GnRH had a significant effect (p < 0.001) in reducing EM. Between days 28 and 60 after AI, the animals that experienced EM were only 2/57 in the T group, while were 13/57 in the C group. Moreover, GnRH treatment produced a significant increase (p < 0.001) in the PAG concentration between day 28 and day 60. Administration of GnRH at day 35 after AI in animals considered at risk of low embryo survival based on PAG levels allowed a reduction in pregnancy losses and improved the pregnancy rate during low-breeding season in buffalo.

Hydrogels based on hyaluronic acid are used to restore volume, hydration, and skin tone, as well as to correct scars, asymmetries or defects of the soft tissue. Hyaluronic acid is often chemically crosslinked with different crosslinking agents in order to improve its mechanical and biological properties. Here we focused on defining the chemical and mechanical characterization of a new hydrogel with specific characteristics: hyaluronic acid polyethylene glycol (PEG)-crosslinked with a high concentration of hyaluronic acid (28 mg/mL), manufactured by MatexLab Spa, via Carlo Urbani 2, ang Via Enrico Fermi, Brindisi, Italy. We made a quantitative and qualitative analysis of the content of sodium hyaluronate in the hydrogel after polymerization and sterilization processes and also evaluated histologically the bio integration of these hydrogels in the cutaneous soft tissues. The results suggest that hyaluronic acid hydrogel PEG-crosslinked have great bio integration, great chemical and mechanical properties, compared with other products available on the market, that are cross-linked with different cross-linking agents. The nontoxicity and nonimmunogenicity of PEG guarantee the lack of allergic and immunological reactions. The PEG-crosslinking technology guarantees a high duration time of the implanted hydrogel because of more resistant physiological degradation., (© 2020 Wiley Periodicals LLC.)

Background: Hyaluronic acid (HA) based hydrogels for esthetic applications found widespread use. HA should be crosslinked for this application to achieve the correct viscoelastic properties and avoid fast degradation by the hyaluronidase enzyme naturally present in the skin: these properties are controlled by the amount of crosslinker and the fraction that is effectively crosslinked (i.e. that binds two HA chains)., Aim: Crosslinking by polyethylene glycol diglycidyl ether (PEGDE) has been more recently introduced and showed attractive features in terms of viscoelastic properties and reduced biodegradation. Aim of this paper is to define a method for the determination of the crosslinking properties of these recently introduced fillers, method that is lacking at the moment., Material and Method: The percentage of crosslinker and the fraction that is effectively crosslinked were determined by proton Nuclear Magnetic Resonance (1H NMR) and by 13C NMR, respectively. The filler were preliminarily washed with acetonitrile to remove residual PEG and then digested by hyaluronidase to obtain a sample that can be analysed by NMR., Results: The crosslinking parameters were determined in four samples of NEAUVIA PEG-crosslinked dermal fillers (produced by MatexLab S.p.A., Italy). The percentage of crosslinker was between 2.8% and 6.2% of HA, whereas the effective crosslinker ratios were between 0.07 and 0.16 (ratio between the moles of effectively crosslinked PEG and total moles of PEG). Moreover, a digestion procedure alternative to enzymatic digestion, based on acidic hydrolysis, was successfully tested for the determination of crosslinker percentage., Conclusions: The proposed method successfully determined the two crosslinking parameters in PEG-crosslinked dermal fillers. The estimated percentage of crosslinker is similar to previously reported data for other crosslinkers, whereas the effective crosslinker ratio is lower for PEG crosslinked hydrogels.

Neauvia Intense is biocompatible, injectable hyaluronic acid (HA) filler PEG cross-linked for facial soft-tissue augmentation that provides volume to tissues. The aim of the present study is to evaluate the sensitivity of Neauvia Intense in hyaluronidase from bovine testes in a time-course analysis. The test is based on the colourimetric determination of the N-acetyl - D - glucosamine (NAG) released by the hyaluronidase in standardised conditions. The in vitro conditions involve the treatment of Neauvia Intense with a known concentration of the enzyme (6080U/ml). The NAG content was determined at different times to assess the kinetics of the degradation (1h, 3h, 6h, 24h, 48h, 72h, 120h, and 168h); the Ehrlich's reagent was used for the colourimetric quantification, by the method described by Reissing and colleagues. The intensity of the violet colour developed after the chemical reaction was proportional to the NAG present in each sample. A microplate reader at 585 nm read the absorbance. The amount of NAG released by the product was proportional to the time of incubation with bovine hyaluronidase, reaching a plateau after 168 hours.

Drug safety is a very relevant issue when dealing with patients with chronic kidney disease (CKD) who need vascular access procedures and interventions. Drug dosage adjustments are needed for patients with acute or chronic kidney disease. In CKD patients, the estimated glomerular filtration rate is used to guide dose adjustments. Determining the influence of renal replacement therapies on drug dosage adjustment is also very important. Safety issues for the following drugs used for situations related to vascular access are reported: anticoagulants and antiplatelet agents, antibiotics, antimicrobials for catheter lock therapy, thrombolytics, local anesthetics, and painkillers. General principles of the interactions of drugs in CKD are also reported., (© 2015 S. Karger AG, Basel.)

Several metabolic diseases present a high cardiovascular mortality due to endothelial dysfunction consequences. In the last years of the past century, it has come to light that the endothelial cells, previously considered as inert in what regards an eventual secretion activity, play a pivotal role in regulating different aspects of the vascular function (endothelial function). It was clearly demonstrated that the endothelium acts as a real active organ, owning endocrine, paracrine and autocrine modulation activities by means of which it is able to regulate the vascular homeostasis. The present review will investigate the relationship between some metabolic diseases and the endothelial dysfunction and in particular the mechanisms underlying the effects of metabolic pathologies on the endothelium. Furthermore, it will consider the possible therapeutic employment of the N-acetilcysteine in such conditions.

Recently a great interest has been expressed in electrophoretic deposition (EPD) of polymers, both as particles and as chains. It is generally accepted that also for polymer particles, the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory is valid, therefore, in principle, polymer suspensions suitable for EPD could be easily obtained by dispersing polymer particles in an aqueous or nonaqueous medium. Nevertheless, this work demonstrated that in order to obtain good quality deposits based on poly(ether ether ketone) (PEEK) and poly(tetrafluoroethylene) (PTFE), some additives have to be used. In the case of PEEK, a dispersant providing citrate anions was successfully used, whereas for PTFE a steric suspension stabilization was reached by adding polyvinylpyrrolidone (PVP). In such a way, codeposition of PEEK and PTFE was achieved. The efficiency of the EPD process was demonstrated by means of differential scanning calorimetry (DSC) measurements. A thermal program consisting of heat/cool/heat cycles at a low rate was used in order to evaluate the crystalline amount of each polymer in the deposits. In order to explain the obtained results, it needed to also consider the dimension and structural characteristic of the polymer particles.

New carbon nanomaterials, i.e., carbon nanotubes and nanofibers, with special physico-chemical properties, are recently studied as support for methanol oxidation reaction electrocatalysts replacing the most widely used carbon black. Particularly, carbon fibrous structures with high surface area and available open edges are thought to be promising. Platelet type carbon nanofibers, which have the graphene layers oriented perpendicularly to the fiber axis, exhibit a high ratio of edge to basal atoms. Different types of carbon nanofibers (tubular and platelet) were grown by plasma enhanced chemical vapour deposition on carbon paper substrates. The process was controlled and optimised in term of growth pressure and temperature. Carbon nanofibers were characterised by high resolution scanning electron microscopy and X-ray photoelectron spectroscopy to assess the morphological properties. Then carbon nanofibers of both morphologies were used as substrates for Pt electrodeposition. High resolution scanning electron microscopy images showed that the Pt nanoparticles distribution was well controlled and the particles size went down to few nanometers. Pt/carbon nanofibers nanocomposites were tested as electrocatalysts for methanol oxidation reaction. Cyclic voltammetry in H2SO4 revealed a catalyst with a high surface area. Cyclic voltammetry in presence of methanol indicated a high electrochemical activity for methanol oxidation reaction and a good long time stability compared to a carbon black supported Pt catalyst.

In dialysis patients, both central venous catheter (CVC) insertion and CVC use during the dialysis procedure pose important legal issues, because of potentially severe, even fatal, complications. The first issue is the decision of the kind of vascular access that should be proposed to patients: an arteriovenous (AV) fistula, a graft, or a CVC. The second issue, when choosing the CVC option, is the choice of CVC: nontunneled versus tunneled. Leaving a temporary nontunneled CVC for a prolonged time increases the risk of complications and could raise a liability issue. Even when choosing a long-term tunneled CVC, nephrologists should systematically explain its potential harms, presenting them as "unsafe for long-term use" unless there is a clear contraindication to an AV native or prosthetic access. Another critical issue is the preparation of a complete, informative, and easy-to-understand consent form. The CVC insertion procedure has many aspects of legal interest, including the choice of CVC, the use of ECG monitoring, the use of ultrasound guidance for cannulation, and the use of fluoroscopy for checking the position of the metal guidewire during the procedure as well as the CVC tip before the end of the procedure. Use of insertion devices and techniques that can prevent complications should obviously be encouraged. Complications of CVC use are mainly thrombosis and infection. These are theoretically expected as pure complications (and not as malpractice effects), but legal issues might relate to inappropriate catheter care (in both the inpatient and outpatient settings) rather than to the event per se. Thus, in the individual case it is indeed very difficult to establish malpractice and liability with a catheter-related infection or thrombosis. In conclusion, we cannot avoid complications completely when using CVCs, but reducing them to a minimum and adopting safe approaches to their insertion and use will reduce legal liability.

This mini-review takes into consideration the physiology, synthesis and mechanisms of action of the nitric oxide (NO) and, subsequently, the causes and effects of the NO bioavailability impairment. In diabetes mellitus the reduced NO bioavailability is caused by the increased free radicals production, secondary to hyperglycemia. The reactive oxygen species oxidize the cofactors of the nitric oxide synthase, diminishing their active forms and consequently leading to a decreased NO production. Furthermore the decreased concentration of reduced glutathione results in a diminished production of nitrosoglutathione. These molecules are important intermediates of the NO pathway and physiologically activate the soluble guanylate cyclase. Their decrease in oxidative states of the cell, therefore, leads to a reduced cGMP production which represents the principal molecule that carries out NO's major effects. Finally we considered the eventual therapeutic strategies to improve NO bioavailability by acting on the causes of its decrease. Therefore the treatments proposed are based on the possibility to counteract the oxidation and, in this context, the physiopathological mechanisms strongly support the treatment with thiols.

Vitamin D deficiency appears to be an underestimated risk factor for cardiovascular disease in patients with chronic kidney disease. Evidence from both basic science and clinical studies supports the possible protective role of vitamin D beyond its effect on mineral metabolism. Toxicity of pharmacologic doses of active vitamin D metabolites, in particular calcitriol, is mainly due to the possibility of positive calcium and phosphorus balance. Therefore, vitamin D analogs have been developed, which suppress PTH secretion and synthesis with reduced calcemic and phosphatemic effects. Observational studies suggest that in hemodialysis patients the use of a vitamin D receptor (VDR) activator, such as calcitriol, doxercalciferol, paricalcitol, or alfacalcidol, is associated with a reduced mortality when compared with nonusers of any VDR activator. In this article the existing literature on the topic is reviewed, although a more robust answer to the question of whether or not VDR activators have beneficial effects in hemodialysis patients will hopefully come from a randomized controlled trial.