2. Experimental Polysorbates 80, sodium chloride, carboxymethyl cellulose (CMC), polyvinyl pyrrolidone (PVP), tragacanth, and magnesium aluminum silicate (Veegum) were purchased from Merck, Germany. Acetaminophen was kindly donated by Chemidarou Pharmaceutical Co., Iran. 2.1. Preparation of Suspensions

Finely powdered (120 mesh) acetaminophen (3.2%) was used to prepare suspensions using Veegum (2%), CMC (0.5%), PVP (1%), or tragacanth (0.75%) alone and their different combinations as structural vehicles (Table 1). Polysorbate 80 (0.35%) and sodium chloride (0.02 and 0.04%) were added as wetting and flocculating Inhibitors,research,lifescience,medical agents, respectively. Then physical stability and rheological properties of the formulations were evaluated. Table 1 Composition of different formulations of acetaminophen

suspensions. 2.2. Physical Stability After preparation, sedimentation volume (F) of the suspensions was measured daily, and heights of sediments were measured when there was no change in 3 consecutive readings. In order to evaluate the Inhibitors,research,lifescience,medical ease of redispersion, suspension samples were rotated PLX-4720 datasheet periodically at 180 degree. The number of revolutions Inhibitors,research,lifescience,medical (n) was recorded when the suspension restored to homogeneity [2]. The crystal growth acetaminophen in different suspensions that were stored two months at room temperature was examined by optical microscope (Olympus, Inhibitors,research,lifescience,medical R4, Japan). 2.3. Rheological Assessment Rheological behavior of the acetaminophen

suspensions was determined using a Brookfield viscometer (Dial reading LVT, USA with no. 3 spindle). Viscosity of samples was determined at 0.3, 0.6, 1.5, 3, 6, 12, 30, and 60rpm after 1min rotation at the room temperature. The results were plotted as rheograms and their rheological behaviors were determined by fitting on the corresponding Newtonian and non-Newtonian equations (1): τN=η′δ,Log δ=Nlog⁡τ−log⁡η′, (1) where τ is shear stress, δ and η′ are shear rate and viscosity Inhibitors,research,lifescience,medical coefficient, respectively. N is an indicator for defining the type of flow. Since the viscosity of pseudoplastic substances decreases with increasing rate of shear, the apparent viscosity of the formulations at shear rates corresponding to 30rpm was obtained from the slope of the tangent to the curve at that point. The area of the hysteresis loop of the rheograms can be calculated from the difference between the areas under the up curve and the down curve by using the trapezoidal Tryptophan synthase rule [4, 6, 7]. 3. Results and Discussion Comparison of the sedimentation volume in acetaminophen suspension without any suspending agent (formulation F1) with those suspensions containing one kind of structural vehicle showed that increasing tragacanth and Veegam could increase the sedimentation volume considerably (Table 2). The highest and the lowest sedimentation volumes were observed in suspensions containing tragacanth (86.5±1.25%) and PVP (13 ± 0.

Light scattering spectroscopy and diffuse reflectance spectroscopy use algorithms to analyze light scattered back to the sensing device by the tissue. This spectroscopic information has been #CP-690550 datasheet randurls[1|1|,|CHEM1|]# able to distinguish neoplastic from non-neoplastic tissue with both good sensitivity and specificity

(92,93) in a few small trials. Optical coherence tomography uses variations in the reflectance of near-infrared light from different tissues to create a high-resolution cross-sectional image of the mucosa (94). One study has shown excellent sensitivity (97%) and specificity (92%) in the recognition of BE without dysplasia (95) while another showed good sensitivity (83%) Inhibitors,research,lifescience,medical and specificity (75%) in identifying high grade dysplasia (96). While many of these endoscopic techniques show promise, there is currently no definitive evidence that they provide additional information beyond careful examination using high-resolution white light endoscopy. Also, most require Inhibitors,research,lifescience,medical specialized equipment and/or training that may not currently be available

outside of specialty centers. Biomarkers The grading of dysplasia currently guides surveillance and treatment decisions; however it is an imperfect predictor of cancer risk. Several Inhibitors,research,lifescience,medical biomarkers have shown promise as objective adjunct tests to improve risk stratification Inhibitors,research,lifescience,medical of patients with BE. Panels of immunohistochemical stains including α-methylacyl-CoA racemase (AMACR), β-catenin, cyclin D1, and p53 show promise in separating grades of dysplasia and in distinguishing true neoplastic progression from reactive changes (97-99). Other

biomarkers which test for DNA abnormalities have been evaluated in cross-sectional or retrospective studies. The detection of aneuploidy, increased tetraploidy, and loss of heterozygosity (LOH) for chromosome 17p in patients with no dysplasia or low grade dysplasia on biopsy Inhibitors,research,lifescience,medical has been shown to have good predictive value for neoplastic progression, but added little information when high grade dysplasia was detected (100-104). These studies utilized flow cytometry to detect DNA content abnormalities in fresh frozen tissue, which may not be practical Thiamine-diphosphate kinase in clinical practice. Fluorescence in situ hybridization can theoretically be used to detect these same abnormalities in fixed tissue and most initial studies show promising results (104-108). Biomarker panels – including detection of chromosomal abnormalities (aneuploidy/tetraploidy, 17p LOH, 9p LOH) or tumor-suppressor gene-methylation patterns – have also been good indicators of progression risk in initial studies (109-111). One methylation-based panel, applied retrospectively, even identified patients who progressed to high grade dysplasia two years before histologic changes were seen (111).

(2008) who reported a lower prevalence, at only 13.8% in a population of patients from Italy. The discrepancies could likely be explained by the different clinical characteristics of our respective samples (e.g., lower level of handicap and higher rate of male patients in Bodini’s study), or by cultural differences, or other factors that remain to be elucidated. As previously reported by several authors (Bodini et al. 2008; Chahraoui et al. 2008; Gay et al. Inhibitors,research,lifescience,medical 2010),

we observed a relation between alexithymia and both anxiety and depression, and at both timepoints of this study. The rates of anxiety and depression were consistently high in this study, with around 40% of MS patients suffering from anxiety problems at both

T1 and T2, and this finding was stable over time. Conversely, the rate of depression tended to decrease between the two evaluations, falling from 40% to 26%. Inhibitors,research,lifescience,medical Multivariate logistic regression showed that alexithymia seems to be more strongly associated with anxiety. These results underline the similar manner in which alexithymia and anxiety are associated, as well as Inhibitors,research,lifescience,medical the stability of these disorders over time. The great emotional difficulty experienced by patients with MS has consistently been reported in the literature (Feinstein et al. 1999; Dahl et al. 2009) and the persistence of emotional disturbances over time has previously been highlighted by other authors (Arnett and Randolph 2006; Beal et al. 2007). It is possible that this persistence arises from a permanent incapacity of these patients to cope with the disease, particularly as prognosis is very uncertain in Inhibitors,research,lifescience,medical terms of progression of handicap (Giordano et al. 2011). The unpredictable Sirtuin inhibitor nature of the progression of MS appears to be a central component in understanding the persistence of the emotional problems. Indeed, MS is characterized by the occurrence of attacks (relapses) of worsening neurological function that are highly unpredictable, and the patient cannot anticipate either the occurrence of an attack, or the type or intensity of symptoms. Predicting

disease progression Inhibitors,research,lifescience,medical is, therefore, a dimension of MS that is extremely challenging. From a clinical point of view, some patients may experience several relapses in the same year, whereas others may go 10 years without an attack. Furthermore, while some Oxygenase attacks can have more or less severe effects that may partially or totally recede, others may herald a functional deficit, such as impaired motor function that can remain and become permanent. While the relapsing-remitting form of MS highlights, in particular, the uncertainty experienced by patients with MS (Montreuil and Lyon-Caen 1993), the progressive form, with its slowly but constantly worsening neurological function, also leaves patients feeling insecure and uncertain about their future, once the symptoms or irreversible deficits begin to appear.

In schizophrenic patients, these deficits may include smaller cell sizes and neuropils, and reduced transcription of certain proteins involved in neuronal transmission, such as growthassociated protein-43 (GAP-43) and subunits

of non-Ar-methyl-D-aspartate (NMD A) glutamate receptors.68 These latter deficits involve the “trisynaptic circuit” of the hippocampus, including the CA3 region of Amnion’s horn, which is also a locus of impaired sensory gating.65 The conceptual (eg, its putative roles in learning and memory, and in filtering out, or gating, unimportant information from the environment) and empirical (ie, its demonstrated abnormalities in schizophrenic patients Inhibitors,research,lifescience,medical and their relatives) significance of the hippocampus thus underscores the importance of determining whether hippocampal-based deficits are associated with the clinical and neuropsychological symptoms

of schizotaxia Inhibitors,research,lifescience,medical we described above. Similar arguments may be made for other brain regions. The third and most important reason for studying the neurobiological etiology of schizotaxia is to provide a foundation for the rational development of Inhibitors,research,lifescience,medical treatment strategies for schizotaxia, and prevention strategies for schizophrenia. Our initial treatment of schizotaxia (described above) involved low doses of Selleck Wortmannin risperidone, one of the newer antipsychotic medications, because we reasoned that it might ameliorate some of the same problems in schizotaxic relatives that it does in schizophrenic patients. While the reasons for its effectiveness remain unclear, they probably do not include its antipsychotic Inhibitors,research,lifescience,medical properties, since the schizotaxic relatives were (by definition) not psychotic. As neurobiological mechanisms of schizotaxia become elucidated, treatments will likely include options that arc broader and more specific than antipsychotic treatments alone. Some of these may be tested in the near future. For example, the demonstration

that nicotine Inhibitors,research,lifescience,medical transiently normalizes impaired sensory gating in relatives implicates cholinergic neurotransmission in the normal mediation of the “filtering” function.69 Interestingly, we recently found that glucose, which also facilitates hippocampal cholinergic function (see, for example, references 70 and 71), improves long-term verbal memory in schizophrenic patients treated with clozapine.72 (-)-p-Bromotetramisole Oxalate Whether glucose can also attenuate cognitive dysfunctions in schizotaxia remains to be tested, but it does illustrate the possibility that a broad range of nonanti-psychotic treatments (with or without concomitant low doses of antipsychotic medications) may be useful in treating schizotaxia. As the biological bases of schizotaxia become clearer, so will diagnostic criteria for the syndrome. This will allow the development of more targeted treatment strategies and homogeneous samples of research subjects.

Second, constellations of genes might at best confer susceptibility

for abnormal emotions, Idelalisib research buy behaviors, and discrete intellectual deficits, which represent the illness intermediate endophenotypes for the illness, but not for diagnostic classifications agreed upon by expert committees. Yet, the designation of an individual as a sufferer of schizophrenia is still based on a cluster of abnormal behaviors, emotions, and perceptions, which together have an impact on social and vocational performances. Similar, but not identical constellations of susceptibility genes might determine the manifestation of any combination of anxiety, Inhibitors,research,lifescience,medical depression, and withdrawn behavior. All such manifestations are not only part and parcel of schizophrenia Inhibitors,research,lifescience,medical or comorbidities, but are also manifestations of other Diagnostic and Statistical Manual of Mental Health (DSM) disorders, such as anxiety disorder and dysthymia. This puts schizophrenia on a continuum with other mental disorders, and leaves the phenotype for which early predictive biological markers are investigated uncertain. It Inhibitors,research,lifescience,medical is possible that our current knowledge of brain functioning

and malfunctioning parallels the knowledge of the cardiovascular system functioning and malfunctioning several hundred years ago. At that time, it was far from obvious that Inhibitors,research,lifescience,medical a common atherosclerotic etiopathophysiology could underlie the occasional palpitations related to mild myocardial ischemia, the sudden chest pain related to acute myocardial infarction, the occurrence of night dyspnea, and the swollen legs related to congestive heart failure, all of which affect physical functioning on a continuum of severity It was also not obvious how to distinguish between the transient elevation of glucose blood levels due to the

stress of acute myocardial infarction, which is an epiphenomenal Inhibitors,research,lifescience,medical marker of active illness not etiologically related to the underlying atherosclerotic illness, and the persistently abnormal values of blood glucose level due to diabetes mellitus, which is a marker of risk etiologically related to the underlying illness. Moreover, it could not even be conceived that different check constellations of genes, such as genes predisposing to abnormal lipid metabolism, abnormal glucose metabolism, and hypertension, could alone or in interaction increase the risk for the same lesion (the atherosclerotic lesion) , which could be manifested as cognitive impairment (vascular dementia) , chest pain, or the inability to walk or sleep flat. No wonder, therefore, that the classification and treatment of psychosis, anxiety and depression might be revolutionized by a more profound biological understanding of brain functioning and malfunctioning.

, 2011). Regulation of HPA axis activity, and specifically reduced expression of CRF (regulated by stress-induced demethylation of Modulators regulatory areas of the gene CRF1) was shown in the subset of vulnerable mice that displayed social avoidance (Elliott et al., 2010) and in mice that displayed short latency to defeat in the resident/intruder paradigm (Wood et al., 2010). Supporting this finding, knockdown of CRF levels diminished stress-induced social avoidance (Elliott et al., 2010). In a separate model of chronic subordinate

colony housing, mice selectively bred for low anxiety were behaviorally resilient to subordination stress, and showed distinct HPA axis responses (Füchsl et al., 2013). Several neurotransmission systems Selleckchem BMS754807 are implicated in social-stress resilience vs. vulnerability: in addition to BDNF-control of dopamine mentioned above, differences in the NAc dopaminergic system resulting from differential maternal behavior are correlated

with increased preference for social interactions in a group of highly groomed rat offspring (Peña et al., 2014). Glutamatergic, serotonergic, and GABAergic systems appear to be involved as well. Vulnerable and resilient animals differ significantly in the expression of AMPA receptors in the dorsal hippocampus, and activation of AMPA receptor during the stress exposure prevented the physiological, neuroendocrine, and behavioral effects of chronic social stress exposure (Schmidt et al., 2010). Knockout of serotonin transporter selleck chemical increases the vulnerability to social avoidance following social defeat (Bartolomucci et al., 2010). Finally, supression of the GABAergic system is seen in the pre-frontal cortex of mice showing depressive symptoms following social defeat (Veeraiah et al., 2014), and in amygdala of mice exposed to peripubertal stress (Tzanoulinou et al., 2014). Similar suppression is found in

the cortex of human patients with PTSD (Meyerhoff et al., 2014). Stress exposure much not only alters social interaction, but that social interaction can in turn play a role in buffering or moderating the effects of that stressor, providing adaptive value of social networks for coping with stress exposure. We can think about stress-resilience in multiple layers: life-long programming of stress-resilient individuals originating from the early life environment and in particular through maternal interactions (Parker et al., 2012; Lyons et al., 2010 and Szyf et al., 2007); short-term resilience after an acute moderate stressor promoting better functioning after a secondary stressor (Kirby et al., 2013); or resilience that comes from mitigating (buffering) the effects of stress by positive, supportive social environment, or even by aggressive social interactions. For example, lower ranking baboons that show displacement of aggression on peers have lower CORT levels (Virgin and Sapolsky, 1997).

At diagnosis, the individuals ranged in age from 30-84 years with a median age of 67.5 years, 13 (52%) males and

12 (48%) females. Table 4 Treatment of rectal cancer patients All carcinomas were histologically confirmed primary rectal adenocarcinomas (Figure 1). Most tumors were moderately differentiated [G1=1 (4%), G2=22 (88%), G3=2 (8%)]. Further pathohistological characteristics (TNM-classification) of the respective rectal cancer are listed in Table 5. Figure 1 Hematoxylin and Eosin (HE). A. Normal rectal mucosa comprising of Lamina mucosa with Goblet cells, Lamina Inhibitors,research,lifescience,medical propia, Crypt of Lieberkühn, Paneth cells, Muscularis mucosae and Lamina submucosa with Blood vessels and other typical components; B. Resected … Table 5 TNM-classification According to Dworak and colleagues, the histopathologic response (grade 0, no regression; grade 1, minimal regression; grade 2, moderate regression; grade 3, good regression; and grade 4, total regression) was as follows (31,32): Regression grade 0→1

(4%) Inhibitors,research,lifescience,medical Regression grade 1 → 5 (20%) Regression grade 2 → 9 (36%) Regression grade 3 → 10 (40%) For further evaluation, the regression grades 0-1 were defined as non-response. The following Inhibitors,research,lifescience,medical table (Table 6) includes further information concerning the patients antecedent. Table 6 Anamnesis (nicotine abuses) and pre-/co-existing diseases The most frequent coexisting disease (found in 48% of the patients) was hypertension. 16% of the patients were smokers. These factors were not differently associated with the intratumoral mutation status. The diabetic patients were diagnosed with higher tumor (T3) and lymph node (N3) stages. Mutation Analysis for KRAS and BRAF KRAS and Inhibitors,research,lifescience,medical BRAF amplifications were electrophoresed on 2% agarose

gel electrophoresis, (Figure 2), resulting in one visible band for each sample. Figure 2 Electrophoresis results of amplified fragments of the KRAS and BRAF gene, analyzed on 2% agarose gel electrophoresis. PCR products of the KRAS gene (A) demonstrate Inhibitors,research,lifescience,medical 173bp sized check details electrophoretic bands (lanes 2-5; lane 7). PCR products of the BRAF gene (B) … Figure 3 illustrates electropherograms of sequence and SNaPshot analysis of BRAF and KRAS genes, respectively. Mutations are found at the first, second and fourth base position of the wildtype sequence (Table 7). Figure 3 A. Mutation analysis of a KRAS gene. SNaPshot and sequencing electropherograms of patient after therapy present a KRAS pG12D mutation G (blue) from > A (green) transition (GGG –> GAG) causing an amino acid change of glycine to glutamate. This … Table 7 KRAS point mutations found and determined for all patients in this study. Each point mutation results in an amino acid change and sustained KRAS activation 9 of 25 patients (36%) before and 11 of 25 individuals (44%) after neoadjuvant radiochemotherapy harboured KRAS mutations (Figure 4). Most mutations are transition ones.

Reliability among the three independent raters was high (weighted Kappa

=0.72 for categories 0-30, 31-39, 40-50) suggesting that this cluster of judgments might be useful to highlight and quantify important, issues during the protocol stage of an RCT. Table I. Average score of three raters for each one of the domains of the RCT protocol. We recognize that validity Inhibitors,research,lifescience,medical is a more problematic issue, as this does depend on the rater’s perspective, but, work is ongoing involving raters from very different backgrounds. In any case, we concur that, consideration of these domains is useful9 and suggest that the Pragmascope is one practical way of doing this. Discussion The world of RCTs has changed remarkably in the last 10 years. Systematic reviewing of trials, Inhibitors,research,lifescience,medical now industrially undertaken through initiatives like the Cochrane Collaboration,20 has highlighted issues with poor design and inconsistent reporting. These systematic reviews are potent to guide care but, are undermined by trial evidence that is difficult or impossible to apply in the real world. For mental health, studies of increasing pragmatism are now being designed and undertaken.21-23 Such pragmatic, real-world, practical design can be dovetailed within explanatory Inhibitors,research,lifescience,medical studies or sit independently. With maintained systematic reviews guiding practice,21 transparent priority setting for research funding for evaluative research,3 and the push towards

defining core out come measures of agreed relevance in trials,24 a great, increase in pragmatic trial activity is likely. Of course explanatory trials have an important place in the portfolio of research, but. the rigorously undertaken but highly pragmatic Inhibitors,research,lifescience,medical trial will give us the opportunity to learn much more about, the real effects of the potent, treatments we give. Appendix. The Pragmascope (Figures 2) Explanation: This tool is based on ten domains described in the development of the Pragmatic-explanatory continuum indicator summary (PRECIS).9 It can be used to assess applicability Inhibitors,research,lifescience,medical of results from

any given randomized controlled trial. Instructions: … Appendix. The Pragmascope (Figures 3) Acknowledgments We would like to thank Dr K. Thorpe for consideration of our rating tool, and Dr B. Park for help calculating Kappa. Contributor Information no Graeme Tosh, Psychiatrist, East Midlands Workforce Deanery, Nottingham, UK. Karla Soares-Weiser, Director, Enhance Reviews Ltd, Oxford, UK. Clive E. Adams, Professor, Institute of Mental Health, University of Nottingham, UK.
An the context of evidence-based medicine,1 randomized control-group trials (RCTs) are considered to be the decisive level of see more scientifically proven evidence as far as therapeutic aspects are concerned.2 Placebocontrolled trials, especially for certain psychiatric indications, are ranked higher in terms of evidence than active control-group studies.

These methods have shed light on a few aspects of organ functioning, in particular the cardiovascular system.34-36 and the brain,37,38 but also the respiratory system.39,40 Indeed, the cardiac rhythm is sensitive to initial conditions and to the fractal dimension of its attractor, and it was found that when the heart rate becomes highly regular, the heart is less capable of adaptation to demands, and that this condition predisposes to arrhythmias

and myocardial Inhibitors,research,lifescience,medical infarction. This chaotic behavior of the cardiac rhythm raises the essential question of the role of chaos in biology in general. In fact, the cardiac system could not function without chaos, since the power of self-organization check details participates in the capacity of the heart to adapt to physiological demands. Dynamical models of the brain are also a domain of research, notably Inhibitors,research,lifescience,medical into the artifical neural networks. There is, however, a risk linked to self-reference stating that we try to understand the brain using our brains, a somewhat problematic circular approach.14 However, it might be that the functional assembly of many researchers’ brains could in itself lead to more that the sum of the constituents Inhibitors,research,lifescience,medical of a model brain. Brain disorders are accompanied by measurable changes in the electroencephalogram

(EEG), most obvious in a series of epileptic fits, where high-amplitude synchronized waves are observed. The various types Inhibitors,research,lifescience,medical of EEG patterns present different attractors and different fractal dimensions. When a healthy person stands with his or her eyes open, the EEG shows low-amplitude high-requency alpha waves, and the corresponding attractor has a high dimension. When the eyes are shut, EEG wave amplitude increases, frequency decreases, and the corresponding fractal dimension is lower. It is small during slow-wave sleep, and even more so during an epileptic fit or a coma.

Thus one can Inhibitors,research,lifescience,medical conclude that the cognitive power, defined as the capacity to perceive and analyze information, parallels the fractal dimension of the EEG.42 In rabbits, electrophysiological measurements in the olfactory lobe show chaotic behavior when the animal is in a resting condition, Thymidine kinase while the presentation of odors leads to different patterns of electrical neuronal activity, less chaotic and nearly periodic.43 Arnold Mandell was the first psychiatrist to combine abstract mathematical models and quantitative experimental finding in an effort to approach clinical questions, for example that of the structure of personality.44 Others are now applying models of a sequentially altered architecture to describe psychiatric disorders. For example, it was proposed that schizophrenia was characterized by nonlinear phenomena alternating with pure randomness in the brain function architecture, a proposal in line with the early theoretical work of Prigogine.

Design This phase will comprise the latter stages of analysis of results of the field study,

preparation of reports to inform the expert panel, a two day seminar to consider the findings of the field study and assembly of the final QI set with associated recommendations. A formal report will be prepared for general scrutiny in addition to publication for the peer-reviewed Inhibitors,research,lifescience,medical literature. A formal procedure for selection of the final QI set will follow the expert panel deliberations, similar to that used in assembly of the Assessing Care Of Vulnerable Elders (ACOVE) indicators [59]. This process involves two rounds of anonymous ratings on a risk-benefit scale with a teleconference group discussion Inhibitors,research,lifescience,medical occurring between rounds [60,61]. Data analysis Primary analysis will be to evaluate the new QIs. The QIs will be adjusted for ascertainment and selection bias through risk adjustment procedures [58]. The determination of appropriate case-mix and risk adjustment procedures will involve simple bi-variable descriptive statistics (correlations, mean differences). Good candidates for adjustment will be included as matching criteria in the QI

adjustment process. The QI adjustment method will use a procedure that has the advantage of being quasi-parametric, Inhibitors,research,lifescience,medical involving matching individual patients in target EDs to randomly selected patients from other EDs. This counterfactual Inhibitors,research,lifescience,medical contrast will include a re-sampling procedure and allow QIs to be expressed as odds ratios or expected proportions given an overall average rate and an empirically based replication (i.e. confidence) interval. Relative to extant methods of risk adjustment this approach is relatively simple, can be implemented in clinical populations of small size and represents as perfect as possible adjustment for differences Inhibitors,research,lifescience,medical in patient mix across clinical

settings. The reliability of QI scores will be evaluated by multiple bootstrapped split-half correlations of patient samples and time-to-time correlations of Trichostatin A repeated QI scores. This is a unit-level analysis, where for each ED we will use a bootstrapping data augmentation approach to generate 20 random half samples of patients. Consideration of the issues specific to patients with cognitive impairment, nursing home residents and those patients requiring palliative care will result in an additional analysis of QI data to next identify whether any QIs are specifically significant for these sub-groups. Comparisons with SAEM QIs will use standard methods for comparing correlation coefficients for the contrasting reliability coefficients, and cross tabulations of tertiles of QIs in similar domains for the validity assessment. Voting Following the final expert panel, the indicators will be presented to the expert panel in a summary document. In the document, each indicator will be described in relation to the agreed name, denominator, numerator and exclusion criteria.