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An inflammation-induced imbalance in the kynurenine pathway (KP) has been reported in major depressive disorder but the utility of these metabolites as predictive or therapeutic biomarkers of behavioral activation (BA) therapy is unknown.
Serum samples were provided by 56 depressed individuals before BA therapy and 29 of these individuals also provided samples after 10 weeks of therapy to measure cytokines and KP metabolites. The PROMIS Depression Scale (PROMIS-D) and the Sheehan Disability Scale were administered weekly and the Beck depression inventory was administered pre- and post-therapy. Data were analyzed with linear mixed-effect, general linear, and logistic regression models. The primary outcome for the biomarker analyses was the ratio of kynurenic acid to quinolinic acid (KynA/QA).
BA decreased depression and disability scores (p's < 0.001, Cohen's d's > 0.5). KynA/QA significantly increased at post-therapy relative to baseline (p < 0.001, d = 2.2), an effect driven by a decrease in QA post-therapy (p < 0.001, uncorrected, d = 3.39). A trend towards a decrease in the ratio of kynurenine to tryptophan (KYN/TRP) was also observed (p = 0.054, uncorrected, d = 0.78). The change in KynA/QA was nominally associated with the magnitude of change in PROMIS-D scores (p = 0.074, Cohen's f2 = 0.054). Baseline KynA/QA did not predict response to BA therapy.
The current findings together with previous research show that electronconvulsive therapy, escitalopram, and ketamine decrease concentrations of the neurotoxin, QA, raise the possibility that a common therapeutic mechanism underlies diverse forms of anti-depressant treatment but future controlled studies are needed to test this hypothesis.
Emotional experiences are often more likely than neutral experiences to be remembered, or to be retrieved richly. In this chapter, we provide an overview of how the effects of emotion arise, emphasizing the effects that operate during the initial experience of the event (encoding), the storage and stabilization of the memory trace for that experience (consolidation), and the accessing of that trace (retrieval). We discuss how these effects of emotion can explain both why emotion enhances many aspects of memory throughout the adult life span and also why there are often age-by-valence interactions in memory, with older adults remembering information more positively than younger adults.
To examine whether self-reported exposure to bullying during childhood is associated with suicide attempts over the life course, and if so, what mechanisms could account for this relationship.
Subjects and methods
A random probability sample comprising 7461 respondents was interviewed for the 2007 survey of psychiatric morbidity of adults in Great Britain. Survey respondents were asked about suicidal attempts and whether they were bullied in childhood.
Recall of being bullied in childhood decreased with age from 25% of 16–24-year-olds to 4% among those 75 or over with few differences in the proportions between men and women. Bullying co-occurred with several victimisation experiences including sexual abuse and severe beatings and with running away from home. Even after controlling for lifetime factors known to increase the risk of suicidal behaviour, adults who reported bullying in childhood were still more than twice as likely as other adults to attempt suicide later in life.
Being the victim of bullying involves the experience of suffering a defeat and humiliation that in turn could lead to entrapment, hopelessness, depression and suicidal behaviour.
Bullying is already known to be associated with substantial distress and other negative consequences and this further evidence of a strong correlation with the risk of suicide in later life should increase further the motivation of society, services and citizens to act decisively to reduce bullying in childhood.
Autism Spectrum Disorders (ASDs) affect 1% of children and are associated with lifelong psychosocial impairments. The majority of children with ASD will experience co-occurring psychiatric disorders. In the UK, antipsychotics remain unlicensed for use in ASDs, however 10% of children with ASD receive antipsychotic treatment; the co-occurring disorders being targeted by these medications remains unclear.
To examine rates of antipsychotic medication use and identify associated co-occurring disorders among children with ASD receiving psychiatric care.
The sample consisted of 2844 children aged 2 to 17 with a NHS clinician recorded ICD-10 diagnoses for ASD between 2008–2013. Clinical variables extracted from their anonymised electronic patient records included disorder severity, medication use, co-occurring ICD-10 diagnoses, family characteristics, demographics and antipsychotic use.
Of the 2844 children (79% male), the majority (57%) had co-occurring psychiatric diagnoses. 313 (11%) received antipsychotic medication. The proportion of children aged 13 to 17 years and 6 to 12 years prescribed antipsychotics was 19% and 7% respectively. After controlling for socio-demographic factors, disorder severity, specialist treatment, inpatient duration, risk of self harm, violence to others, self injurious behaviour, maltreatment history, parental mental illness, caregiver anxiety, and neighbourhood deprivation, multivariate regression analysis revealed only hyperactivity disorders (O.R 1.94, 95%C.I. 1.32–2.86), psychotic disorders (O.R 5.12 95% C.I. 2.6–10.1), mood disorders (O.R 2.02, 95%C.I. 1.04–3.92) and intellectual disability (O.R 2.89 95% C.I. 1.89–4.71) were associated with anti-psychotic use.
The prescription of antipsychotic medications in this UK ASD clinical sample is strongly associated with specific co-occurring psychiatric disorders and intellectual disability.
Previously, a number of observational studies have found no association between contact with services and improved outcomes in children with psychopathology, despite the existence of effective interventions. The British Child and Adolescent Mental Health Survey (BCAMHS) 2004 is a study of 5,325 children aged 5-16, with data on parent-reported mental health-related public sector service contacts and psychopathology over three years, allowing exploration of the association in a large community-based dataset.
Describe the trajectories of children in contact and not in contact with services over three years from 2004-2007
Explore the association between mental health-related service contact over the study period and outcomes in terms of parent-rated psychopathology
This study is a secondary analysis of children's trajectories by service contact status (no contact, contact 2004 only, contact 2007 only, contact 2004 & 2007). The main measure of psychopathology over time was the well-validated Strengths and Difficulties Questionnaire. Multivariable linear regression was used to examine the association between contact and outcomes in children with a psychiatric disorder at baseline in 2004.
Children in contact with services demonstrated the highest levels of psychopathology over time, and the 2007-only contact group displayed a trajectory of increasing difficulties. Overall, contact with services was not associated with improvement in outcomes, following adjustment for measured confounders.
The effectiveness of contact alone with services was not demonstrated in our findings. Despite methodological limitations, this underlines the need for continuing development and consistent implementation of effective interventions, alongside initiatives evaluating outcomes within services.
Inorganic trace mineral salts in the premix have a detrimental effect on the stability of vitamins due to redox reactions. A study was conducted to investigate the effect of dietary supplementation of different levels of vitamin premix with different mineral premixes on the performance and bone characteristics of broilers. A 2 x 2 factorial dietary treatment was used with two levels of vitamins and two types of minerals in the premix. A total of 1056, one-day old chicks were randomly assigned to four dietary treatments with 12 replicate pens of 22 chicks for 28 d. An interactive effect between vitamin levels and mineral sources on weight gain and feed intake of chickens was detected. Chickens fed the diet containing 100% vitamin premix with either source of mineral premix had higher (P < 0.01) weight gain and feed intake than those fed the diet containing 30% vitamin premix with either source of mineral premix. However, the chickens fed the diet containing the 30% vitamin premix with the organic minerals had higher (P < 0.01) weight gain and feed intake than those fed the diet containing 30% vitamin premix with inorganic minerals. Chickens fed the diet containing organic mineral premix had lower (P < 0.05) mortality and feed to gain ratio and higher (P < 0.01) bone breaking strength and ash content of tibia than those fed the inorganic mineral premix treatment. Chickens fed the diet containing 100% vitamin premix had higher (P < 0.01) breaking strength of femur and tibia ash than those fed the diet containing 30% vitamin premix. The results from this trial indicated that total replacement of inorganic trace minerals with organic minerals can increase the storage stability of vitamins in feed premixes containing both vitamins and trace minerals, which is reflected in better growth performance in poultry.
The influence of pharmaceuticals on the environment is an increasing concern among environmental toxicologists. It is known that their growing use is leading to detectable levels in wastewater, conceivably causing harm to aquatic ecosystems. Psychotropic medication is one such group of substances, particularly affecting high-income countries. While these drugs have a clear place in therapy, there is debate around the risk/benefit ratio in patients with mild mental health problems. Therefore, it is necessary to evaluate the wider implications as risks could extend beyond the individual to non-target organisms, particularly those in rivers and estuaries.
Vaccination is increasingly being recognised as a potential tool to supplement ‘stamping out’ for controlling foot-and-mouth disease (FMD) outbreaks in non-endemic countries. Infectious disease simulation models provide the opportunity to determine how vaccination might be used in the face of an FMD outbreak. Previously, consistent relative benefits of specific vaccination strategies across different FMD simulation modelling platforms have been demonstrated, using a UK FMD outbreak scenario. We extended this work to assess the relative effectiveness of selected vaccination strategies in five countries: Australia, New Zealand, the USA, the UK and Canada. A comparable, but not identical, FMD outbreak scenario was developed for each country with initial seeding of Pan Asia type O FMD virus into an area with a relatively high density of livestock farms. A series of vaccination strategies (in addition to stamping out (SO)) were selected to evaluate key areas of interest from a disease response perspective, including timing of vaccination, species considerations (e.g. vaccination of only those farms with cattle), risk area vaccination and resources available for vaccination. The study found that vaccination used with SO was effective in reducing epidemic size and duration in a severe outbreak situation. Early vaccination and unconstrained resources for vaccination consistently outperformed other strategies. Vaccination of only those farms with cattle produced comparable results, with some countries demonstrating that this could be as effective as all species vaccination. Restriction of vaccination to higher risk areas was less effective than other strategies. This study demonstrates consistency in the relative effectiveness of selected vaccination strategies under different outbreak start up conditions conditional on the assumption that each of the simulation models provide a realistic estimation of FMD virus spread. Preferred outbreak management approaches must however balance the principles identified in this study, working to clearly defined outbreak management objectives, while having a good understanding of logistic requirements and the socio-economic implications of different control measures.
Depression can impair the immunogenicity of vaccine administration in adults. Whereas many vaccinations are administered in childhood, it is not known whether adolescent or adult onset depression is associated with impairments in the maintenance of protection of childhood vaccines. This study tested the hypothesis that individuals with adolescent or adult onset mood disorders would display compromised immunity to measles, a target of childhood vaccination.
IgG antibodies to measles were quantified using a solid phase immunoassay in volunteers with bipolar disorder (BD, n = 64, mean age of onset = 16.6 ± 5.6), currently depressed individuals with major depressive disorder (cMDD, n = 85, mean age of onset = 17.9 ± 7.0), remitted individuals with a history of MDD (rMDD, n = 82, mean age of onset = 19.2 ± 8.6), and non-depressed comparison controls (HC, n = 202), all born after the introduction of the measles vaccine in the USA in 1963.
Relative to HC, both the cMDD group (p = 0.021, adjusted odds ratios (OR) = 0.47, confidence interval (CI) = 0.24–0.90), and the rMDD group (p = 0.038, adjusted OR = 0.50, CI = 0.26–0.97) were less likely to test seropositive for measles. Compared with unmedicated MDD participants, currently medicated MDD participants had a longer lifetime duration of illness and were less likely to test seropositive for measles.
Individuals with adolescent or adult onset MDD are less likely to test seropositive for measles. Because lower IgG titers are associated with increased risk of measles infection, MDD may increase the risk and severity of infection possibly because of impaired maintenance of vaccine-related protection from measles.
Schizophrenia (SZ) is a severe neuropsychiatric disorder associated with disrupted connectivity within the thalamic-cortico-cerebellar network. Resting-state functional connectivity studies have reported thalamic hypoconnectivity with the cerebellum and prefrontal cortex as well as thalamic hyperconnectivity with sensory cortical regions in SZ patients compared with healthy comparison participants (HCs). However, fundamental questions remain regarding the clinical significance of these connectivity abnormalities.
Resting state seed-based functional connectivity was used to investigate thalamus to whole brain connectivity using multi-site data including 183 SZ patients and 178 matched HCs. Statistical significance was based on a voxel-level FWE-corrected height threshold of p < 0.001. The relationships between positive and negative symptoms of SZ and regions of the brain demonstrating group differences in thalamic connectivity were examined.
HC and SZ participants both demonstrated widespread positive connectivity between the thalamus and cortical regions. Compared with HCs, SZ patients had reduced thalamic connectivity with bilateral cerebellum and anterior cingulate cortex. In contrast, SZ patients had greater thalamic connectivity with multiple sensory-motor regions, including bilateral pre- and post-central gyrus, middle/inferior occipital gyrus, and middle/superior temporal gyrus. Thalamus to middle temporal gyrus connectivity was positively correlated with hallucinations and delusions, while thalamus to cerebellar connectivity was negatively correlated with delusions and bizarre behavior.
Thalamic hyperconnectivity with sensory regions and hypoconnectivity with cerebellar regions in combination with their relationship to clinical features of SZ suggest that thalamic dysconnectivity may be a core neurobiological feature of SZ that underpins positive symptoms.
Phased Array Feed (PAF) technology is the next major advancement in radio astronomy in terms of combining high sensitivity and large field of view. The Focal L-band Array for the Green Bank Telescope (FLAG) is one of the most sensitive PAFs developed so far. It consists of 19 dual-polarization elements mounted on a prime focus dewar resulting in seven beams on the sky. Its unprecedented system temperature of ~17 K will lead to a 3 fold increase in pulsar survey speeds as compared to contemporary single pixel feeds. Early science observations were conducted in a recently concluded commissioning phase of the FLAG where we clearly demonstrated its science capabilities. We observed a selection of normal and millisecond pulsars and detected giant pulses from PSR B1937+21.
Children with poor mental health often struggle at school. The relationship between childhood psychiatric disorder and exclusion from school has not been frequently studied, but both are associated with poor adult outcomes. We undertook a secondary analysis of the British Child and Adolescent Mental Health Surveys from 2004 and its follow-up in 2007 to explore the relationship between exclusion from school and psychopathology. We predicted poorer mental health among those excluded.
Psychopathology was measured using the Strengths and Difficulties Questionnaire, while psychiatric disorder was assessed using the Development and Well-Being Assessment and applying Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM IV) criteria. Exclusion from school and socio-demographic characteristics were reported by parents. Multi-variable regression models were used to examine the impact of individual factors on exclusion from school or psychological distress.
Exclusion from school was commoner among boys, secondary school pupils and those living in socio-economically deprived circumstances. Poor general health and learning disability among children and poor parental mental health were also associated with exclusion. There were consistently high levels of psychological distress among those who had experienced exclusion at baseline and follow-up.
We detected a bi-directional association between psychological distress and exclusion. Efforts to identify and support children who struggle with school may therefore prevent both future exclusion and future psychiatric disorder.
Academic health systems and their investigators are challenged to systematically assure clinical research regulatory compliance. This challenge is heightened in the emerging era of centralized single Institutional Review Boards for multicenter studies, which rely on monitoring programs at each participating site.
To describe the development, implementation, and outcome measurement of an institution-wide paired training curriculum and internal monitoring program for clinical research regulatory compliance.
Standard operating procedures (SOPs) were developed to facilitate investigator and research professional adherence to institutional policies, federal guidelines, and international standards. An SOP training curriculum was developed and implemented institution-wide. An internal monitoring program was launched, utilizing risk-based monitoring plans of pre-specified frequency and intensity, assessed upon Institutional Review Boards approval of each prospective study. Monitoring plans were executed according to an additional SOP on internal monitoring, with monitoring findings captured in a REDCap database.
We observed few major violations across 3 key domains of clinical research conduct and demonstrated a meaningful decrease in the rates of nonmajor violations in each, over the course of 2 years.
The paired training curriculum and monitoring program is a successful institution-wide clinical research regulatory compliance model that will continue to be refined.
The oxidation (rancidity) of fat is a very common feed quality issue, which can negatively affect growth performance and meat quality of broilers. Besides other factors, metal ions such as Zn, Cu and Fe can facilitate lipid peroxidation in feed. The objective of the current study was to investigate the effect of feeding corn soy diets containing fresh or oxidised soybean oil with different forms of microminerals on production performance of broiler chicks. Dietary treatments consisted of a 2 × 2 factorial structure with two kinds of soybean oil (oxidised or fresh) and two forms of microminerals (inorganic or organic). Mineral proteinate (Bioplex®, Alltech Inc.) including Zn, Mn, Cu and Fe was used as the organic source and was supplemented at the level equivalent to 25% of an inorganic source in the control diets. Organic selenium (Sel-Plex®, Alltech Inc.) at 0.3 mg/kg of diet was used to replace sodium selenite used at 0.3 mg/kg of diet in control diet. Oxidised soybean oil was prepared by convection heat (90°C for a period of seven days in a convection oven). A total of 1152 one-day old chicks were allotted randomly to the four dietary treatments using 12 replicates of 24 chicks per pen. Chicks were raised in floor pens for 42 days in an environmentally controlled room with free access to feed and water. There was no statistical interaction between oil source and mineral form on performance or mineral content of breast meat. Feeding oxidised oil increased (P < 0.05) feed intake and decreased gain to feed ratio (FCE) of chicks. Supplementation with organic minerals improved (P < 0.05) weight gain and FCE of chicks. The breast meat of chicks fed organic mineral had higher (P < 0.01) Se content than those from the control group. The results indicated that the addition of organic minerals to broiler diets can minimise the negative impact of oxidised oil on the performance of broiler chicks.
The identification of the factors that influence the persistence of psychiatric disorder may assist practitioners to focus on young people who are particularly prone to poor outcomes, but population-based samples of sufficient size are rare.
This secondary analysis combined data from two large, population-based cross-sectional surveys in Great Britain (1999 and 2004) and their respective follow-ups (2002 and 2007), to study homotypic persistence among the 998 school-age children with psychiatric disorder at baseline. Psychiatric disorder was measured using the Development and Well-Being Assessment applying DSM-IV criteria. Factors relating to the child, family, and the severity and type of psychopathology at baseline were analysed using logistic regression.
Approximately 50% of children with at least one psychiatric disorder were assigned the same diagnostic grouping at 3-year follow-up. Persistent attention-deficit/hyperactivity disorder and anxiety were predicted by poor peer relationship scores. Persistent conduct disorder was predicted by intellectual disability, rented housing, large family size, poor family function and by severer baseline psychopathology scores.
Homotypic persistence was predicted by different factors for different groups of psychiatric disorders. Experimental research in clinical samples should explore whether these factors also influence response to interventions.
Introduction: The addition of computerized physician order entry (CPOE) to Emergency Departments in recent years has led to speculation over potential benefits and pitfalls. Recent studies have shown benefits to CPOE, though there lacks sufficient evidence on how it could change physician behaviour. Physician practices are known to be difficult to change, with getting evidence into daily practice being the main challenge of knowledge translation. Our study aims were to determine if well-designed electronic order sets for CPOE improved MD practices. Methods: The Calgary Zone Pain Management in the Emergency Department Working Group relied on a GRADE-based literature review for identifying best practices for analgesia and antiemetics, resulting in soft changes to the dedicated analgesia and antiemetic electronic order set noting working group preference, and emphasizing hydromorphone over morphine, as well as 4 mg ondansetron over 8 mg. The new electronic order set was started in the only Calgary Region order entry system on December 11th, 2014. Data was collected from July 2014 - May 2015. A Yates chi-squared analysis was completed on all orders in a category, as well as the subgroups of ED staff and residents, and orders placed using the new order set. Results: A total of 100460 orders were analyzed. The use of hydromorphone increased significantly across all 4 EDs. IV hydromorphone use increased (5.82% of all opioid orders up to 26.93%, P<0.0001) with a reciprocal decline in IV morphine (67.81% of all opioid orders down to 46.56%, P<0.0001). Similar effects were observed with ondansetron 4 mg IV orders increasing (1.37% of all ondansetron orders to 18.64%, P<0.0001) with a decrease in 8 mg dosing (15.75% of all ondansetron orders to 7.23%, P<0.0001). These results were replicated to a lesser degree in the non-ED staff and non-order set subgroups. Implementation of the new order set resulted in an increase of its use (37.64% of all opioid orders up to 49.29%, P<0.0001). Finally, a cost-savings analysis was completed showing a projected annual savings of $185,676.52 on medications alone. Conclusion: This data supports the manipulation of electronic order sets to help shape physician behaviour towards best practices. This provides another strong argument towards the benefits of CPOE, and can help maintain best practices in Emergency Medicine.
Diets rich in fruits and vegetables (FV), which contain (poly)phenols, protect against age-related inflammation and chronic diseases. T-lymphocytes contribute to systemic cytokine production and are modulated by FV intake. Little is known about the relative potency of different (poly)phenols in modulating cytokine release by lymphocytes. We compared thirty-one (poly)phenols and six (poly)phenol mixtures for effects on pro-inflammatory cytokine release by Jurkat T-lymphocytes. Test compounds were incubated with Jurkat cells for 48 h at 1 and 30 µm, with or without phorbol ester treatment at 24 h to induce cytokine release. Three test compounds that reduced cytokine release were further incubated with primary lymphocytes at 0·2 and 1 µm for 24 h, with lipopolysaccharide added at 5 h. Cytokine release was measured, and generation of H2O2 by test compounds was determined to assess any potential correlations with cytokine release. A number of (poly)phenols significantly altered cytokine release from Jurkat cells (P<0·05), but H2O2 generation did not correlate with cytokine release. Resveratrol, isorhamnetin, curcumin, vanillic acid and specific (poly)phenol mixtures reduced pro-inflammatory cytokine release from T-lymphocytes, and there was evidence for interaction between (poly)phenols to further modulate cytokine release. The release of interferon-γ induced protein 10 by primary lymphocytes was significantly reduced following treatment with 1 µm isorhamnetin (P<0·05). These results suggest that (poly)phenols derived from onions, turmeric, red grapes, green tea and açai berries may help reduce the release of pro-inflammatory mediators in people at risk of chronic inflammation.
Paternal depressive symptoms are associated with children's emotional and behavioural problems, which may be mediated by negative parenting. But there is no research on the influence of paternal depressive symptoms on children's emotion regulation and limited literature investigating fathers’ parenting as a mediator in the pathway between paternal depressive symptoms and children's externalizing and internalizing problems. We aimed to investigate the mediating role of father–child conflict (at 3 years) in the association between postnatal paternal depressive symptoms (at 9 months) and children's emotional and behavioural problems (at 7 years) (aim 1). We also examined whether mediation pathways were more pronounced for boys or for girls (aim 2).
Secondary data analysis was conducted on the Millennium Cohort Study, when children were 9 months, 3 years and 7 years old (n = 3520). Main study variables were measured by self-report questionnaires. Fathers completed the Rutter Scale (depressive symptoms) and the Parent–Child Relationship Questionnaire (father–child conflict), while mothers completed the Strengths and Difficulties Questionnaire and the Social Behaviour Questionnaire (child emotional and behavioural problems, emotion regulation). We used structural equation modelling to estimate direct, indirect and total effects of paternal depressive symptoms on child outcomes, mediated by father–child conflict whilst adjusting for relevant covariates (maternal depressive symptoms, child temperament, marital conflict, and socio-economic factors such as poverty indicator and fathers’ education level). Multi-group and interaction analysis was then conducted to determine the differential effect by gender of the association between paternal depressive symptoms on child outcomes via father–child conflict.
Father–child conflict mediated the association between paternal depressive symptoms and emotion regulation problems [standardized indirect effect (SIE) 95% confidence interval (CI) −0.03 to −0.01, p < 0.001; standardized total effect (STE) 95% CI −0.05 to −0.01, p < 0.05] (aim 1). Father–child conflict mediated a larger proportion of the effect in boys (SIE 95% CI −0.03 to −0.01, p < 0.001; STE 95% CI −0.05 to 0.00, p = 0.063) than it did in girls (SIE 95% CI −0.02 to −0.01, p < 0.001; STE 95% CI −0.04 to 0.01, p = 0.216) (aim 2).
Father–child conflict may mediate the association between postnatal paternal depressive symptoms and children's emotion regulation problems. Paternal depressive symptoms and father–child conflict resolution may be potential targets in preventative interventions.
With the increasing use of complex quantitative models in applications throughout the financial world, model risk has become a major concern. Such risk is generated by the potential inaccuracy and inappropriate use of models in business applications, which can lead to substantial financial losses and reputational damage. In this paper, we deal with the management and measurement of model risk. First, a model risk framework is developed, adapting concepts such as risk appetite, monitoring, and mitigation to the particular case of model risk. The usefulness of such a framework for preventing losses associated with model risk is demonstrated through case studies. Second, we investigate the ways in which different ways of using and perceiving models within an organisation both lead to different model risks. We identify four distinct model cultures and argue that in conditions of deep model uncertainty, each of those cultures makes a valuable contribution to model risk governance. Thus, the space of legitimate challenges to models is expanded, such that, in addition to a technical critique, operational and commercial concerns are also addressed. Third, we discuss through the examples of proxy modelling, longevity risk, and investment advice, common methods and challenges for quantifying model risk. Difficulties arise in mapping model errors to actual financial impact. In the case of irreducible model uncertainty, it is necessary to employ a variety of measurement approaches, based on statistical inference, fitting multiple models, and stress and scenario analysis.