[Metabolic management and nutrition in critically ill patients with renal dysfunction : Recommendations from the renal section of the DGIIN, ÖGIAIN, and DIVI]. / Metabolische Führung und Ernährung von Intensivpatienten mit renaler Dysfunktion : Empfehlungen der Sektionen Niere der DGIIN, ÖGIAIN und DIVI.

BACKGROUND: Intensive care patients with renal failure or insufficiency comprise a heterogeneous group of subjects with widely differing metabolic patterns and nutritional requirements. They include subjects with various stages of acute kidney injury (AKI), acute-on-chronic renal failure (A-CKD), without/with renal replacement therapy (RRT), chronic kidney disease (CKD), and subjects on regular hemodialysis or peritoneal dialysis therapy (HD/PD). GOALS: Development of recommendations by the renal section of DGIIN (Deutsche Gesellschaft für Internistische Intensivmedizin und Notfallmedizin), ÖGIAIN (Österreichische Gesellschaft für Internistische und Allgemeine Intensivmedizin und Notfallmedizin) and DIVI (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin) for the metabolic management and the planning, indication, implementation, and monitoring of nutrition therapy in this heterogeneous group of patients. MATERIALS AND METHODS: The recommendations are based on recent evidence and current recommendations of DGEM (Deutsche Gesellschaft für Ernährungsmedizin), ASPEN (American Society for Parenteral and Enteral Nutrition) and ESPEN (European Society for Clinical Nutrition and Metabolism) and also the KDGIO (Kidney Disease: Improving Global Outcomes) clinical practice guidelines for AKI and the expert knowledge and clinical experience of the authors. RESULTS: Nutrition support in these patient groups is not fundamentally different from that in other disease states but must consider the multiple variations in metabolism and nutrient requirements. Nutrition therapy must be adapted to the stage of disease and especially, in those patients on RRT. Nutritional needs can differ widely between patients but also in the same patient during the course of the disease. CONCLUSIONS: Thus, the patient with renal failure requires an individualized approach in nutrition support and because of the altered metabolism of many nutrients and intolerances for electrolytes and fluids, the nutrition support in patients with renal insufficiency requires close clinical and laboratory monitoring.

[Regional citrate anticoagulation in renal replacement therapy in the intensive care station : Recommendations from the renal section of the DGIIN, ÖGIAIN and DIVI]. / Regionale Zitratantikoagulation bei Nierenersatzverfahren auf der Intensivstation : Empfehlungen der Sektionen Niere der DGIIN, ÖGIAIN und DIVI.

BACKGROUND: Regional citrate anticoagulation (RCA) in continuous renal replacement therapy can effectively anticoagulate dialysis circuits without having adverse effects on systemic heparin application. In particular, in continuous renal replacement therapy RCA is well established and represents a safe procedure with longer filter lifetimes and fewer bleeding complications. OBJECTIVES: To provide guidance on the indications, advantages and disadvantages, and use of RCA, current recommendations from the renal section of the DGIIN (Deutschen Gesellschaft für Internistische Intensivmedizin und Notfallmedizin), ÖGIAIN (Österreichischen Gesellschaft für Internistische und Allgemeine Intensivmedizin und Notfallmedizin) and DIVI (Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin) are stated. MATERIALS AND METHODS: The recommendations in this paper are based on the current KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, other published guidelines and protocols as well as the expert knowledge and clinical experience of the authors. RESULTS: The use of commercially available machines with coupled pumps and integrated safety features, effective personal training and standardized protocols for clinical usage (SOP) is particularly important for the safe clinical use of RCA in renal replacement therapy. Contrary to previous recommendations, even liver failure or shock with lactic acidosis may no longer be an absolute contra-indication for RCA. However, these particular patients have to be carefully monitored for signs of citrate accumulation.

[Extracorporeal renal replacement therapy in acute kidney injury : Recommendations from the renal section of the DGIIN, ÖGIAIN and DIVI]. / Extrakorporale Nierenersatztherapie bei akuter Nierenschädigung : Empfehlungen der Sektionen "Niere" der DGIIN, ÖGIAIN und DIVI.

BACKGROUND: Acute kidney injury (AKI) is a common complication in intensive care unit (ICU) patients. The incidence of AKI in ICU patients exceeds 50% and the associated morbidity and mortality rates increase with severity of AKI. In addition, long-term consequences of AKI are underestimated and several studies show impaired long-term outcome after AKI. In about 5-25% of ICU patients with AKI renal replacement therapy (RRT) is required. OBJECTIVES: To assist in indication, timing, modality and application of renal replacement therapy of adult patients, current recommendations from the renal sections of the DGIIN (Deutschen Gesellschaft für Internistische Intensivmedizin und Notfallmedizin), ÖGIAIN (Österreichischen Gesellschaft für Internistische und Allgemeine Intensivmedizin und Notfallmedizin) and DIVI (Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin) are stated. MATERIALS AND METHODS: The recommendations stated in this paper are based on the current KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, recommendations from the 17th Acute Disease Quality Initiative (ADQI) Consensus Group, the French Intensive Care Society (SRLF) with the French Society of Anesthesia Intensive Care (SFAR) and the expert knowledge and clinical experience of the authors. RESULTS: Today, different treatment modalities for RRT are available. Although continuous RRT and intermittent dialysis therapy as well as continuous dialysis therapy have comparable outcomes, differences exist with respect to practical application as well as health-economic aspects. Individualized risk stratification might be helpful to choose the right time to start and the right treatment modality for patients.

[Dose adjustment of anti-infective drugs in patients with renal failure and renal replacement therapy in intensive care medicine : Recommendations from the renal section of the DGIIN, ÖGIAIN and DIVI]. / Dosierung von Antiinfektiva bei Nierenversagen und Nierenersatztherapie in der Intensivmedizin : Empfehlungen der Sektionen Niere der DGIIN, ÖGIAIN und DIVI.

BACKGROUND: Many anti-infective drugs require dose adjustments in critically ill patients with acute kidney injury (AKI) and renal replacement therapy, in order to achieve adequate therapeutic drug concentrations. OBJECTIVES: The fundamental pharmacokinetic and pharmacodynamic principles of drug dose adjustment are presented. Recommendations on anti-infective drug dosage in intensive care are provided. MATERIALS AND METHODS: We established dose recommendations of selected anti-infective drugs based on information in the summary of product characteristics, published studies and recommendations, pharmacokinetic and pharmacodynamic considerations, and the experience and expert opinion of the authors. RESULTS: Out of a total of 37 anti-infective drugs (31 antibiotics, 2 antivirals, 4 antifungals) 8 can be administered independent of renal function. For 29 anti-infective drugs, a specific recommendation on drug dosage could be made in case of intermittent hemodialysis and for 24 anti-infective drugs in case of continuous hemo(dia)filtration. CONCLUSIONS: Recommendations on dosing of important anti-infective drugs in critically ill patients with AKI and renal replacement therapy are provided.

[Prevention of acute kidney injury in critically ill patients : Recommendations from the renal section of the DGIIN, ÖGIAIN and DIVI]. / Prävention der akuten Nierenschädigung beim kritisch kranken Patienten : Empfehlungen der Sektionen Niere der DGIIN, ÖGIAIN und DIVI.

BACKGROUND: Acute kidney injury (AKI) has both high mortality and morbidity. OBJECTIVES: To prevent the occurrence of AKI, current recommendations from the renal section of the DGIIN (Deutschen Gesellschaft für Internistische Intensivmedizin und Notfallmedizin), ÖGIAIN (Österreichischen Gesellschaft für Internistische und Allgemeine Intensivmedizin und Notfallmedizin) and DIVI (Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin) are stated. MATERIALS AND METHODS: The recommendations stated in this paper are based on the current Kidney Disease Improving Global Outcomes (KDIGO) guidelines, the published statements of the "Working Group on Prevention, AKI section of the European Society of Intensive Care Medicine" and the expert knowledge and clinical experience of the authors. RESULTS: Currently there are no approved clinically effective drugs for the prevention of AKI. Therefore the mainstay of prevention is the optimization of renal perfusion by improving the mean arterial pressure (>65 mm Hg, higher target may be considered in hypertensive patients). This can be done by vasopressors, preferably norepinephrine and achieving or maintaining euvolemia. Hyperhydration that can lead to AKI itself should be avoided. In patients with maintained diuresis this can be done by diuretics that are per se no preventive drug for AKI. Radiocontrast enhanced imaging should not be withheld from patients at risk for AKI; if indicated, however, the contrast media should be limited to the smallest possible volume.

[Acute kidney injury: choice of the initial modality for renal replacement therapy]. / Akutes Nierenversagen--Auswahl der Nierenersatztherapie.

Continuous and intermittent renal replacement therapies are thought to be equally adequate approaches for the treatment of patients with acute kidney injury. Accordingly, current guidelines advocate the use of different modalities in a complementary fashion, i.e., to tailor therapy to the specific clinical situation. In patients with hemodynamic instability or at risk of cerebral edema, continuous renal replacement therapy or prolonged intermittent renal replacement therapy should, however, be preferred. Intermittent hemodialysis, on the other hand, remains the therapy of choice for the rapid correction of life-threatening electrolyte abnormalities or metabolic acidosis. During the further course of treatment, an individualized approach should be continued which may include a switch between modalities based on current therapeutic goals and potential risks for side effects of renal replacement therapy.

[Treatment of acute renal failure in Germany: Analysis of current practice]. / Versorgung des akuten Nierenversagens auf deutschen Intensivstationen: Analyse der aktuellen Behandlungspraxis.

BACKGROUND AND OBJECTIVES: There are currently no reliable data on the differential use of renal replacement therapy (RRT) options for critically ill patients with acute renal failure in Germany. PATIENTS AND METHODS: A questionnaire-based survey was delivered to 2265 German intensive care units. The questionnaire contained 19 questions regarding RRT. RESULTS: A total of 423 German intensive care units participated in the survey. The offered modalities of RRT varied significantly: the smaller the facility, the fewer different RRT options were available. Intermittent dialysis procedures were available in only 35% of hospitals with up to 400 beds. In university hospitals, hemodynamically unstable patients were exclusively treated by continuous RRT, whereas in hospitals with up to 400 beds, intermittent RRT was also used. In addition, treatment practice was also dependent on the specialization of the treating physicians: Isolated acute renal failure was treated more often intermittently by nephrologists compared to anesthesiologists (79.7 vs. 43.3%). Nephrologists also used extracorporeal RRT more often in cardiorenal syndrome (54.3 vs. 35.8%), whereas anesthesiologists preferred them in sepsis (37.3 vs. 23.1%). The choice of anticoagulant varied as well: Hospitals with up to 400 beds offered regional citrate anticoagulation in only 50% compared to 90% of university hospitals. CONCLUSIONS: Currently, RRT treatment in acute renal failure on German intensive care units seems to be dependent on the size, local structures, and education of the intensivists rather than patient needs. Our results demonstrate the necessity to establish cross-disciplinary standards for the treatment of acute renal failure in German intensive care units.

[Adsorption therapy in sepsis]. / Adsorbertherapie bei Sepsis.

BACKGROUND: The activation of multiple pro- and anti-inflammatory mediators is a key feature in the pathophysiology of sepsis. Many of these mediators may directly contribute to organ dysfunction and determine disease severity. So far our ability to modulate these upregulated mediator pathways is very limited. Therefore the adsorption of such mediators via an extracorporeal circuit may be a beneficial intervention during sepsis. OBJECTIVES: Recent technical innovations have made this intervention feasible. Both systems for exclusive mediator adsorption and for adsorption beside a conventional renal replacement therapy are now available. Some of the membranes can adsorb a broad range of mediators by rather unspecific binding, whereas others specifically adsorb endotoxin or mediators. DISCUSSION: Whilst biochemical efficacy could be demonstrated by some of the systems, controlled and randomized studies demonstrating improved clinical endpoints are still lacking. Therefore the use of such therapies outside clinical studies cannot yet be recommended.

[Treatment of acute renal failure in Germany: a structural analysis]. / Versorgung des akuten Nierenversagens in Deutschland--Eine strukturelle Analyse.

INTRODUCTION: There are no reliable data on the structure and practice of the care of critically ill patients with acute renal failure in Germany. METHODS: We carried out a detailed survey by sending a questionnaire to 2265 German Intensive Care Units. The questionnaire contained 19 questions regarding renal replacement therapy. RESULTS: 423 German intensive care units participated in the survey. Most of the ICUs are headed interdisciplinary (47%) or by anesthesiologists (30%), with significant differences depending on the size of the clinic, with primarily interdisciplinary management in smaller clinics. The offered type of renal replacement therapy varies significantly, the smaller the house the fewer methods are available. Thus, intermittent dialysis procedures are offered only in 35% of hospitals with up to 400 beds. The indication for the initiation of acute renal replacement therapy in intensive care is provided predominantly (53%) by an anesthesiologist. A nephrologist is only involved in 22% of all intensive care units. The indication is based primarily on a "clinical criteria", but these are poorly defined. CONCLUSION: Our results demonstrate the need for cross-disciplinary standards for the treatment of acute renal failure in German intensive care units.

[New KDIGO guidelines on acute kidney injury. Practical recommendations]. / Neue KDIGO-Leitlinien zur akuten Nierenschädigung. Praktische Handlungsempfehlungen.

The incidence of acute kidney injury (AKI) in critically ill patients is very high and is associated with an increased morbidity and mortality. In 2012 the Kidney Disease: Improving Global Outcome (KDIGO) guidelines were published in which evidence-based practical recommendations are given for the evaluation and management of patients with AKI. The first section of the KDIGO guidelines deals with the unification of earlier consensus definitions and staging criteria for AKI. The subsequent sections of the guidelines cover the prevention and treatment of AKI as well as the management of renal replacement therapy (RRT) in patients with AKI. In each section the existing evidence is discussed and a specific treatment recommendation is given. The guidelines appreciates that there is insufficient evidence for many of the recommendations. As a specific pharmacological therapy is missing, an early diagnosis, aggressive hemodynamic optimization, tight volume control, and avoidance of nephrotoxic drugs are the only interventions to prevent AKI. If renal replacement therapy is required different modalities are available to provide an effective therapy with a low rate of adverse effects.

Use of target temperature management after cardiac arrest in Germany--a nationwide survey including 951 intensive care units.

INTRODUCTION: Target temperature management (TTM) after cardiac arrest is recommended by international guidelines, which have been last updated in 2010. Here we investigate the status of implementation in a nationwide survey in Germany which took place in 2012. METHODS: We conducted a nationwide telephone survey including a total of 951 German intensive care units (ICUs). ICUs were identified by using the online registry for hospitals in Germany. A questionnaire was used for the interview about basic data of the intensive care unit and about details concerning use and implementation of TTM after cardiac arrest. RESULTS: The overall response rate was 91% (865/951). 86% (742/865) of ICUs used TTM after cardiac arrest and implementation peaked in 2010. 95% (702/736) of the ICUs using TTM perform treatment independently of the initial rhythm and 48% (355/738) apply TTM with the use of a feedback device for cooling and controlled re-warming. However, 22% (166/742) still use conventional methods like ice and cold infusion and only 61% (453/742) of the participants provided a written standard operating procedure (SOP). CONCLUSION: With a delay of several years, TTM after cardiac arrest is now implemented in the majority of German ICUs. The moderate proportion of ICUs using SOPs for TTM and feedback-controlled cooling devices indicates the need of further improvement in post cardiac arrest care.

PD and loss of peritoneal function.

During long-term treatment with peritoneal dialysis both peritoneal membrane structure and function undergo significant changes that not only correlate with the time under treatment, but also with the frequency and severity of infections. In addition, peritoneal dialysis fluid bio-incompatibility may constitute a hazard for the longevity of the peritoneum as the dialysis membrane. In particular, the presence of glucose degradation products may lead to impaired peritoneal cell function as well as to increased protein glycation and peritoneal AGE deposition. Results from recent prospective randomised studies suggest that treatment with new GDP-depleted PD fluids may lead to a significant improvement of clinical outcomes in PD patients.

Correlation between HSP-72 expression and IL-8 secretion in human mesothelial cells.

BACKGROUND: Cytotoxicity of peritoneal dialysis fluid (PDF) and peritoneal inflammation are currently regarded as the two major culprits for chronic mesothelial injury and peritoneal membrane failure. In this study, we correlated induction of HSP-72, as a marker of the cellular stress response, to secretion of IL-8, as a marker for pro-inflammatory cytokines, in mesothelial cells upon sublethal PDF exposure. METHODS: Primary omental cell cultures of human mesothelial cells were subjected to sublethal PDF exposure times (CAPD2, Fresenius, Germany). At the end of a 24 hour recovery period, induction of HSP-72 in the cell homogenate and IL-8 secretion in the supernatant was assessed by immunodensitometry and ELISA, respectively. RESULTS: PDF exposure times from 15 min to 60 min resulted in progressively increased HSP-72 expression levels (267 vs 320 vs 419% of controls, p<0.05 vs controls) as well as increased IL-8 secretion (323 vs 528 vs 549% of controls, p<0.05 vs controls) with full cell viability (MTT unchanged to control). HSP-72 expression was statistically significantly correlated with IL-8 secretion. CONCLUSIONS: The significant correlation between HSP-72 expression and IL-8 secretion suggests that the regulation of pro-inflammatory pathways in mesothelial cells exposed to PDF may represent an integral part of their stress response. Future studies to investigate the cellular regulatory mechanism involved are warranted.

Role of mesothelial cell-derived granulocyte colony-stimulating factor in interleukin-17-induced neutrophil accumulation in the peritoneum.

Recent studies suggest that peritoneal CD4(+) T lymphocytes may control recruitment of polymorphonuclear leukocytes (PMN) during peritonitis by an interleukin-17 (IL-17)-dependent mechanism. IL-17 and granulocyte colony-stimulating factor (G-CSF) have been proposed to form an axis that regulates PMN transmigration. Here we report on the role of G-CSF released by human peritoneal mesothelial cells (HPMCs) in IL-17A-mediated peritoneal PMN accumulation. In vitro exposure of HPMCs to IL-17A resulted in a time- and dose-dependent release of G-CSF. This effect was related to the induction of G-CSF mRNA and mediated through the nuclear factor-kappaB (NF-kappaB) pathway. The novel observation was that IL-17A-stimulated NF-kappaB activation in HPMCs followed a biphasic profile, with an early induction (45 min), followed by the return to basal levels (90 min), and a delayed induction (3 h). Tumor necrosis factor alpha synergistically amplified IL-17A-induced G-CSF production by enhanced NF-kappaB activation and through stabilization of G-CSF mRNA. Intraperitoneal (i.p.) administration of IL-17A in Balb/c mice resulted in increased local levels of G-CSF and selective PMN accumulation. Administration of anti-G-CSF blocking antibody before IL-17A injection significantly reduced the IL-17A-triggered PMN infiltration. This effect occurred despite increased i.p. levels of PMN-specific chemokines KC and macrophage inflammatory protein-2 seen in animals treated with anti-G-CSF antibody. These data demonstrate that the mesothelium-derived G-CSF plays an important role in IL-17A-induced PMN recruitment into the peritoneum.

Comparison of icodextrin- and glucose-based peritoneal dialysis fluids in their acute and chronic effects on human peritoneal mesothelial cells.

BACKGROUND: Icodextrin-based peritoneal dialysis fluids (PDFs) display several features that may potentially improve their biocompatibility compared to conventional glucose-containing solutions. So far, however, the studies assessing the biocompatibility profile of icodextrin toward human peritoneal mesothelial cells (HPMC) has produced mixed results. The present study was performed to examine the acute and chronic impact of icodextrin on HPMC in vitro in comparison with standard glucose-based PDF. METHODS: Omentum-derived HPMC were either acutely pre-exposed to or incubated chronically (for up to 10 days) in the presence of icodextrin-PDF. Parallel cultures were treated with conventional PDFs containing either 1.5% or 4.25% glucose. All fluids were tested at neutral pH. HPMC were assessed for viability, proliferation, IL-6 secretion and generation of reactive oxygen species (ROS). RESULTS: Incubation in the presence of icodextrin-PDF significantly reduced HPMC proliferation in a manner similar to that of 1.5% glucose-PDF. In addition, exposure to icodextrin-PDF impaired viability and IL-6 release from HPMC. This effect occurred both after the short pre-treatment with neat icodextrin-PDF for 1-4 hours and after prolonged incubation (up to 10 days) in media supplemented with icodextrin-PDF (1:1). The dysfunction of icodextrin-treated HPMC was of the magnitude that was between the effects exerted by 1.5%- and 4.25%-glucose PDF. Furthermore, exposure of HPMC to icodextrin-PDF induced a dose-dependent increase in ROS generation which was comparable to that produced by 1.5%-glucose PDF. CONCLUSION: Exposure to icodextrin-PDF may impair viability and function of HPMC. The detrimental effects of icodextrin-PDF are at least as serious as those produced by conventional heat-sterilized low glucose-based PDF.

Interleukin-17: a mediator of inflammatory responses.

Interleukin-17 (IL-17) is a prototype member of a new cytokine family with six species identified to date. IL-17 is secreted mainly by activated CD4(+) and CD8(+) T lymphocytes, while its receptor is distributed ubiquitously. IL-17 has been classified as a proinflammatory cytokine because of its ability to induce the expression of many mediators of inflammation, most strikingly those that are involved in the proliferation, maturation and chemotaxis of neutrophils. Increased levels of IL-17 have been associated with several conditions, including airway inflammation, rheumatoid arthritis, intraperitoneal abscesses and adhesions, inflammatory bowel disease, allograft rejection, psoriasis, cancer and multiple sclerosis. This review provides an overview of IL-17 activities, concentrating on those that lead to neutrophil recruitment.

Acute renal failure. Extracorporeal treatment strategies.

The mortality for acute renal failure remains to be high (around 50-70%) despite manifold improvements in terms of techniques and equipment for renal replacement therapies as well as patient monitoring and intensive care support. At present, it is not clear if the method chosen for renal replacement therapy, i.e. intermittent hemodialysis or continuous hemofiltration, might impact significantly on the outcome of these patients. Whilst earlier retrospective studies suggested that CVVH might result in better survival and renal recovery in acute patients, recent prospective studies were unable to confirm these findings. These studies were, however, not evenly randomised in terms of severity of illness or too small to produce conclusive results. In clinical routine CVVH is typically chosen for treating patients with hemodynamic instability and volume overload. If one decides to perform CVVH, however, a filtrate volume of at least 35 ml/kg body weight and hour should be used as this was shown to be associated with better survival as compared to smaller filtrate volumes. A second controversy exists to date whether the choice of the dialyzer membrane might be of significant relevance for the outcome of patients with acute renal failure. Earlier studies indicated that the use of biocompatible membranes in these patients may result in improved patient survival and renal recovery. More recently, however, these results could not be confirmed by larger randomized, prospective clinical studies. Thus, the choice of the dialyzer membrane should be based on individual assessment rather than treatment bias.

Extracorporeal treatment strategy in acute renal failure.

The mortality of acute renal failure remains high (around 50-70%) despite manifold improvements in terms of techniques and equipment for renal replacement therapies as well as patient monitoring and intensive care support. At present, it is not clear if the method chosen for renal replacement therapy, i.e. intermittent hemodialysis or continuous hemofiltration, might impact on the outcome of these patients. Whilst earlier retrospective studies suggested that CVVH might result in better survival and renal recovery in acute patients, recent prospective studies indicated that this may not be the case or, conversely, outcomes may be better with IHD. These studies were, however, not evenly randomised in terms of illness severity or were too small to produce conclusive results. In addition, a meta-analysis of 9 published prospective studies in 692 pts. indicated a similar mortality with CVVH vs. IHD. Some of the studies enrolled for this meta-analysis, however, suffered from methodological and/or randomisation problems, thus this important question remains to date unanswered. Typically, CVVH is chosen for treating patients with hemodynamic instability and volume overload. In such cases, however, CVVH should be performed with a filtrate volume of at least 35 ml/kg body weight per hour as this was shown to be associated with better survival as compared to smaller filtrate volumes. A second controversy exists to date whether the choice of the dialyzer membrane might be of relevance for the outcome of patients with acute renal failure. Earlier studies indicated that the use of biocompatible membranes in these patients may result in improved patient survival and renal recovery. More recently, however, similar studies could not confirm these results. Another meta-analysis of controlled prospective trials (671 patients in 7 separate studies) calculated a relative mortality risk of 1.01 for cuprophan vs. biocompatible membranes. Thus, the choice of the dialyzer membrane should be based on individual assessment rather than treatment bias.