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Value of biopsy in a cohort of children with high-titer celiac serologies: observation of dynamic policy differences between Europe and North America
Kamran Badizadegan ORCID: orcid.org/0000-0003-4900-94551,
David M. Vanlandingham2,
Wesley Hampton2 &
Kimberly M. Thompson1
Healthcare systems implement change at different rates because of differences in incentives, organizational processes, key influencers, and management styles. A comparable set of forces may play out at the national and international levels as demonstrated in significant differences in the diagnostic management of pediatric Celiac Disease (CD) between European and North American practitioners.
We use retrospective clinical cohorts of 27,868 serum tissue transglutaminase (tTG) immunoglobulin A levels and 7907 upper gastrointestinal endoscopy pathology reports to create a dataset of 793 pathology reports with matching tTG results between July 1 of 2014 and July 1 of 2018. We use this dataset to characterize histopathological findings in the duodenum, stomach and esophagus of patients as a function of serum tTG levels. In addition, we use the dataset to estimate the local and national cost of endoscopies performed in patients with serum tTG levels greater than 10 times the upper limit of normal.
Using evidence from a US tertiary care center, we show that in the cohort of pediatric patients with high pre-test probability of CD as determined by serum tTG levels, biopsy provides no additional diagnostic value for CD, and that it counter-intuitively introduces diagnostic uncertainty in a number of patients. We estimate that using the European diagnostic algorithms could avoid between 4891 and 7738 pediatric endoscopies per year in the US for evaluation of CD.
This study considers the North American and European management guidelines for the diagnosis of pediatric CD and highlights the slow adoption in North America of evidence-based algorithms developed and applied in Europe for triage of endoscopy and biopsy. We suggest that system dynamics influences that help maintain the status quo in North America include a variety of social and economic factors in addition to medical evidence. This work contributes to the growing body of evidence that the dynamics that largely favor maintaining status quo management policies in a variety of systems extend to clinical medicine and potentially influence clinical decisions at the level of individual patients and the population.
Contributions to literature
This study adds to a growing body of evidence suggesting that in children with a high pre-test probability of Celiac Disease, invasive endoscopy with biopsy adds little to no additional diagnostic information with respect to Celiac Disease, and its system-wide costs may exceed any benefits.
This study provides a system dynamics framework for understanding the roots of policy differences between European and North American practitioners with respect to clinical practice guidelines.
This study adds to a growing body of literature dedicated to systems and methods for timely development and maintenance of evidence-based clinical practice guidelines and testing algorithms across the healthcare landscape.
Healthcare organizations adopt performance improvements at different rates because of differences in incentives, organizational processes, and management styles [1]. An important complicating factor in complex healthcare systems like the United States (US) is the lack of full transparency in costs, performance metrics, and clinical outcomes. As such, better or different clinical strategies may not be implemented widely, rapidly, or at all [2].
The adoption of novel practices or performance improvements may face a comparable set of resistance forces at the national or international levels. These forces accelerate the adoption of processes deemed favorable to individual providers or healthcare systems (e.g., safer medications or higher reimbursements), and decelerate the adoption of disruptive processes deemed unfavorable (e.g., elimination of revenue-generating procedures or adoption of standardized protocols). One notable example of delayed clinical implementation at the international level is the diagnostic management of pediatric Celiac Disease (CD).
The policies and positions of the European (ESPGHAN) and North American (NASPGHAN) Societies for Pediatric Gastroenterology, Hepatology and Nutrition shape the practice of pediatric gastroenterology. These sister societies frequently issue consensus guidelines, and until 2012 had equivalent diagnostic guidelines for the management of CD. In 2012, however, ESPGHAN issued a set of revised guidelines that allowed a "no-biopsy" diagnostic pathway for patients with a serum immunoglobulin A anti-tissue transglutaminase antibody (tTG) titer greater than 10 times the upper limit of normal (>10x ULN) [3]. Support for this revised position included a detailed analysis of the clinical evidence [4], the opinion of practicing physicians [5], and the results from preliminary clinical testing in a variety of conditions [6, 7].
At the time of the publication of ESPGHAN criteria, North American experts appropriately suggested that "there is still a long way to go but we are headed in the right direction" towards no-biopsy diagnosis of CD in any patient [8]. Despite multiple opportunities to reach consensus since 2012, NASPGHAN and the American College of Gastroenterology continue to maintain biopsy as a required part of the diagnosis for every suspected case of CD [9, 10]. The American Gastroenterological Association clinical update recently discussed both European and North American approach [11], but did not adopt a specific position regarding the no-biopsy approach in any patient group. Since 2012, the European experts reaffirmed and extended their position that pediatric CD can be diagnosed without biopsy in a selected group of children by following the recommended guidelines [12].
Given the substantial costs and health implications of endoscopy with biopsy in children, we explore the value of the information provided by biopsy in children with high titer serum tTG results in a large North American referral center. We show that with high pre-test probability of CD based on serum tTG values, duodenal biopsy provides no additional diagnostic value for CD, consistent with ESPGHAN findings. Moreover, biopsy counter-intuitively introduces diagnostic uncertainty in a number of patients necessitating further clinical action or follow-up. We briefly explore the economic consequences of biopsies and present a system dynamics framework to understand feedback mechanisms that enforce the status quo in North America. The remainder of this background provides relevant information about the pathophysiology and diagnosis of CD, including the evolution of diagnostic recommendations from by ESPGHAN and the North American response.
Pathophysiology of CD
CD has a prevalence of 0.4–1% [13] and is in the differential diagnosis of children with any gastrointestinal symptom, particularly with predisposing conditions, including autoimmune disease, diabetes, Down syndrome, and family history [14]. Serological screening is the first line of action for evaluation of any patient with clinical suspicion of CD [3, 9, 10, 13, 15,16,17,18]. Patients with positive serology are typically referred for upper gastrointestinal (UGI) endoscopy and biopsies. Since CD is a small intestinal disease, duodenal histological abnormalities are considered the hallmark of active disease [7, 16, 17, 19,20,21,22,23,24,25]. Small intestinal abnormalities in CD were described in 1960s [26,27,28,29,30,31], and widespread availability of endoscopy made duodenal biopsy the de facto diagnostic standard. For decades, histology served as the only reliable biomarker for the disease, became known as the "gold standard," and has remained such in spite of significant advances in laboratory testing and endoscopic imaging.
In spite of its central role in diagnosis, biopsy has well-known limitations [24, 32]. Overlap exists between histopathological findings in CD and other conditions ranging from infections to systemic disorders [24]. Writing on behalf of Gastrointestinal Pathology Society and the Association for Study of Celiac Disease, Robert et al. (2018) concluded that "correlation of histologic findings in duodenal biopsies with patient demographics, symptoms, medication use, evidence of H. pylori infection, and laboratory data, especially serological and genetic tests for Celiac Disease is required for correct diagnosis." Thus, consideration of histopathology as the gold standard is not supported in practice by the need for extensive clinical correlation to reach a correct diagnosis. The widely-used Marsh histological classification acknowledges the presence of a histological spectrum, emphasizing less than perfect sensitivity and specificity of biopsy [24, 33, 34]. Importantly, all classical descriptions of CD histopathology relied on gluten-sensitivity as the definitive evidence of CD, rather than proposing the presence of pathognomonic histological features [30, 33, 35]. Pathologically, CD may show: (i) no specific histopathological findings, (ii) classical histopathology of active CD, or (iii) concurrent or superimposed confounding pathologies. Although duodenal biopsy can provide confirmation of CD if and when classical features are present, the overall performance characteristics of biopsy remain poorly quantified and variable because of histological overlap between multiple different inflammatory entities (reviewed in [24]).
A key issue limiting the reliability of biopsy is histological variability in tissue expression of CD [36,37,38,39,40]. This biological variability that can result in diagnostic uncertainty is further confounded by well-known tissue processing and interpretive errors in pathology, and biopsies in 4–30% of patients may be inadequate due to technical issues or interpretive disagreements [41,42,43,44,45,46,47]. Thus, recognizing that negative or non-diagnostic duodenal biopsies do not exclude CD [9, 15], practice guidelines suggest that follow-up endoscopy with additional biopsies may be justified or necessary in some patients with clinical and serological evidence of CD (i.e., high pre-test probability) for whom the laboratory reports a negative initial biopsy result [9, 14, 15, 17]. Longitudinal studies have also demonstrated histological evolution over time in patients who carry the diagnosis of CD based on clinical, serological and genetic data [48]. In these patients, duodenal histology at presentation can be non-diagnostic, suggesting that biopsy is an inherently suboptimal test in early CD.
European movement towards no-biopsy
Acknowledging that abnormal histology is a biomarker for CD, one can appreciate the potential existence of other biomarkers (e.g., imaging, serologies or genotypes) with performance characteristics similar to, or possibly better than biopsy. Unlike histopathology, some biomarkers (e.g, genotypes) are independent of age and exposure to gluten, and therefore more generally applicable as a diagnostic tool.
An equally important concept is the probabilistic nature of all diagnostic information [49]. For example, diabetes confers 5–10% probability of CD [50], and a first-degree relative with CD is associated with 7.5% probability of CD [51]. Together, these prior probabilities imply that a patient with diabetes and an affected first-degree relative has a 7.5–16% probability of CD, depending on the level of linkage between these risk factors. Similar arguments can be made for Down syndrome, associated with CD in up to 18.6% [52], and for multiple other conditions highly correlated with CD [14, 32]. In these circumstances when the pre-test probability of CD is high, if serum tTG level rises from normal on gluten-free diet to >10x ULN after exposure to gluten, there is virtually no alternative diagnosis other than CD, regardless of any biopsy findings. The immediate utility of this probabilistic approach has been shown by others [53]. Therefore, the key policy issue is defining the population(s) in which additional testing (e.g., biopsy) provide diagnostic value and for which the benefits from the information exceed the costs of obtaining it [54].
Based on the Bayesian concept of essentially 100% positive predictive value for CD in a (i) symptomatic child, with (ii) serum tTG >10x ULN, and (iii) positive results of a second Celiac-specific test, ESPGHAN concluded that CD may be diagnosed without biopsy provided that (iv) signs and symptoms subside on gluten-free diet (i.e., establishment of gluten-sensitivity) [3]. These guidelines reaffirmed clinical experience suggesting that biopsy is not always necessary in patients with high pre-test probability of CD [20, 55]. The guidelines further recognize that histological variability can lead, and has led, to the need to perform multiple biopsies (with the additional procedure costs and risks) in individual patients with high-probability of CD who have indefinite or otherwise non-diagnostic biopsies at presentation [36,37,38,39,40].
Since 2012, the ESPGHAN no-biopsy approach has been evaluated in a variety of settings, demonstrating the overall effectiveness of the strategy [6, 22, 25, 41, 56,57,58,59]. These studies have shown opportunities for improvement, but none presented a significant challenge to the core concept that a sub-population of patients exists in which CD can correctly and confidently be diagnosed without biopsy. In one such study, the no-biopsy algorithm showed a positive predictive value of 0.988 and a negative predictive value of 0.958 [41]. This and similar recent observations [60, 61] led to reaffirmation and further extension of no-biopsy approach to include asymptomatic children as well [12].
North American response
In spite of years of accumulated evidence, debate continues in the US about the adoption of any no-biopsy approach [10, 11, 14, 16,17,18, 23]. Published practice guidelines require a positive concordance between serologies and biopsy for the diagnosis of CD, and recommend obtaining multiple biopsies from distal duodenum and the duodenal bulb regardless of the pre-test probability of the disease [9, 10, 15]. A recent clinical practice guideline discussed a "biopsy-avoiding" approach and acknowledged the existence of patients in which the pre-biopsy probability of CD is "virtually 100%," but did not specifically endorse a no-biopsy protocol [11]. Confirming the validity of the ESPGHAN guidelines in other populations has been identified as a critical need because of potential clinical differences between different patient populations [8].
An important concern raised by the proponents of an all-biopsy approach (i.e., biopsy every suspected CD case) is the uncertainty about tTG assay performance [8, 9, 14, 23, 62]. These include differences in platforms, technologies, and lack of harmonization among different laboratories that prevent cross-institutional comparison of laboratory results. Others point out a missed opportunity to diagnose incidental disorders as a disadvantage of the no-biopsy approach [8, 9, 23] without providing any formal policy, cost-benefit, or value-of-information analysis as support. Some clinicians express concern that a gluten-free diet may be cumbersome, expensive, and adversely impact the quality of life of the individual. They require confirmation of the diagnosis at the highest level of certainty before recommending a lifelong treatment [9, 62]. Thus, they implicitly value the benefits of biopsy more than its costs.
Nationwide Children's Hospital (NCH) is a referral center for evaluation and management of CD in the US. Since July of 2014, patients with differential diagnosis of CD have undergone tTG testing using QUANTA Flash® chemiluminescence assay (INOVA Diagnostics, Inc., San Diego, CA) which has extended analytical range (see Additional file 1) and superior performance for CD [63,64,65]. In addition, all duodenal biopsies at NCH are evaluated by experience pathologists and subject to clinicopathological consensus review.
Creation of study dataset
We retrieved serum tTG IgA measured between July 1, 2014 and July 1, 2018 (27,868 tTG results). We excluded 243 adult patients (> 21 years old) and one with unknown age. Seven results with non-numeric values (assay error or cancellation) were also excluded. The remaining 27,617 results included 25,327 negatives (< 20 Chem'U), 2207 positives within reportable range (20 to 4965 Chem'U) and 83 positives higher than reportable range (> 4965 Chem'U). We did not correlate tTG levels with total IgA as this study focuses on tTG levels above the upper limit of normal, and conclusions remain independent of any potential false negative tTG values due to IgA deficiency.
We additionally retrieved pathology reports for patients with duodenal biopsy between July 1, 2014 and July 1, 2018 (7907 reports). NCH uses Marsh classification [34] for any biopsy of confirmed or suspected CD. Thus, text strings "Marsh" and/or "Celiac" in the "Final Diagnosis," "Diagnosis Comment," and/or "Microscopic Description" fields of pathology reports are indicative of evaluation for CD. Thus, we limited the retrieved reports to include only those with the words "Celiac" or "Marsh" in any of the above 3 fields. This yielded 895 pathology reports after excluding reports of 6 patients > 21 years of age.
The final analysis dataset was created by matching every pathology report to the nearest (in absolute time) tTG result for every unique medical record number. This excluded 96 reports without a matching tTG (patients with tTG done elsewhere and/or patients with tTG result or pathology report outside of the study period). The remaining 793 pathology reports were used for further analysis. We did not track gender or access other clinical records.
Histopathological characterization
Histopathological findings provided by institutional pathologist in each of the 793 reports were categorized by an experienced gastrointestinal pathologist (KB). The "Celiac Disease" category included patients in whom duodenal biopsies showed increased intraepithelial lymphocytes and various degrees of villous blunting, crypt hyperplasia, and lymphoplasmacytic expansion of the lamina propria (Marsh 2 to 3c). Patients in "Indefinite Duodenitis" category either had questionable increase in intraepithelial lymphocytes with no villous blunting (Marsh 0–1), or had active or chronic duodenitis with no increase in intraepithelial lymphocytes or had confounding findings such as granulomas or marked eosinophilia. Patients in the "No Duodenitis" category had no intraepithelial lymphocytosis or other findings to suggest active or a chronic duodenitis. Cases with incidental findings not specifically associated with CD and not sufficient for a diagnosis of duodenitis were grouped under No Duodenitis. These included isolated pyloric metaplasia in duodenal bulb, focal lymphangiectasia, or mildly increased lamina propria eosinophils.
In addition to duodenal biopsies, histological findings in the stomach (786 cases) and esophagus (772 cases) were categorized. For each site, biopsies were classified as normal or abnormal, with abnormal biopsies further classified either as "significant" (unexpected and clinically actionable findings) or as "incidental" (either expected clinically actionable findings or unexpected minor findings requiring no definite clinical action).
In the stomach, significant findings included new diagnoses of H. pylori gastritis, or other forms of active or chronic active gastritis, including active eosinophilic gastritis and gastric ulcer. Incidental findings included any form of chronic gastritis or chronic inflammation without activity, including any reactive epithelial changes or focal metaplasia. Incidental finding also included any gastric intraepithelial lymphocytosis in the setting of CD (a known feature of CD), as well as gastritis in any patient with preoperative diagnosis of gastritis (an expected finding).
In the esophagus, significant findings included any esophagitis with greater than 8 intraepithelial eosinophils per high power field, as well as esophageal ulcers with or without fungal or viral organisms, in any patient with no preoperative diagnosis of esophagitis. In the absence of clear clinical guidelines, we considered a finding of isolated intraepithelial eosinophils (1 or 2 in a high-power field) as "normal" and eosinophil counts between 3 and 8 per high-power field as "incidental" in any patient with no preoperative diagnosis of esophagitis. We also classified occasional neutrophils with no infectious etiology and the description of increased intraepithelial lymphocytes with no specific diagnosis of esophagitis as incidental. We considered any reference to "mild reactive changes" in isolation as a normal finding. We did not encounter any other diagnostic category in the esophagus or stomach of the patients in this study of potential clinical importance for this study.
Actual cost of endoscopy with biopsy fluctuates widely based on clinical facility, insurance, type of anesthesia, level of pathology services, and multiple smaller clinical charges [66]. The actual cost of endoscopy to each patient in our study is impossible to calculate without a detailed search of the billing records, which we did not attempt because of disproportionate risk of privacy breach for the level of data obtained.
Published cost estimates are available from advocacy groups including New Choice Health™ indicating national average of $3000 per UGI endoscopy, ranging from $1600 to $12,100 [67]. For the biopsies obtained from the esophagus, stomach, duodenal bulb and duodenum per endoscopy represented by 4 charge codes in our study, pathology charges would range from $281 (average global Medicare in 2018) to $2169 (average chargemaster for two top pediatric hospitals in 2018). Separately, Miller et al. estimate $12,490 for endoscopy with biopsy [68] in a pediatric hospital. We estimate the cost of endoscopy with biopsy would range from a low of New Choice Health plus Medicare pathology ($1600 + $281 = $1881), to a high of New Choice Health plus tertiary care pathology ($12,100 + $2169 = $14,269).
Estimation of the number of pediatric procedures is equally challenging with no published data. We chose to scale NCH procedures to the national level based on the number of providers at NCH and the State population. There were 1630 pediatric gastroenterologists in the US in 2017, including 97 (6%) in Ohio [69]. Meanwhile, there were 25 pediatric gastroenterologists at NCH, representing 26% of Ohio and 1.5% of the US. Therefore, every NCH procedure scales to 3.8 in Ohio and 67 in the US. Alternatively, the number of procedures can be scaled to the national level based on US population data. US Census Data show that Ohio represented 3.6% of the US in 2018 [70]. Assuming that NCH performs 26% of pediatric gastrointestinal services in Ohio, every NCH procedure scales to 106 procedures in the US. We therefore estimate range of 67–106 procedures in the US for every NCH procedure.
Table 1 summarizes patient characteristics as a function of serum tTG. Table 1 rows represent 2 key tTG result subgroups: Negative (< 20 Chem'U) and Positive (≥20 Chem'U), including the non-consequential designation of "Weak Positive" recommended by the assay manufacturer for positive results < 30 Chem'U. Positives are further divided into 3 categories: (i) ≥20–200 (<10x ULN), (ii) > 200 (>10x ULN), and (iii) > 2000 Chem'U (>100x ULN). The cutoff of 200 represents ESPGHAN decision point [3, 12] and 2000 Chem'U is an arbitrary cutoff because the assay has a wide analytical range spanning more than two orders of magnitude above the upper limit of normal (Additional file 1). We did not study patients with negative tTG any further.
Table 1 Biopsied patient characteristics as a function of serum tTG
Duodenal histopathology
Every endoscopy included two sets of duodenal biopsies by protocol: one set of 4 biopsies from the distal duodenum and one set of 2 biopsies from the duodenal bulb. The percentage of endoscopies with "No Duodenitis" decreased with increasing serum tTG as expected (Table 1). None of the 292 endoscopies with serum tTG >10x ULN had normal duodenal biopsies, suggesting that high-titer tTG values are virtually diagnostic for some form of duodenal abnormality.
Figure 1 expands on the distribution of tTG versus duodenal histopathology for patients with positive serology. As seen in Fig. 1(a), the upper region of the analytical range of tTG is highly associated with pathological diagnosis of CD. Applying an arbitrary cut-off of 2000 Chem'U (100x ULN), the duodenal biopsies in all 109 patients are diagnostic for CD (Marsh 2 to 3c). Applying the ESPGHAN cut-off of 200 Chem'U (10x ULN, Fig. 1a, dashed horizontal line), 289 out of 292 endoscopies (99%) are diagnostic for CD, and 3 show Indefinite Duodenitis.
Histopathological classification of duodenal biopsies in 535 patients with positive serum tTG results. Box and whisker plot are generated using Microsoft Excel® and show the individual data (circles), as well as minimum value, first quartile, median, third quartile, maximum value, and outliers. Panel a shows all data, while panel b is limited to tTG results between 20 and 200 Chem'U. Three outliers labeled 1, 2 and 3 in the Indefinite Duodenitis group of Panel a are discussed in the body of the manuscript
We further explored the three cases with tTG >10x ULN and Indefinite Duodenitis (Fig. 1(a), data points marked 1, 2 and 3). Point #1 represents biopsies in a patient whose tTG values came down on a gluten-free diet, but did not normalize (partial sensitivity to gluten). In this patient, duodenal biopsies showed an active duodenitis, but only mild intraepithelial lymphocytosis. In addition, gastric biopsies showed focal active gastritis, raising the possibility of a superimposed process. These led to an indefinite result for CD by the pathologist. Point #2 corresponds to biopsies from a patient with tTG values completely responsive to gluten-free diet and with endoscopic abnormalities, but none of this patient's biopsies show a specific histopathological abnormality. This patient carries a clinical diagnosis of CD, and indefinite duodenal biopsies are thought to represent a heterogenous tissue distribution, resulting in false negative histopathology. Point #3 corresponds to biopsies from a patient with Crohn's disease proven by clinical and histopathological criteria. This patient's tTG responds to a gluten-free diet, but biopsies are confounded by features of Crohn's.
Figure 1(b) expands the data for endoscopies in patients with serum tTG values ranging from 20 to 200 Chem'U (positive but <10x ULN). This group shows significant uncertainty in histological correlation, and a large number of patients with positive tTG have indefinite or no histological findings diagnostic for CD. In these patients, endoscopies may provide the greatest potential diagnostic value, because a significant number of patients have no evidence of duodenitis, thus raising the possibility of false positive serology
Esophagus and stomach
UGI procedures in children almost always include "protocol" biopsies of esophagus and stomach. In our dataset, 789 of 793 procedures included one or more biopsies from the esophagus (772 cases) or stomach (786 cases). Figure 2 summarizes the number of significant and incidental findings in these biopsies as a function of serum tTG.
Significant and incidental findings in the esophagus and stomach as a function of serum tTG values
Figure 2 shows an anticipated trend of fewer significant and incidental findings as the pre-test probability of CD goes up. In approximately 4% of procedures in patients with tTG > 200 Chem'U, there are significant (clinically actionable) findings (Fig. 2, red bars). In the 292 cases reviewed, findings included 4 H. pylori gastritis, 1 gastric ulcer, 1 esophageal candidiasis, 6 esophagitis with eosinophilia, and 1 esophagitis with eosinophilia and concomitant H. pylori gastritis. (Determination of significance is based on the limited clinical information on pathology requisitions and does not represent detailed record review.)
In contrast, we see a larger number of incidental findings (Fig. 2, blue bars), for which we cannot assess the clinical value or costs. This included 154 patients (53%) with "chronic inactive gastritis" or "chronic inflammation" (146 mild and 8 moderate), 10 patients (3%) with low-grade esophageal eosinophilia (3–8 eosinophils per high power field), and a few other incidental findings including chronic carditis, focal active gastritis and focal intestinal metaplasia. Majority of these findings, especially mild inactive gastric inflammation (146 patients), are generally non-specific and not actionable. The severity and frequency of incidental findings in our study are comparable to other diagnostic modalities [71], but our study design did not include a medical record search to determine if any of the diagnoses resulted in specific clinical action.
Complications and costs
There were no known serious adverse events or significant pathology errors. Avoiding procedures in a population similar to the NCH population with serum tTG >10x ULN would result in local and national cost savings shown in Table 2. These estimates do include other costs to patients and their families, including pre-op and post-op clinical visits, ancillary services, lost time and wages, and delays in CD diagnosis associated with delaying adoption of a gluten-free diet.
Table 2 Annual health system cost savings associated with avoiding endoscopies in pediatric patients with tTG values >10x ULN (> 200 Chem'U)
Development and update of clinical practice guidelines is a complex process [72,73,74] that may be hindered unless all stakeholders are aligned. Our studies add to a growing body of evidence that as the pre-test probability of CD increases, the value of diagnostic information progressively decreases in duodenal biopsies (Fig. 1). Our results are even more striking because unlike the ESPGHAN algorithm [3, 12], we did not include a second line of testing or consider clinical predisposing factors. Thus, the question facing North American policy makers is: What specific evidence would be required to eliminate invasive procedures in children who are effectively proven to have CD by non-invasive means?
With little to no value of information in biopsies for patients with high clinical probability of CD, the European guidelines present a no-biopsy pathway [3, 12], but questions remain about the barriers to adoption of any no-biopsy approach in America. Given the dominance of US in the North American policy decisions, the feedback loops that enforce the all-biopsy approach are likely rooted in collective medical evidence, as well as the set of beliefs, workflows, and financial incentives that actively or subconsciously shape the practice of medicine in the US. Considering a system dynamics approach [75], we observe that such system-wide forces collectively act in favor of maintaining the procedure-centric status quo in the US. In Fig. 3 we show a system-wide causal loop diagram highlighting potential factors that affect the decision to biopsy, which for the sake of discussion we group into three general categories: cultural, financial, and biomedical.
Causal loop diagram highlighting factors that could affect the decision to biopsy. Green standard font shows factors that generally reinforce the decision to biopsy. Red italic font show factors that would generally shift the balance away from doing a biopsy
Cultural influences include the beliefs, assumptions, and values that underlie a given professional practice. Important practice elements that positively enforce the biopsy include the "gold standard" concept and ease of "access" to pathology with subspecialty "expertise" in the US. As discussed, the validity of biopsy as a "gold standard" remains questionable because of biological variability, lack of histopathological specificity, specimen quality issues, pathologists' expertise, and interobserver variability. In spite of these limitations, North American practitioners maintain an absolute diagnostic role for histopathology. This position is reinforced by nearly universal access to pathology laboratories, many of which provide subspecialty service in gastrointestinal pathology, resulting in real or perceived notion of diagnostic expertise and quality. Combined with similarly accessible endoscopy services across most of North America, biopsy as a diagnostic modality is almost never a limiting factor.
Financial incentives provide substantial reinforcement for the all-biopsy approach by actively or passively shaping the clinical practice. Endoscopy and biopsies generate significant revenues for physicians and healthcare systems in North America and there is no meaningful scrutiny with respect to the delivery of value-based care. In addition, highly subspecialized healthcare services are routinely under pressure to defray investment and maintenance costs by maximizing case volume, case complexity and reimbursement rate. As such, the healthcare system costs that would normally have a negative impact on biopsy are offset by favorable revenues, while costs to patients, families and the society are ignored or downplayed.
Also reinforcing an all-biopsy approach is the belief that biopsy results in clinically valuable incidental findings that would otherwise go undiagnosed with a no-biopsy approach. These additional diagnoses become positive externalities representing a perceived win-win situation for all parties involved. In support of these arguments, we show that 4% of procedures in patients with tTG values > 200 Chem'U result in a clinically actionable histopathological finding in the esophagus or stomach (Fig. 2). While these "freebies" seem valuable to the system, they represent an optimism bias that highly values potential (albeit rare) actionable findings without consideration of their cost to patients and the healthcare system. The idea that endoscopy is an effective screening method for incidental identification of upper gastrointestinal disease is not an accepted idea in clinical practice. In symptomatic children who undergo diagnostic UGI procedures, the yield for any positive diagnosis is less than 40% [76]. Our case series, which represents one of the largest pediatric endoscopy studies to date, shows that truly unexpected clinical findings in the stomach and esophagus occur in approximately 6% for all comers and less than 4% in patients with high pre-test probability of CD (Fig. 2). Furthermore, these small percentage of clinically actionable and unsuspected diagnoses come at the expense of a large number of incidental findings that may stigmatize patients with an "abnormality" of no known significance and may lead to additional follow-up testing, including follow-up endoscopies to document resolution of findings. Lastly, the contention that clinically significant diagnoses would go undetected but for the endoscopy for CD remains unproven. Patients with eosinophilic esophagitis or H. pylori gastritis routinely receive diagnoses based on clinical signs and symptoms, and will receive endoscopy as necessary for those conditions. The suggestion that routine endoscopy is not necessary in some patients for the diagnosis of CD does not preclude endoscopy in these patients.
Perhaps one of the most under-emphasized factors in unconditional recommendation to biopsy is the concept of indeterminate pathological diagnoses that are either biological (i.e., patchy disease or evolving disease) or technical (i.e., poor biopsies or lack of expertise). These uncertainties are manifest in the well-known correlation between the number of biopsies and the diagnosis of CD, with doubling of the rate of diagnosis as the number of biopsies double [36]. This phenomenon also underlies the NASPHGAN requirement to obtain multiple biopsies from distal duodenum and the duodenal bulb [9, 10, 15], and the need for repeat endoscopy is acknowledged globally when the first set of biopsies are indeterminate [14, 17]. Technical quality issues limit evaluation in approximately 10% of cases [45], and the true rate and overall cost of repeat UGI endoscopy with biopsy secondary to indeterminate biopsies remains unknown. At NCH, 24% of all UGI endoscopies and 7% of endoscopies reported in Table 1 represent repeat endoscopies, but our analysis cannot determine how many of the repeats (if any) occurred for indeterminate biopsies.
Lack of laboratory harmonization represents an oft-cited reason for the need to biopsy, and it is one of the most important sources of variability and uncertainty in the diagnosis of CD. Serological assays for CD are neither standardized nor harmonized between laboratories in North America. Multiple different assays and assay technologies are used to measure tTG, and existing data do not allow or facilitate physician efforts to calibrate or "harmonize" one laboratory's test results against another. The assumption that a positive serum in laboratory A would result in a positive result in laboratory B appears reasonable, specialty for highly abnormal results, but exceptions do occur. In addition, the important quantitative relationship between various positive results represented in Fig. 1 in our dataset remains unknown across North American laboratories. Thus, the probabilistic relationship between tTG and histopathological diagnosis shown in Fig. 1 may not directly apply to other assay technologies with different analytical sensitivity or dynamic range (see Additional file 1). ESPGHAN effectively addressed this issue by choosing a relative cut-off value expressed in "upper limit of normal." However, clinical laboratory harmonization remains a critical need and challenge in the management of CD [77].
Finally, a critical issue that has not received as much attention is the fundamental problem of categorizing a continuous variable (serum tTG) into categories (positive and negative) (generally reviewed in [78]). When considering all "positive" serum tTG values together as a single entity, biopsy becomes necessary for a reliable classification of CD (Fig. 1). However, when viewing serum tTG as a quantitative test with a wide dynamic range (data from Table 1 depicted graphically in Additional file 1), we can easily appreciate the direct relationship between tTG and the probability of CD. In fact, the 100% probability of histologically confirmed CD in our study for tTG values greater than 2000 Chem'U (Fig. 1, panel A) demonstrates the high positive predictive value of the test in this range. Significant recent advances have increased the analytical range for serum tTG by 2–3 orders of magnitude [64], resulting in superior diagnostic performance in the evaluation of CD [63, 65]. Timely adoption and implementation of these technological advances into medical management is necessary for maintaining best-practice guidelines.
Complication rates represent another factor that can influence the decision to biopsy. However, in our experience and the experience of others [79, 80], complications related to UGI endoscopy requiring unanticipated medical attention remain very rare. In a recent study of nearly 10,000 pediatric endoscopies, Kramer and Narkewicz identified a total of 160 (1.67%) complications that resulted in additional medical evaluation and costs, none of which resulted in significant morbidity or mortality (unplanned surgery, ICU admission, or death) [81]. The long-term health impacts of UGI endoscopy in children, if any, remain unknown.
Our studies are limited by the absence of actual cost data for the cohort of patients described here. Our clinical results are also limited by the absence of detailed chart reviews required to determine the nature of follow up in each patient. These limitations do not affect the main clinical conclusions regarding the value of biopsy in patient with high tTG titers, and we believe detailed chart and billing reviews in this large cohort of children has privacy risks that are higher than any potential benefit to the study.
Clinical management of children with CD provides an informative case study of medical management and policy making between Europe and North America. Starting from the same set of literature and evidence, they reach different conclusions about adoption of diagnostic evidence. We propose that factors that underlie national policy positions go beyond medical evidence, and include system-wide and often hidden or subconscious cultural and economic factors (Fig. 3) that influence decision to biopsy or not.
We acknowledge lack of laboratory harmonization as a significant obstacle in implementation of standard diagnostic algorithms. This issue was avoided in our clinical study by relying only on one assay, but given the large number screening tests for CD, global laboratory harmonization is urgently needed to enable cross-institutional studies that are necessary for development of national practice guidelines. Harmonization is technologically feasible [82, 83], but requires strong policy incentives, which professional societies can demand from laboratories (for example, consider the precedents set by Cystic Fibrosis Foundation and Children's Oncology Group).
Another obstacle to change is favorable reimbursement structure and ease of access to specialty care resulting in an implicit bias toward performing procedures. Based on individual incentives, practitioners may over-emphasize the value of factors that favor biopsy (access to subspecialty pathology and value of incidental findings), and de-emphasize costs to the system (procedure cost and cost of managing indeterminate results) and costs to patients (time missed from work and school).
While complication rates for pediatric endoscopy are low, the risk of clinical adverse events is not zero. Furthermore, histopathology carries adverse events, including lost or mislabeled specimens and interpretive errors. Combining these costs with financial costs associated with procedures, the value of information obtained by biopsy in thousands of patients who meet the European no-biopsy criteria appears qualitatively less than the costs. Moreover, over-emphasis on the role of biopsy undermines movement towards clinical laboratory harmonization that could reduce current uncertainty in laboratory diagnosis of CD.
In summary, we suggest that system-wide factors that result in the continued practice of an all-biopsy approach in North America go beyond medical evidence and include a complex set of social and economic factors. Individual practitioners who face an ever-changing and increasingly complex environment tend to err on the side of caution which naturally translates into multiple tiers of testing before a child is diagnosed with CD. However, invasive procedures in children come with non-zero risks of adverse events, as well as multiple hidden costs to patients, families, and the healthcare system. In order to make better decisions about the diagnostic management of CD across a heterogenous collection of health care systems and laboratories, critical need exists for clinical laboratories to standardize or at least harmonize CD biomarkers such as serum tTG results. This will help eliminate a frequently cited obstacle in making informed policy decisions regarding the need for additional diagnostic testing such as biopsy. Finally, price and cost transparency are necessary requisites in continued assessment of best-practice guidelines to determine when any given diagnostic procedure cost exceeds its value of information. With increasing healthcare expenditures and complexities, we hope this study motivates discussions about systems thinking that could potentially resolve current policy differences in pediatric CD, and in general enable timely adoption and implementation of cost-effective and evidence-based clinical guidelines.
The datasets generated and/or analyzed during the current study are not publicly available due to the fact that they contain sensitive and/or protected health information, but are available from the corresponding author on reasonable request.
Chem'U:
Chemiluminescence Units (unit of measure for QUANTA Flash® assay)
ESPGHAN:
European Society for Pediatric Gastroenterology, Hepatology and Nutrition
IgA:
tTG:
Tissue transglutaminase (serology)
NASPGHAN:
North American Society for Pediatric Gastroenterology, Hepatology and Nutrition
NCH:
UGI:
Upper gastrointestinal endoscopy
ULN:
Upper limit of normal
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Kid Risk, Inc., Orlando, FL, USA
Kamran Badizadegan & Kimberly M. Thompson
Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA
David M. Vanlandingham & Wesley Hampton
Kamran Badizadegan
David M. Vanlandingham
Wesley Hampton
Kimberly M. Thompson
The studies were designed by KB and further developed by KB and KMT. KB, WH and DV developed methods and tools to extract of data from the laboratory information systems and performed the initial data analyses. Additional data analysis and data visualization was performed by KB and KMT. The manuscript was drafted by KB and KMT, and all authors contributed to subsequent revisions. All authors read and approved the final manuscript.
KB has > 25 years of experience with the diagnosis of Celiac Disease and began these studies as a quality management activity during the time that he was serving as the laboratory medical director at Nationwide Children's Hospital. DMV and WH have expertise in business analytics and laboratory informatics. KMT is an expert in decision sciences, health policy and system dynamics.
Correspondence to Kamran Badizadegan.
These studies were approved by the Institutional Review Board of Nationwide Children's Hospital (IRB18–00698). No consent to participate was required for this study. No administrative approval was required to access the data/records described in the study.
Demonstration of differences in dynamic range (Analytical Measurement Range or AMR) for different clinical assays commonly used to measure serum tTG IgA levels.(PDF 934 kb)
Badizadegan, K., Vanlandingham, D.M., Hampton, W. et al. Value of biopsy in a cohort of children with high-titer celiac serologies: observation of dynamic policy differences between Europe and North America. BMC Health Serv Res 20, 962 (2020). https://doi.org/10.1186/s12913-020-05815-0
Value of information


Occasionally, after working on your complex design project for many hours, you may see this warning message: "Warning! Available windows resources are critically low. SOLIDWORKS cannot open any more windows. Close some open SOLIDWORKS documents."
If you ignore that warning message, you may see this critical error message and end up the SOLIDWORKS application may be crashed.
Above warning messages happened typically after you had used SOLIDWORKS for many hours and opened/closed many documents without restarting the SOLIDWORKS application. But interestingly, if you check the memory usage of SOLIDWORKS application in the Task Manager, mostly you may find out that the system still has plenty amount of RAM left over and you may wonder why the warning message window resources are critically low was reported when the RAM is not used up?
Physical Memory – the amount of RAM in the system.
Virtual Memory – the Page File used by the SOLIDWORKS process.
Desktop Heap – OS memory reserved for USER Objects like windows, menus, cursors, icons, and menu keyboard shortcuts.
GDI Objects – Resources that support graphics like fonts, bitmaps, brushes, pens, and drawing surfaces.
Test condition: SW2017SP4.1, Win8.1, open parts from Windows Explorer.
Comment: Test 1 shows the GDI Objects and User Objects value ( from Task Manager) is proportional to the number of parts opened in SOLIDWORKS. If use default setting GDIProcessHandleQuota = 10000, SOLIDWORKS is able to open 47parts before reaching the limit.
Test condition: Open 100X documents from Windows Explorer.
Comment: Test 2 shows, when opening assembly documents, SOLIDWORKS will use slightly more GDI objects and User Objects compare with opening the part and drawing documents. Above test result also shows SW2017 uses about 10 more GDI objects and User Objects per document compare with SW2016.
Comment: Compare Test 3 and Test 2, when opening documents from PDM vault, SOLIDWORKS application will use more GDI Objects and User Objects compares with opening from Windows Explorer. Take SW2017SP4.1 as an example, it will use 100 more GDI Objects per document when opening files from PDM vault. Based on the result from Test 1, for the same GDI limit, now you can only open 30 documents instead of 47 documents, which means for PDM user, they need to increase the GDI Objects and User Objects limits to avoid the warning message from SOLIDWORKS Resource Monitor.
Press WIN + R key to lunch the Run command dialogue, type Regedit and press Enter.
2. Click OK if you see this UAC warning message.
3. Navigate to HKEY_LOCAL_MACHINE\SOFTWARE\Microsoft\Windows NT\CurrentVersion\Windows and locate the registry keys: GDIProcessHandleQuota and USERProcessHandleQuota, the range for GDIProcessHandleQuota is 256 ~ 65536 and the default value is 10000 ( Decimal), the range for USERProcessHandleQuota is 200 ~ 18000 and the default value is 10000 ( Decimal).
5. Reboot the computer after you had made change to the registry value.
6. Use the Testlimit tool to check if the setting works. Below picture shows my GDI objects limit is 36860 and my User Objects limit is 20000.
Hopefully this study will help you have a better understanding of Windows Resources and how to set the GDI Objects and User Objects based on your working condition to improve your SOLIDWORKS reliability. Feel free to comment and share this post.
Note 1: I also performed another study to see what is the effect to windows resources used by SOLIDWORKS application after open and close multiple documents, it seems the GDI objects and RAM used by SOLIDWORKS application will not be completely released after the documents are closed, for example, the GDI objects grows from 898 to 3456, and the RAM used grows from 360MB to 1075MB after open and close documents for 20 times, which means it is advisable for user to restart the SOLIDWORKS application periodly to completely release the windows resource, to ensure the stability of using SOLIDWORKS application.
Note 2: The Windows resource limits how many files can be opened concurrently by an application. I just did another test, you won't be able to open more than 60 files using 32bit Excel, this time, the limitation is the amount of RAM can be addressed by a 32bit application, you will see this kind of error message when Excel hits the limit.
I also tried to compare the GDI objects and User objects per document when opening Excel files from Windows Explorer and PDM Vault. When opening files from PDM Vaults, the number of GDI objects and User objects per document are slightly higher, but the difference is not as significant as compared with opening SOLIDWORKS documents from Windows Explorer and PDM Vault.
Thanks Shaodun Lin for sharing, this would be helpful in handling the large number of file and large assemblies more efficiently.
Thank you sir. This is very informative and helpfull.
Yes! Thank you very much indeed Shaodun!
Thank you, I'm sure this will answer a lot of questions that have come up here before.
As others have said, Thank you.
I think this deserves a link on Glenn Schroeder's FAQ pages as this issue has often been asked about.
Yes I saw that and applaud his efforts much like I appreciate yours. I wanted to tie this in as well as I think what Shaodun Lin has done is enlightening and helpful.
I wish SOLIDWORKS Resource Monitor could see (without rebooting pc) if I use tool like rammap.exe to clear Standby List, which is really stupid way how Windows steals RAM from us.
Why doesn't diagnostics tell us about this?
Having "Run System Diagnostics" in that list implies that if I run system diagnostics, then it will help me find out the current issue that is bringing up the yellow exclamation mark.
This tells me nothing about the reason that I am getting a warning.
If GDI Objects is commonly an issue, then why isn't it shown in the list above?
And additionally, why is it telling me that there is a warning, simply because a Solidworks process is open?
Didn't it want me to run system diagnostics in the first place? Won't closing Solidworks release the GDI objects and RAM once I close it (among other things)? Meaning that the diagnostics will no longer be able to tell if I am putting a heavy load on the computer with the assembly that I am having an issue with.
Not very many being used.
I realize that this may not be the place to put this, but the real question that I have, is why doesn't System Diagnostics actually do a system diagnostic on the items that actually affect Solidworks? And specifically, why can't it run a load test and figure out where the issues lie using the assembly that I currently have open (which is where I am having the problem anyway)?
I have run the benchmark test, and honestly I am not sure that it reliably reflects any type of workload that I have put (or would put) against the computer. The assembly that it opens and then does a bunch of stuff to is either a VERY small assembly, or doesn't actually represent anything that I would work on. It zips through a whole bunch of things that are significantly slowed down for me when I do similar things manually.
I love that we are getting this information, but shouldn't System Diagnostics be a real system diagnostic?
Maybe I went the wrong direction, but it confuses me.
Did you get an SPR # for this ER?
BTW, That was a great writeup of how inadequate the System Diagnostics are.
"I love that we are getting this information, but shouldn't System Diagnostics be a real system diagnostic?"
Not yet. But if/when I do, I will update it here.
I changed the default values for the GDI and User objects on Monday and since then have not had a certain problem occur. I want to set the values back to the default to see if that corresponds to the problem occurrence, but I don't know what the default values are. Can someone enlighten me please?
I went this way too. seems to have fixed the problem easier than the above mentioned method. One would think that the install and upgrade of SolidWorks would be able to go in and make the changes to the computer mentioned above so that the user would not see this problem and be able to be more productive.
Re: What is my PC's bottleneck?
Re: SW2018 - How's the stability?


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Here at Edgbaston Dental Centre, we aim to inspire, educate and empower you to enjoy your Dental and Hygiene care. We combine a soothing atmosphere, outstanding patient care, and the latest techniques to create the ultimate in dental experiences for our patients. Our philosophy is one of integrating Dentistry and physical well-being , promoting the important link of how your teeth may affect your health and your health may affect your teeth! We have experience in smile rejuvenation, taking worn, tired teeth and transforming them into bright, beautiful smiles. Whether you are seeking a subtle enhancement or a full smile makeover, we have an option for you! Our resident professional experts are here to help you understand the growing realisation of whole-body approaches to your health. We will give expert informed advice and always aim to give you as much support as you require. Your complete satisfaction is our intention and commitment to you. We dedicate ourselves to creating a happy lasting journey with all our clients, who are motivated by our centre of excellence. It is our intention that you feel confident, happy and relaxed with us and enjoy your time with us at Edgbaston Dental Centre. Only a five-minute drive from central Birmingham , the practice is housed in a contemporary building with plenty of free parking available to patients. Tastefully decorated, our spacious suite is modern, yet inviting with indoor fish tanks, a large and diverse selection of CDs, Plasma TV's , and plenty of recent-issue magazines are on-hand to help you unwind. Our friendly, professional team is always available to meet with our patients personally and to address any concerns you might have. We schedule our appointments with plenty of time in-between so you will not feel rushed. We also always welcome new patients, priding ourselves on our excellent customer service and professional approach to health care. Modern well-equipped surgeries help us to offer the latest techniques using high quality materials under stringent cross-infection control. Our aim is to protect and maintain your natural teeth through high quality dentistry, accurate and comprehensive diagnosis and highly proficient technical skills in a safe environment. Treating you - our patient, as we would wish ourselves and our families to be treated.


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US Open 2014: Michael Jordan watches on as Roger Federer cruises
US Open 2014: Roger Federer beats Marinko Matosevic to reach the second round as basketball legend Michael Jordan watches on
By Marianne Bevis in New York
Wednesday 27 August 2014, 14:37 UK
Roger Federer in first-round action in New York Photo: Marianne Bevis
Cheered on by basketball legend Michael Jordan, Roger Federer became the first player to claim 50 match wins this season with a straight-sets victory in the first round at the US Open Tuesday night.
Federer enjoyed a 6-3 6-4 7-6(4) win over Australian Marinko Matosevic to set up a second-round meeting with another Australian, big-serving 26-year-old Sam Groth.
The five-time former champion Federer is now 23-1 in New York's famous night matches, has won 68 matches at Flushing Meadows, and is playing in a record 60th consecutive Grand Slam.
Asked about Jordan's presence, Federer said: "I was so happy that he came into the world of tennis for a little bit and that he got to see me as the character in the whole show was pretty cool.
MJ #selfie #HisAirness pic.twitter.com/Bv4HJVecqa
— Roger Federer (@rogerfederer) August 26, 2014
"I met him yesterday for the first time and it was a big deal for me; it's been a special past 24 hours. We talked how I prepare, how much I play, where I go next; we exchanged ideas about our respective sports. That's what you talk about.
"He was my all-sports idol growing up. [NBA] was big on the German TV station, the NBA highlights. That's where I saw him do all his moves. I was into his great athleticism. That's what inspired me."
Jordan sat in Federer's box throughout the match, in which the Swiss debuted his new shoe, the Nike Zoom Vapor 9 Tour AJ3, which looked somewhat like the Air Jordans sported by the former Chicago Bulls icon during his legendary career.
Asked what about Jordan inspired him, Federer said, "His longevity, the way he made it look easy, his will to win, wanting to be the best, delivering under pressure, being a superstar in a team sport, carrying his team for so many years. There's so many things that he did well and represented the game really nicely, I thought. That's why he also became my idol."
US Open 2014: Verdasco's 400th win just one more shout for over-30s
US Open 2014: No magic Grand Slam receipe, insists Eugenie Bouchard

redpajama_set_name: RedPajamaCommonCrawl


Our Cordova Bar Stool combines our deluxe bucket with an interior channeled back and our "Western" hand-turned wood frame in a walnut finish. Hand crafted luxury restaurant bar stools is what we specialize in. Our restaurant bar stools can be upholstered in any color using almost any type of upholstery vinyl or leather. If you are looking for bar stools that might last longer than your bar, you have come to the right place. Made in the USA.


Description Odometer is 6299 miles below market average! Certified. Clean CARFAX. ABS brakes, Air Conditioning, Alloy wheels, Automatic temperature control, Dual front impact airbags, Dual front side impact airbags, Exterior Parking Camera Rear, Front dual zone A/C, Heated Front Bucket Seats, Leather Seat Trim, Power driver seat, Power moonroof, Power steering, Power windows, Radio: AM/FM/CD/SiriusXM Audio System, Rear window defroster, Rear window wiper, Remote keyless entry, Steering wheel mounted audio controls, Tilt steering wheel, Trip computer, Variably intermittent wipers.


Harrison Ford's actress wife Calista Flockhart has jetted to be by his hospital bedside as his Star Wars set injury may be worse than originally thought.
The actor was flown from Pinewood Studios in Buckinghamshire to the John Radcliffe hospital in Oxford after a door from the Millennium Falcon spacecraft on set fell on him.
And as he reaches day four in hospital, Flockhart is jetting to be by his side.
While it is understood the 71-year-old actor broke his ankle, it is now feared his injuries could be worse than previously thought.
Confirming her impending arrival in the UK, Calista told The Telegraph she was 'en route'.
MORE: Star Wars Episode VII: Harrison Ford injured, but what does this mean for the production?
While Harrison recovers, film bosses are thrashing out a schedule to work around the actor's absence and hope he will return soon to film shots from the waist up.
A spokesman for Star Wars Episode 7's producer Disney said: 'Harrison Ford sustained an ankle injury during filming today on the set of Star Wars: Episode VII.


In character forum - only post IC stuff here. Everything else should go to the OOC forum.
Out of character forum - do not post In character information here!
Lots of you like to write - so feel free to post your masterpieces here! NOTE: We are experiencing issues with forum timeouts at the moment. Please read the post on this in the OOC forum before attempting to post!


I'm 15 my parents are okay with me getting a tattoo what are some tattoo parlors that tat at 15 with a parent consent in Pittsburgh Pa?
Can using soap to wash hair over a long period of time (months or more) cause hair to lighten/bleach in color?
Best answer: NO, we used a bar of soap for 13 years, and my hair is as black as coal. It was used even before I was born, that's the only thing we used to clean almost anything.
ALL the people in the Asia, have black hair. Shampoos weren't invented until the mid 60's, at least that's when I first saw bottled shampoo, when we moved to the USA.
Lightened hair can be done, from lemon juice & sunburned from the sun. Using tea does that to your hair too. If you want to protect your hair from getting lighter, wear a hat, or bring an umbrella.
I took cocaine as a one-off about 3 months ago. Will it show up on a hair follicle test?
I'm worried about my hairline and temples thinnning, are they ok? And what can I start using now to prevent thinnning?
I get offended when people say I look young. How do I look my age?
Best answer: Why are you literally me. Im also 5'1, weigh 105 pounds, have olive skin, and brown hair and eyes. And i get the same annoying comments like, "yeah, you kinda look like a kid, haha," expecting that im going to find this funny. And when I wear makeup I look like a girl playing with her mom's makeup and i hate it. the best you can do is ignore the comments, and if you feel like a woman, try to give off that confidence as best you can because that's all you can do.
Is this price too expensive for a tattoo?
First time getting a tattoo and I've decided to get the Stark sigil in honor of Game of Throne's final season. I've thought about getting this for years and have finally decided to. I messaged a very popular shop in the downtown area of where I live and got a quote. $300 for a 4 inch tattoo on my forearm, black ink. And I have to give a $100 deposit to make an appointment. Their quality of work is exceptionally good and all heal beautifully. They mainly do that minimalistic, thin line style that's become popular along with some color realism. As stated above, I just wanted black ink but there's a catch. They can't just "copy" the design and tattoo it on me. They have to create something original and inspired by it. Huge concern for me as I simply wanted the Stark sigil and nothing more. But my main concern is that they're overcharging... I looked into some reviews and saw that some people paid (unhappily) $120 for barely an inch tattoo and someone else $750 for a 6 inch tattoo; both not including tips. I don't want to be cheap because that leads to a horribly done tattoo that can even get infected but I also don't want to overpay for something that's relatively small. Thoughts? I can afford it and if they come up with a great design I'll go for it. I just don't want to overpay.
True/false: it's more hygienic for a women to shave her arms?
Best drugstore smudge proof under eye concealer?
Do EYE CREAMS work if you have genetic eye bags? I have genetic upper and lower bags, if I use eye cream will it make it less puffy?
Best answer: It will make no difference but eye bags on a man's face adds character to it.
Will itching an area of the scalp make hair loss (instant) more likely in that place?
I have a vintage old spice antipersperant spray can from the 70s, never opened before. is it safe to use or will it damage my skin?
Why do people not like hair loss?
Best answer: Most people do not like hair loss because of insecurity, or fear of how someone may think about how they look.
Best answer: If the product you are using has a matte finish, it will have a matte finish no matter how you use it because it is supposed to have a matte finish.
My barber's clippers went wrong and now i have this small bald spot. My question is, will it be permanent? I'm hoping not.?


"Michael was born after an 11-hour labor ... The foster mother described Michael as a good baby who enjoyed being talked to and who smiled and cooed.
Michael Wear read this clinical report about himself when he stumbled upon a folder in his parents' basement as a teenager.
Also in that folder was a loving letter to the parents who would adopt him: "Never be threatened by my being his birth mother. The longing I feel for him is so intense that I could never explain it to you, but I cannot go back on my decision. I know I have made the right choice."
His birth mother continued: "The reason I am going into all of this is because I want you to try to love him without any reservation. You see, he has my love, but he won't know that firsthand. I have had to trust many people in this past year that I never would have met if not for my pregnancy, and though I am a trusting person, this is different. This tiny life was in my care until just over two months ago. Now he is with people I don't even know. The separation is difficult, but the worry is worse. I am trusting him to you and I am sure you will make wonderful parents to him, but it's not enough to give me peace of mind. What I have turned to is God. I am entrusting him first of all to God."
In an essay for the online magazine Catapult, Wear shares this and more. He discovered that day that in their short time together, his birth mother loved to sing to him the song "You Are My Sunshine." He writes: "I immediately thought back to the kindergarten assembly at which I'd sung that song. I thought of how my love of music eventually led me to Billie Holiday, Sarah Vaughan and a whole catalog of songs that my grandparents fell in love to. I sang so many of those songs with them; these were some of my most treasured family memories. How much of this love of music -- one I had found and cultivated myself -- was, in part, a gift from my birth mother?"
Wear's essay is a reflection on hope. As the father of a newborn, he is still discovering things about the birth mother he has never met. Wear is making connections with her, as he holds his little girl in his arms. He writes, remembering the day during Lent last year when he and his wife discovered that they would soon be parents: "There is a profound connection between hope and parenthood. Hope requires an openness to possibility, to vulnerability and to potential disappointment."
It's no mistake or coincidence that Wear's reflection would appear during the season of Lent, and at a time when we're having some brutally graphic public debates about life in its earliest stages. In his sharing of some of the most intimate experiences of his life, Wear is recognizing our need for heralds of hope. Rather than the prideful exuberance that our media and politics breed by their seeming omnipresence in our lives (which we allow by keeping the screens in front of our faces long beyond what could possibly be helpful to anyone), Wear offers something different, leading with gratitude about one woman's heroic sacrifice that has made every day of his life possible. The still unfolding story of his life and the life of his family is a reminder and a gift to the rest of us that the health of our politics reflects the health of our lives. First things first -- and there may be hope for our politics yet.


Former U-21 youth international Mike van der Hoorn signed a 3-year contract at Swansea City in the summer of 2016, including an option for another season. Swansea City paid a transfer fee of ca. 2.5ME at Ajax which was less than the 4.0 ME Ajax paid in 2013 when they bought the defender from FC Utrecht.
Van der Hoorn played with the Netherlands U-21 team at the 2013 Euros U-21 championship. He played two games including the semi-finales against Italy U-21 which the Dutch youth squad lost.


I just downloaded WhatsApp Messenger on my BlackBerry.
It is a Smartphone Messenger which replaces SMS. This app even lets me send pictures, video and other multi-media!
WhatsApp Messenger is available for BlackBerry, iPhone, Android and Nokia and there is no PIN or username to remember - it works just like SMS and uses your internet data plan.
Get it now from http://www.whatsapp.com/download/ and say good-bye to SMS.


We LOVED doing this one. Sali is absolutely passionate about fragrance and during the episode she talks about perfume wardrobes, saying farewell to signature scents, perfume as an art form and why she can't get enough of Chanel no 5.
Rachel discovers an £8.99 perfume that smells just like Coco Madameoiselle and I tell you about a new perfume brand that is set to shake up the entire beauty industry.
If you're enjoying the podcast please please subscribe and rate us on iTunes and spread the word.
NEXT WEEK we have Elle Macpherson talking about Inner Beauty and Wellness.


Last year I had the pleasure of attending an event at Bella Collina in San Clemente thanks to Mary Lallande of Jay's Catering. I loved this venue! It's in San Clemente for couples in the OC it works out perfectly. If you don't live in the OC, it still might be perfect venue for you. I'm telling you it's gorgeous!
Pictures taken by Bobby Brown, who is also an amazing photog! So what do you think? I love this space. It's even more breathtaking in person!


The 2019 UNT Fall Housing Fair will be held on Wednesday, March 27, 2019 from 11:00am to 1:00pm at the Willis Main Library Mall. The Housing Fair invites off-campus apartment communities and other Denton area resources to campus to present first hand information to students. These communities provide students attending the housing fair information such as floor plans, price breakdowns, and move-in specials. It is a must event for all current freshman who will be looking for off campus housing as Sophomores for Fall 2019.


- Map of Switzerland. Swiss Bank Corporation. Ca. 1970s.
Lomax, Alan. Alan Lomax Collection, Manuscripts, Europe--Switzerland . to 1979, 1970. Manuscript/Mixed Material. https://www.loc.gov/item/afc2004004.ms270367/.
Lomax, A. (1970) Alan Lomax Collection, Manuscripts, Europe--Switzerland . to 1979. [Manuscript/Mixed Material] Retrieved from the Library of Congress, https://www.loc.gov/item/afc2004004.ms270367/.
Lomax, Alan. Alan Lomax Collection, Manuscripts, Europe--Switzerland . to 1979, 1970. Manuscript/Mixed Material. Retrieved from the Library of Congress, <www.loc.gov/item/afc2004004.ms270367/>.


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Fresh Market board to conduct strategic review
Jon Springer | Oct 20, 2015
The Fresh Market on Tuesday said the company and its board of directors would conduct a strategic and financial review of the business with an eye on "value-enhancing initiatives" including a recapitalization or a sale.
The acknowledgement comes in the wake of reports last week that there was interest from company founder Ray Berry in taking the specialty food retailer private in combination with Apollo Capital Management, although The Fresh Market's statement did not address that possibility specifically.
Analysts have said that a going-private transaction would allow The Fresh Market to address pricing concerns, store closures and other issues away from the scrutiny of the public markets. Others have speculated that a strategic buyer such as Sprouts Farmers Market could have interest in the chain.
Sprouts at one time was privately held by Apollo; according to reports, its success in partnership with Apollo attracted Berry's interest in reacquiring the company. Berry holds 4.1% of The Fresh Market's stock.
Sprouts wasn't immediately available for comment.
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The Fresh Market saw its comp sales turn negative in the last reported quarter as a result of competitive challenges, slow inflation, and ineffective promotions, officials said. The company dismissed CEO Craig Carlock in January, and last month, hired former Food Lion CEO Rick Anicetti to succeed interim CEO Sean Crane. Crane remains the company's COO.
"Since joining the company, Rick and his team have been working to identify and execute on opportunities to improve the company's sales growth and to drive operational efficiencies," Rich Noll, Fresh Market's lead independent director, said in a statement. "An update on these findings will be provided when the company reports its third quarter fiscal 2015 earnings in November. The board of directors has determined, consistent with its obligations to the company and its stockholders and together with the work being done by management, that it is also prudent to conduct a strategic and financial review of the business focusing on the company's and its stockholders' best interests."
The Greensboro, N.C.-based company cautioned that the review may not result in any specific action, and said it did not intend to comment further before the board approves a specific action or concludes its review.
Founded in 1982, The Fresh Market is a specialty grocery retailer focused on high-quality products and a high level of customer service. It operates 178 stores in 27 states.
TAGS: News
Craig Carlock out as Fresh Market CEO
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