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Objective School anxiety is a prevalent mental health concern that drives school-related disability among youth with chronic pain. The only available measure of school anxiety—the School Anxiety Inventory, Short Version (SAI-SV)—lacks content specificity for measuring school anxiety in pediatric pain populations. We aimed to refine the SAI-SV by obtaining qualitative data about unique school situations that are anxiety-provoking for youth with pain and characterizing the nature of symptoms experienced in these situations. Methods Adolescents with chronic pain (n = 16) completed a semistructured interview focused on experiences with anxiety in school-related academic and social contexts. We employed thematic analysis to extend the empirical understanding of school anxiety from the perspective of patients suffering from pain and to generate new item content. The content was refined with iterative feedback from a separate group of adolescents with chronic pain (n = 5) and a team of expert pain psychologists (n = 3). Results We identified six themes within the data and generated new items designed to capture anxiety related to negative interactions with teachers and peers, falling behind with schoolwork, and struggles with concentration and fatigue. Participants and experts rated new item content as highly relevant for use among youth with pain. The updated item bank was named the School Anxiety Inventory for Chronic Pain. Conclusions Future research is needed to complete the psychometric evaluation of the item bank and finalize items to be included in a measure that can be used in research and clinical settings. Implications for treating school-related anxiety among youth with pain are also discussed.

Objective Juvenile-onset fibromyalgia (JFM) is a chronic debilitating pain condition that negatively impacts physical, social and academic functioning. Cognitive-behavioral therapy (CBT) is beneficial in reducing functional disability among adolescents with JFM but has only a modest impact on pain reduction and does not improve physical exercise participation. This randomized controlled trial (RCT) aims to test whether a novel intervention that combines CBT with specialized neuromuscular exercise training (the Fibromyalgia Integrative Training program for Teens “FIT Teens”) is superior to CBT alone or a graded aerobic exercise (GAE) program. Design/Methods This 3-arm multi-site RCT will examine the efficacy of the FIT Teens intervention in reducing functional disability (primary outcome) and pain intensity (secondary outcome), relative to CBT or GAE. All interventions are 8-weeks (16 sessions) in duration and are delivered in small groups of 4–6 adolescents with JFM. A total of 420 participants are anticipated to be enrolled across seven sites with approximately equal allocation to each treatment arm. Functional disability and average pain intensity in the past week will be assessed at baseline, post-treatment and at 3-, 6-, 9- and 12-month follow-up. The 3-month follow-up is the primary endpoint to evaluate treatment efficacy; longitudinal assessments will determine maintenance of treatment gains. Changes in coping, fear of movement, biomechanical changes and physical fitness will also be evaluated. Conclusions This multi-site RCT is designed to evaluate whether the combined FIT Teens intervention will have significantly greater effects on disability and pain reduction than CBT or GAE alone for youth with JFM. Clinical trials.gov registration: NCT 03268421.

INTRODUCTION A variety of factors influence parent responses to pain behaviors they observe in their adolescents with chronic pain. Certain parental responses to pain, such as attention or overprotection, can adversely impact adolescent adaptive functioning and correspond to poor clinical outcomes. OBJECTIVES It was hypothesized that the relationship between adolescent pain behaviors and functional disability was mediated by maladaptive parenting (protective, monitoring, solicitousness) responses. MATERIALS AND METHODS Participants were 303 adolescents and their mothers presenting to a pain clinic. Adolescents completed measures of functional disability and pain intensity; mothers completed measures assessing adolescent pain behaviors, their own catastrophizing about their adolescent's pain, and responses to pain. A path model tested the direct and indirect associations between pain behaviors and disability via 3 parenting responses, controlling for average pain intensity and parent pain catastrophizing. RESULTS Greater pain behavior was associated with increased protective responses (α path, P

Objective Despite the availability of measures for assessing physical, psychological, and health impact in children with chronic pain, there are not established guidelines for interpretation of children’s pain outcomes following psychological treatment. The purpose of this topical review is to discuss clinical significance as a neglected area of consideration in pediatric chronic pain assessment and to make recommendations on how the field can move toward benchmarking on core outcome domains. Method We review definitions of clinical significance and examples of several methodologies that have been used in other populations or are emerging in pediatric chronic pain including anchor-based methods, distribution-based methods, or multimethod approaches. Results Few measures across pediatric chronic pain outcome domains have established clinical significance of scores to interpret meaningful change following treatment limiting the interpretability of findings from clinical trials. In the context of clinical practice, several efforts to examine clinical significance to improve the translation of evidence-based measurement into standard clinical decision-making exist. Conclusions Recommendations are provided to encourage additional validation efforts of outcome measures in pediatric chronic pain and to encourage authors to report clinical significance in clinical trials of psychological interventions for pediatric chronic pain.

Objective School anxiety is a prevalent and debilitating mental health problem among youth with chronic pain. Despite evidence that anxiety in the context of school is associated with significant school-related disability, no studies have examined specific aspects of school anxiety in a pediatric chronic pain population. Materials and methods Adolescents with chronic pain (n=30) and age-matched and sex-matched controls (n=30) and their parents completed questionnaires assessing school anxiety and functioning. Results Adolescents with chronic pain reported significantly more cognitive, behavioral, and psychophysiological symptoms of school anxiety relative to healthy controls. Youth with pain also endorsed significantly greater school anxiety in situations involving negative social evaluation and peer aggression. Exploratory analyses indicated that adolescents with chronic pain reporting school refusal behaviors more strongly endorsed behavioral and psychophysiological school anxiety symptoms, and more symptoms in social-evaluative situations. Youth with pain reporting lower school functioning endorsed more cognitive school anxiety symptoms and anxiety in situations involving academic failure relative to those reporting higher functioning. Discussion Present results offer a nuanced perspective into the underlying sources of school anxiety among adolescents with chronic pain. Our findings may inform future research efforts and targeted school functioning interventions. In particular, findings suggest that an individualized approach to the assessment of school anxiety which considers the unique sources of anxiety (eg, social vs. academic) may lay the groundwork for the refinement of school functioning interventions in pediatric chronic pain.

To evaluate whether clinical anxiety in children presenting to a pediatric pain management center is associated with a poorer treatment response for those who completed pain-focused cognitive behavioral therapy (CBT).The total sample consisted of 175 children, 40 of whom completed CBT for chronic pain. The Screen for Child Anxiety Related Emotional Disorders was completed at initial evaluation and outcome measures (average pain intensity and the Functional Disability Inventory) were collected during the initial evaluation and at the end of CBT. Group differences in outcomes were examined following CBT. The role of anxiety in CBT initiation and completion was also explored.Presence of clinical anxiety was associated with greater initiation and/or completion of pain-focused CBT but also a poorer treatment response. Specifically, the group with subclinical anxiety exhibited a substantial reduction in pain intensity, and the group with clinical anxiety exhibited a more limited response to treatment (F [1, 36] = 13.68 P.01). A similar effect was observed for Functional Disability Inventory, such that the group with clinical anxiety had a significantly smaller response to treatment (F [1, 38] = 4.33 P.05). The difference in pain and disability between groups following CBT suggest moderate effects (Cohen d = 0.77 and 0.78, respectively).Although youths with clinical anxiety are more likely to start and/or complete pain-focused CBT, anxiety has an adverse impact on CBT treatment response in children with chronic pain. Identification of patients with anxiety and use of tailored behavioral interventions may improve clinical outcomes.

Juvenile-onset fibromyalgia (JFM) is typically diagnosed in adolescence and characterized by widespread pain and marked functional impairment. The long-term impact of JFM into adulthood is poorly understood. The objectives of this study were to describe physical and psychosocial outcomes of youth diagnosed with JFM in early adulthood (~ 8-year follow-up), examine longitudinal trajectories of pain and depressive symptoms from adolescence to young adulthood, and examine the impact of pain and depressive symptoms on physical functioning over time. Participants were 97 youth with JFM enrolled in a prospective longitudinal study in which pain symptoms, physical and psychosocial functioning were assessed at four time points over approximately eight years. At the Time 4 follow-up (M(age) = 24.2 years), the majority continued to suffer from pain and impairment in physical, social, and psychological domains. However, trajectories of pain and emotional symptoms showed varying patterns. Longitudinal analysis using growth mixture modeling revealed two pain trajectories (Steady Improvement and Rapid Rebounding Improvement); whereas depressive symptoms followed three distinct trajectories (Low-Stable, Improving, and Worsening). Membership in the Worsening Depressive symptoms group was associated with poorer physical functioning over time (p < .001) compared to the Low-Stable and Improving groups. This study offers evidence that while JFM symptoms persist for most individuals, pain severity tends to decrease over time. However, depressive symptoms follow distinct trajectories that indicate subgroups of JFM. In particular, JFM patients with worsening depressive symptoms showed decreasing physical functioning and may require more intensive and consistent intervention to prevent long-term disability.

OBJECTIVE: The current study tested the utility of the PROMIS Pediatric Pain Interference (PPI) in relation to the widely-used Functional Disability Inventory (FDI) in a small-scale clinical trial. METHODS: Forty youth with juvenile fibromyalgia (JFM) were randomized to either CBT only or a combined CBT and neuromuscular exercise group (i.e., FIT Teens). Participants completed the PPI and FDI at baseline, post-treatment, and three-month follow-up. RESULTS: The PPI and FDI were significantly correlated at baseline (r = .51) and post treatment (r = .53), and demonstrated similar improvements (d PPI = .87, d FDI = 1.22, p

Purpose Juvenile-onset fibromyalgia (JFM) affects physical, social, and emotional functioning. Little is known about how social support and social interactions are impacted in the transition to young adulthood for patients diagnosed with JFM. Methods Young adults (M age = 21.6) diagnosed with JFM during adolescence (N = 94) and matched healthy controls (N = 33) completed measures of social network size and diversity, perceived social support, physical functioning, and depressive symptoms as part of a cross-sectional survey study. Results No difference in social network diversity was found, although JFM patients reported fewer total people within their social networks. JFM patients reported poorer emotional and tangible support and fewer positive social interactions than healthy controls. After controlling for condition and pain intensity, the level of perceived social support was a significant predictor of physical functioning and depressive symptoms, whereas social network size also contributed uniquely to physical functioning. Conclusions Given the developmental importance of social support in adolescence and young adulthood, interventions should include methods of improving social support into fibromyalgia management.

INTRODUCTION For a large portion of youth, pain-associated functional gastrointestinal disorders (FGIDs) are associated with significant impairment over time. Clinically feasible methods to categorize youth with FGIDs at greatest risk for persistent pain-related impairment have not yet been identified. METHODS Measures of functional disability, pain intensity, and anxiety were collected on 99 patients with FGIDs (ages 8-18) during a visit to a pediatric gastroenterology office to assess for the presence of risk. Follow-up data were obtained on a subset of this sample (n = 64) after 6 months, either in person or via mail. The present study examined whether a greater number of risk factors at baseline predicted greater pain-related disability at follow-up. RESULTS Patients were divided into 4 groups based on number of risk factors present at the initial assessment: 0 (18.2%), 1 (24.2%), 2 (26.3%), and 3 (31.3%). The presence of 2 or 3 risk factors significantly predicted greater disability at follow-up compared to those with 0 risk factors (R = 0.311) and those with just 1 risk factor (Cohen's d values of -1.07 and -1.44, respectively). DISCUSSION A simple approach to risk categorization can identify youth with FGIDs who are most likely to report increased levels of pain-related impairment over time. These findings have important clinical implications that support the utility of a brief screening process during medical care to inform referral for targeted treatment approaches to FGIDs.

Functional abdominal pain (FAP) in children, is a set of recurrent pain conditions without an organic cause (1), is highly prevalent and can lead to substantial impairment including decreased involvement in social, academic, and other daily activities (2–4). Based on Rome-III criteria, subtypes of FAP include functional dyspepsia, irritable bowel syndrome, and abdominal migraine (1). Youth with FAP who have the greatest level of impairment may be characterized by anxiety, expressed as maladaptive thinking about pain, or other family risk factors (i.e., overprotective parenting) that are potentially modifiable with behavioral intervention (5). Greater impairment has been associated with the child’s use of poor psychological coping strategies such as catastrophic thinking about pain [e.g., belief that pain will not resolve or get worse, (6)] as well as parental responses to pain, such as overprotection (i.e., checking in repeatedly about pain symptoms) or minimizing/criticism (7). Understanding how children develop maladaptive coping strategies in response to FAP involves recognition of the caregiving environment in which these coping behaviors develop (8). A recent community-based study found that the impact of child catastrophizing on disability was less pronounced in the context of high levels of adaptive parenting behaviors (e.g., promotion of children’s well behaviors) in generally healthy schoolchildren dealing with occasional pain (9). There is emerging evidence that the joint impact of parenting factors and child pain catastrophizing is relevant for understanding impairment in samples of youth with mixed chronic pain conditions (10, 11) and in youth with organic causes of abdominal pain, such as Inflammatory Bowel Disease (12) Multiple studies in pediatric chronic pain have documented the impact of parenting factors in children’s adjustment to pain. For example, parent protection and criticism have been implicated in predicting disability in youth with an array of chronic pain conditions (13–15) and more specifically in children with FAP (16–20). Some research suggests that parental overprotectiveness (i.e., limiting the child’s normal activities and/or giving the child special attention secondary to pain) and/or minimizing (i.e., criticism) uniquely influence FAP-related disability (16, 18) whereas other research did not find evidence of such relationships (20). Given the tendency for pain conditions to occur in families, it is conceivable that parents’ catastrophizing may be related to the expression of disability in youth with FAP, though this research has generally focused on the role of parent catastrophizing about their own pain versus their child’s pain (17), though there are several recent exceptions (12, 21). In youth with Inflammatory Bowel Disease, parent catastrophizing about their child pain partially explained the relationship between child pain behavior and parental protective responses; however, the relationship between these factors and child impairment was not examined (12). Yet another recent investigation has found support for the role of child pain catastrophizing underlying the association between parent catastrophizing about their child’s pain and pain related disability in a school-based sample of adolescents (21). However, it is unclear if child pain catastrophizing is related to disability in the presence of other parental responses to child pain (i.e., overprotection, criticism, or symptom monitoring) in youth with FAP. Thus, investigating multiple parenting behaviors can be beneficial to fully capture the range of responses that children with FAP may receive from their caregivers. In general, models examining the simultaneous influence of child and parenting factors in predicting impairment in youth with chronic pain have focused on mixed pediatric pain samples, youth with IBD, or healthy controls and have shown mixed results (10, 13, 15, 22, 23), with some support that catastrophizing may mediate the relationship between parenting factors and disability, particularly in youth with chronic musculoskeletal pain (10, 15). Guite and colleagues also found that child pain catastrophizing may account for the relationship between pain intensity and disability (10); thus, it may be valuable to examine if these variables operate similarly in youth with FAP. Thus, the purpose of this study is to examine how pain catastrophizing in children and parental responses to their child’s pain interact to affect disability in a clinical sample of youth with FAP. We predict that child pain catastrophizing will mediate the relationship between parental responses to pain (i.e., protectiveness, encouragement/symptom monitoring, and minimization) and disability, consistent with prior literature. We also investigated the role of child pain catastrophizing in mediating the relationship between pain intensity and disability to assess whether these factors operate similarly in predicting disability in our sample as compared to prior research in youth with musculoskeletal pain (10). We undertook exploratory analysis examining the role of parent pain catastrophizing about the child’s pain in relation to parent responses to pain and disability. This project is the first part of an ongoing research program in developing tailored interventions for youth with FAP and their caregivers.

Patients presenting for treatment of chronic pain often believe that pain reduction must be achieved before returning to normal functioning. However, treatment programs for chronic pain typically take a rehabilitative approach, emphasizing decreasing pain-related disability first with the expectation that pain reduction will follow. This information is routinely provided to patients, yet no studies have systematically examined the actual trajectories of pain and disability in a clinical care setting. In this study of youth with chronic pain (N = 94, 8 to 18 years), it was hypothesized that 1) functional disability and pain would decrease over the course of psychological treatment for chronic pain and 2) functional disability would decrease more quickly than pain intensity. Participants received cognitive behavioral therapy (CBT) for pain management (M = 5.6 sessions) plus standard medical care. The Functional Disability Inventory and a Numeric Rating Scale of average pain intensity were completed by the child at every CBT session. Hierarchical linear modeling was conducted to examine the longitudinal trajectories of disability and pain. Standardized estimates of the slopes of change were obtained to test differences in rates of change between pain and disability. Results showed an overall significant decline in functional disability over time. Although pain scores reduced slightly from pretreatment to posttreatment, the longitudinal decline over treatment was not statistically significant. As expected, the rate of change of disability was significantly more rapid than pain. Evidence for variability in treatment response was noted, suggesting the need for additional research into individual trajectories of change in pediatric pain treatment.

The primary objective of this study was to estimate a clinically significant and quantifiable change in functional disability to identify treatment responders in a clinical trial of cognitive-behavioral therapy (CBT) for youth with juvenile fibromyalgia (JFM). The second objective was to examine whether baseline functional disability (Functional Disability Inventory), pain intensity, depressive symptoms (Children's Depression Inventory), coping self-efficacy (Pain Coping Questionnaire), and parental pain history predicted treatment response in disability at 6-month follow-up. Participants were 100 adolescents (11-18 years of age) with JFM enrolled in a recently published clinical trial comparing CBT to a fibromyalgia education (FE) intervention. Patients were identified as achieving a clinically significant change in disability (i.e., were considered treatment responders) if they achieved both a reliable magnitude of change (estimated as a > or = 7.8-point reduction on the FDI) using the Reliable Change Index, and a reduction in FDI disability grade based on established clinical reference points. Using this rigorous standard, 40% of patients who received CBT (20 of 50) were identified as treatment responders, compared to 28% who received FE (14 of 50). For CBT, patients with greater initial disability and higher coping efficacy were significantly more likely to achieve a clinically significant improvement in functioning. Pain intensity, depressive symptoms, and parent pain history did not significantly predict treatment response. Estimating clinically significant change for outcome measures in behavioral trials sets a high bar but is a potentially valuable approach to improve the quality of clinical trials, to enhance interpretability of treatment effects, and to challenge researchers to develop more potent and tailored interventions.

Little is known regarding treatment choices of youth diagnosed with juvenile-onset fibromyalgia (JFM) as they move into young adulthood. Additionally, there is little empirical evidence to guide youth with FM into appropriate treatment options, leading to a variety of therapies used to manage FM symptoms. The purpose of this descriptive study was to examine all therapies used by individuals with JFM as they entered young adulthood and the perceived effectiveness of these treatments. As part of a larger follow-up study, participants completed a web-based survey of all current and past treatments received for FM symptoms 2 years after their initial presentation and diagnosis at a pediatric rheumatology clinic. One hundred ten out of 118 eligible patients participated in the follow-up assessment as young adults (mean age 18.97 years; 93.6% female). A majority of participants reported use of conventional medications (e.g., antidepressants, anti-convulsants) and nondrug therapies (e.g., psychotherapy). Currently and within the past 2 years, antidepressant medications were the most commonly used to manage FM. Complementary treatments were used less often, with massage being the most popular choice. Although currently used treatments were reported as being effective, past treatments, especially medications, were viewed as being more variably effective. This is a potential reason why young adults with JFM might try more complementary and alternative approaches to managing their symptoms. More controlled studies are needed to investigate the effectiveness of these complementary methods to assist treatment providers in giving evidence-based treatment recommendations.

Catastrophizing is a coping style linked to poorer patient outcomes. Little attention has focused on the parent-adolescent dyad and catastrophizing as a shared coping style. The purpose of this study was to: (1) examine the effects of adolescent and parent pain catastrophizing on adolescent functioning and (2) explore concordance in catastrophizing in parent-adolescent dyads, with equal interest in outcomes of dyads with discordant coping styles.Pain intensity, catastrophizing, depressive symptoms, quality of life, and pain behaviors were assessed in adolescents (ages 11 to 17) presenting to a pediatric chronic pain clinic (N=240).Significant correlations between (1) parent and adolescent catastrophizing; (2) catastrophizing and pain behaviors; and (3) catastrophizing and adolescent outcomes were found. Parents and adolescents were classified into concordant or discordant dyads based on catastrophizing with a majority of dyads (70%) showing concordant coping styles. Among discordant dyads, functional disability and depressive symptoms were significantly higher in a dyad with a high catastrophizing adolescent and low catastrophizing parent.Results provide further support for catastrophizing being a maladaptive coping strategy for adolescents with pain and their parents. Greater adolescent catastrophizing was related to increased pain behaviors and poorer adolescent functioning. Parent catastrophizing also seems related to poorer adolescent outcomes, and most parent-adolescent dyads showed concordance in use of catastrophizing, which may suggest a shared tendency for adaptive or maladaptive styles of coping with pain. Future research should investigate pain coping at a dyadic or family level to explore how family coping styles magnify distress and disability or buffer adolescents from such problems.

This study examined the factor structure of the Children's Depression Inventory (CDI) among children and adolescents with chronic pain using exploratory and confirmatory factor analysis in a large, multisite sample of treatment-seeking youth. Participants included 1,043 children and adolescents (ages 8–18) with a range of chronic pain complaints who presented for initial evaluation at 1 of 3 tertiary care pediatric chronic pain clinics across the United States. They completed the CDI and reported on pain intensity and functional disability. Factor analysis was conducted using a 2-step (exploratory and confirmatory) approach. Results supported a 5-factor model for the CDI with good fit to the data. The distribution and item-total correlations of the somatic items (eg, pain complaints, fatigue) were explored in this sample. Results indicate that the CDI is a useful tool for assessing depressive symptoms in youth with chronic pain, but some caution is warranted in interpreting the clinical significance of scores in light of the overlap of specific symptoms common to both pain and depression. Perspective The CDI can be considered a valid tool for assessing mood symptoms in children with chronic pain. Caution is encouraged when interpreting the clinical significance of scores due to symptom overlap between chronic pain and depression.

A recent randomized multisite clinical trial found that cognitive-behavioral therapy (CBT) was significantly more effective than fibromyalgia education (FE) in reducing functional disability in adolescents with juvenile fibromyalgia (JFM). The primary objective of this study was to examine the psychological processes of CBT effectiveness by evaluating changes in pain coping, catastrophizing, and coping efficacy and to test these changes as mediators of continued improvements in functional disability and depressive symptoms at 6-month follow-up. One hundred adolescents (11–18 years old) with JFM completed the clinical trial. Coping, catastrophizing, and coping efficacy (Pain Coping Questionnaire) and the outcomes of functional disability (Functional Disability Inventory) and depressive symptoms (Children's Depression Inventory) were measured at baseline, posttreatment, and 6-month follow-up. Participants in both conditions showed significant improvement in coping, catastrophizing, and efficacy by the end of the study, but significantly greater improvements were found immediately following treatment for those who received CBT. Treatment gains were maintained at follow-up. Baseline to posttreatment changes in coping, catastrophizing, and efficacy were not found to mediate improvements in functional disability or depressive symptoms from posttreatment to follow-up. Future directions for understanding mechanisms of CBT effectiveness in adolescents with chronic pain are discussed. Perspective CBT led to significant improvements in pain coping, catastrophizing, and efficacy that were sustained over time in adolescents with juvenile fibromyalgia. Clinicians treating adolescents with JFM should focus on teaching a variety of adaptive coping strategies to help patients simultaneously regain functioning and improve mood.

Objective To examine the differential presentation(s) of psychological and health-related outcomes in young adults with juvenile-onset fibromyalgia (FM) with and without a history of trauma, compared to healthy controls. Methods In total, 110 participants (86 with juvenile-onset FM and 24 healthy controls, with a mean age of 23.4 years) completed a structured clinical interview to assess for trauma and psychological comorbidities, as well as self-report questionnaires on pain, physical functioning, and health care utilization. Results Of the juvenile-onset FM participants, 37% (n = 32) reported a history of trauma. Three group comparisons (i.e., juvenile-onset FM with trauma versus juvenile-onset FM with no trauma versus healthy controls) revealed that juvenile-onset FM participants significantly differed from healthy controls on all psychological and health-related outcomes. Further, although juvenile-onset FM participants with and without a history of trauma did not significantly differ on pain and physical functioning, juvenile-onset FM participants with a history of trauma were significantly more likely to have psychological comorbidities. Conclusion This is the first controlled study to examine the differential outcomes between juvenile-onset FM participants with and without a history of trauma. Group comparisons between juvenile-onset FM participants and healthy controls were consistent with previous research. Further, our findings indicate that juvenile-onset FM participants with a history of trauma experience greater psychological, but not physical, impairment than juvenile-onset FM participants without a history of trauma.

Juvenile fibromyalgia syndrome (FMS) is a chronic pain condition that is estimated to affect 2–7% of school-age children (1–3), primarily adolescent girls. As in adult fibromyalgia (FM), juvenile FMS is characterized by persistent and widespread musculoskeletal pain, sleep difficulty, fatigue, and mood disturbances (3). Patients with juvenile FMS experience substantial impairment in physical, school, social, and emotional functioning (4–6), and the majority of them continue to have ongoing symptoms and functional disability into late adolescence and early adulthood (7). Although progress has been made in the understanding and treatment of adult FM (8), there are few studies of juvenile FMS. Two recent meta-analytic reviews of cognitive–behavioral therapy (CBT) clinical trials for FM arrived at slightly different conclusions, with one supporting the effectiveness of CBT (9) and the other reporting no significant effect on pain and function (10). However, both reviews indicated significant improvement in coping and emphasized the need for higher quality trials of CBT. It is unclear whether findings from the 2 meta-analytic reviews, based mainly on adult FM patients, are applicable to pediatric patients. In a recent meta-analysis of psychological therapies for pediatric chronic pain (mostly headache and abdominal pain), Palermo et al (11) reported a large positive effect for pain reduction. It is possible that behavioral interventions found to be promising for adults with FM can be even more effective in juvenile FMS because they are implemented at an early age when pain coping and lifestyle factors are more malleable. There are no rigorously controlled studies of CBT for juvenile FMS at present. Early evidence for possible efficacy of CBT for improving function and decreasing pain and symptoms of depression in children and adolescents with juvenile FMS was shown in 2 small-scale studies (12,13). Unfortunately, neither study controlled for the nonspecific therapeutic effects of attention and support from health professionals, which by themselves could have resulted in improved outcomes. Therefore, the specific effects of CBT that go beyond providing emotional support and include intensive training in behavioral pain coping skills targeted at improving functioning by increasing patients' psychological coping and confidence in pain self-management skills have not yet been tested in a controlled study. We performed a multisite, randomized controlled trial in a sample of children and adolescents with juvenile FMS to rigorously assess the safety and efficacy of an 8-session, individually delivered CBT intervention compared to an 8-session supportive FM education program in reducing functional disability, pain severity, and depressive symptoms. The CBT treatment protocol was developmentally tailored for older school-age children and adolescents and included parental instruction to ensure family support for the behavioral interventions. We hypothesized that 1) CBT would be significantly more effective than FM education in reducing functional disability (primary outcome) in youth with juvenile FMS and 2) CBT would be significantly more effective than FM education in reducing pain severity and symptoms of depression (secondary outcomes). Unlike a “no-treatment” placebo control, the FM education condition was designed to be an “attention control” condition in which the nonspecific psychological benefits of the therapeutic relationship and educational information provided were expected to lead to some improvement in the short term (posttreatment assessment). However, we hypothesized that CBT would lead to sustained benefit and be demonstrably superior to FM education in reducing disability, pain, and symptoms of depression 6 months after the end of active treatment (end-of-study assessment). Selection of the outcome domains of function, pain severity, and symptoms of depression was consistent with the Pediatric Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (PedIMMPACT) guidelines for measurement of outcomes in clinical trials of pediatric chronic pain (14). Functional disability was selected as the primary outcome because the goal of CBT is to reduce pain-related disability by teaching patients both coping and self-management behaviors (and providing parental guidance in behavior management) to improve function, while secondarily reducing pain severity and symptoms of depression. Other outcomes of interest such as tender point sensitivity, health-related quality of life (HRQOL), sleep quality, and physician's global assessment were also measured at each assessment.

Noroviruses are the major cause of human epidemic nonbacterial gastroenteritis. Viral replication requires a 3C cysteine protease that cleaves a 200 kDa viral polyprotein into its constituent functional proteins. Here we describe the X-ray structure of the Southampton norovirus 3C protease (SV3CP) bound to an active site-directed peptide inhibitor (MAPI) which has been refined at 1.7 Å resolution. The inhibitor, acetyl-Glu-Phe-Gln-Leu-Gln-X, which is based on the most rapidly cleaved recognition sequence in the 200 kDa polyprotein substrate, reacts covalently through its propenyl ethyl ester group (X) with the active site nucleophile, Cys 139. The structure permits, for the first time, the identification of substrate recognition and binding groups in a noroviral 3C protease and thus provides important new information for the development of antiviral prophylactics.

Pain behaviors provide meaningful information about adolescents in chronic pain, enhancing their verbal report of pain intensity with information about the global pain experience. Caregivers likely consider these expressions when making judgments about their adolescents’ medical or emotional needs. Current validated measures of pain behavior target acute or procedural pain and young or non-verbal children, while observation systems may be too cumbersome for clinical practice. The objective of this research was to design and evaluate the Adolescent Pain Behavior Questionnaire (APBQ), a parent-report measure of adolescent (11–19 years) pain expressions. This paper provides preliminary results on reliability and validity of the APBQ. Parent-adolescent dyads ( N = 138) seen in a multidisciplinary pain management clinic completed the APBQ and questionnaires assessing pain characteristics, quality of life, functional disability, depressive symptoms, and pain catastrophizing. Principal components analysis of the APBQ supported a single component structure. The final APBQ scale contained 23 items with high internal consistency ( α = 0.93). No relationship was found between parent-reported pain behaviors and adolescent-reported pain intensity. However, significant correlations were found between parent-reported pain behaviors and parent- and adolescent-reported functional disability, pain catastrophizing, depressive symptoms, and poorer quality of life. The assessment of pain behaviors provides qualitatively different information than solely recording pain intensity and disability. It has clinical utility for use in behavioral treatments seeking to reduce disability, poor coping, and distress.

Juvenile primary fibromyalgia syndrome (JPFS) is a chronic pain condition associated with significant impairment in physical functioning, but no studies have used newer technologies such as actigraphy to document objective physical activity levels in JPFS. This is the first study to objectively describe physical activity in JPFS patients and examine the relationship of pain, perceived functional impairment, and depressive symptoms on physical activity. One hundred four clinically referred adolescents with JPFS (ages 11 to 18 years) wore a hip-mounted actigraph for 1 week. Data on pain intensity, functional disability, depressive symptoms, and psychiatric diagnoses were obtained using self- and parent-report measures and a standardized psychiatric interview. Results showed that younger patients were more active. Pain intensity was not significantly associated with physical activity levels overall, but the most highly active group of adolescents reported lower levels of pain and disability than the least active. Parent report of adolescents' physical functioning and depressive symptoms were significantly correlated with adolescents' physical activity levels. Actigraphy provides a unique source of information about physical functioning which is distinct from adolescents' self-report of physical functioning in JPFS. Preliminary findings suggest that further study of factors that predict perceived and actual physical functioning in JPFS is warranted. Perspective This study presents the results of physical activity monitoring in adolescents with JPFS using actigraphy. Results indicate that actigraphy provides a unique source of objective information that can advance our understanding of physical disability in JPFS and the factors associated with physical impairment.

Escherichia coli strains causing avian colibacillosis and human neonatal meningitis, urinary tract infections, and septicemia are collectively known as extraintestinal pathogenic E. coli (ExPEC). Characterization of ExPEC strains using various typing techniques has shown that they harbor many similarities, despite their isolation from different host species, leading to the hypothesis that ExPEC may have zoonotic potential. The present study examined a subset of ExPEC strains: neonatal meningitis E. coli (NMEC) strains and avian-pathogenic E. coli (APEC) strains belonging to the O18 serogroup. The study found that they were not easily differentiated on the basis of multilocus sequence typing, phylogenetic typing, or carriage of large virulence plasmids. Among the APEC strains examined, one strain was found to be an outlier, based on the results of these typing methods, and demonstrated reduced virulence in murine and avian pathogenicity models. Some of the APEC strains tested in a rat model of human neonatal meningitis were able to cause meningitis, demonstrating APEC's ability to cause disease in mammals, lending support to the hypothesis that APEC strains have zoonotic potential. In addition, some NMEC strains were able to cause avian colisepticemia, providing further support for this hypothesis. However, not all of the NMEC and APEC strains tested were able to cause disease in avian and murine hosts, despite the apparent similarities in their known virulence attributes. Thus, it appears that a subset of NMEC and APEC strains harbors zoonotic potential, while other strains do not, suggesting that unknown mechanisms underlie host specificity in some ExPEC strains.

ColV plasmids of extraintestinal pathogenic Escherichia coli (ExPEC) encode a variety of fitness and virulence factors and have long been associated with septicemia and avian colibacillosis. These plasmids are found significantly more often in ExPEC, including ExPEC associated with human neonatal meningitis and avian colibacillosis, than in commensal E. coli . Here we describe pAPEC-O103-ColBM, a hybrid RepFIIA/FIB plasmid harboring components of the ColV pathogenicity island and a multidrug resistance (MDR)-encoding island. This plasmid is mobilizable and confers the ability to cause septicemia in chickens, the ability to cause bacteremia resulting in meningitis in the rat model of human disease, and the ability to resist the killing effects of multiple antimicrobial agents and human serum. The results of a sequence analysis of this and other ColV plasmids supported previous findings which indicated that these plasmid types arose from a RepFIIA/FIB plasmid backbone on multiple occasions. Comparisons of pAPEC-O103-ColBM with other sequenced ColV and ColBM plasmids indicated that there is a core repertoire of virulence genes that might contribute to the ability of some ExPEC strains to cause high-level bacteremia and meningitis in a rat model. Examination of a neonatal meningitis E. coli (NMEC) population revealed that approximately 58% of the isolates examined harbored ColV-type plasmids and that 26% of these plasmids had genetic contents similar to that of pAPEC-O103-ColBM. The linkage of the ability to confer MDR and the ability contribute to multiple forms of human and animal disease on a single plasmid presents further challenges for preventing and treating ExPEC infections.

The human pathogen Shiga-toxigenic Escherichia coli (STEC) O157:H7 contains a ycbQRST fimbrial-like operon, which shares significant homology to the family of F17 fimbrial biogenesis genes f17ADCG found in enterotoxigenic E. coli. We report that growth of STEC O157:H7 strain EDL933 in minimal Minca medium at 37°C and during adherence to epithelial cells led to the production of fine peritrichous fimbriae, which were found to be composed of a major subunit of 18 kDa whose N-terminal amino acid sequence matched the predicted protein product of the ycbQ gene; and showed significant homology to the F17a-A fimbrin. Similar to the F17 fimbriae, the purified STEC fimbriae and the recombinant YcbQ protein fused to a His peptide tag bound laminin, but not fibronectin or collagen. Thus, we propose the name E. coli YcbQ laminin-binding fimbriae (ELF) to designate the fimbriae encoded by the ycbQRST operon. The role of ELF as an adherence factor of STEC to cultured epithelial cells was investigated. We provide compelling evidence demonstrating that ELF contributes to adherence of STEC to human intestinal epithelial cells and to cow and pig gut tissue in vitro. Deletion in the fimbrin subunit gene elfA (or ycbQ) in STEC strain EDL933 led to an isogenic strain, which showed significant reduction (60%) in adherence to HEp-2 cells in comparison with the parental strain. In addition, antibodies against the purified ELF also partially blocked adherence of two STEC O157:H7 strains. These observations suggest that ELF functions as an accessory adherence factor that, along with other known redundant adhesins, contributes to the overall adhesive properties of STEC O157:H7 providing these organisms with ecological advantages to survive in different hosts and in the environment.

Mutations in the human PBGD (porphobilinogen deaminase) gene cause the inherited defect AIP (acute intermittent porphyria). In the present study we report the structure of the human uPBGD (ubiquitous PBGD) mutant, R167Q, that has been determined by X-ray crystallography and refined to 2.8 Å (1 Å=0.1 nm) resolution (Rfactor=0.26, Rfree=0.29). The protein crystallized in space group P21212 with two molecules in the asymmetric unit (a=81.0 Å, b=104.4 Å and c=109.7 Å). Phases were obtained by molecular replacement using the Escherichia coli PBGD structure as a search model. The human enzyme is composed of three domains each of approx. 110 amino acids and possesses a dipyrromethane cofactor at the active site, which is located between domains 1 and 2. An ordered sulfate ion is hydrogen-bonded to Arg26 and Ser28 at the proposed substrate-binding site in domain 1. An insert of 29 amino acid residues, present only in mammalian PBGD enzymes, has been modelled into domain 3 where it extends helix α23 and forms a β-hairpin structure that contributes to a continuous hydrogen-bonding network spanning domains 1 and 3. The structural and functional implications of the R167Q mutation and other mutations that result in AIP are discussed.

Objective.Adolescents with juvenile-onset fibromyalgia (JFM) have increased rates of psychiatric disorders, but to our knowledge no studies have examined psychiatric disorders in adolescents with JFM when they enter young adulthood. This study examined the prevalence of psychiatric disorders in young adults diagnosed with JFM during adolescence and the relationship between mental health diagnoses and physical functioning.Methods.Ninety-one young adults (mean age 21.60, SD 1.96) with a history of JFM being followed as part of a prospective longitudinal study and 30 matched healthy controls (mean age 21.57, SD 1.55) completed a structured interview of psychiatric diagnoses and a self-report measure of physical impairment.Results.Young adults with a history of JFM were more likely to have current and lifetime histories of anxiety disorders (70.3% and 76.9%, respectively) compared with controls (33.3% for both, both p < 0.001). Individuals with JFM were also more likely to have current and lifetime histories of major mood disorders (29.7% and 76.9%, respectively) compared with controls (10% and 40%, p < 0.05). The presence of a current major mood disorder was significantly related to impairment in physical functioning [F (1, 89) = 8.30, p < 0.01] and role limitations attributable to a physical condition [F (1, 89) = 7.09, p < 0.01].Conclusion.Psychiatric disorders are prevalent in young adulthood for individuals with a history of JFM, and a current major mood disorder is associated with greater physical impairment. Greater attention to early identification and treatment of mood disorders in patients with JFM is warranted.

In the present study, we compared the dynamics and composition of microtubules in cell lines derived from the human breast adenocarcinoma MCF-7 containing either the wild-type p53 (wt-p53; MN1) or a dominant-negative variant of p53 gene (mut-p53; MDD2). Mut-p53 cells were significantly resistant to the cytotoxicity of the microtubule-targeted drugs (vinca alkaloids and taxanes), as compared with wt-p53 cells. Studies by high-resolution time-lapse fluorescence microscopy in living cells indicated that the dynamics of microtubules of mut-p53 cells were altered in complex ways and were significantly increased as compared with microtubules in wt-p53 cells. The percentage of time microtubules spent in growing and shortening phases increased significantly, their catastrophe frequency increased, and their overall dynamicity increased by 33%. In contrast, their shortening rate and the mean length shortened decreased. Cells containing mut-p53 displayed increased polymerisation of tubulin, increased protein levels of the class IV beta-tubulin isotype, STOP and survivin, and reduced protein levels of class II beta-tubulin isotype, MAP4 and FHIT. We conclude that p53 protein may contribute to the regulation of microtubule composition and function, and that alterations in p53 function may generate complex microtubule-associated mechanisms of resistance to tubulin-binding agents.

5-Aminolevulinic acid synthase (ALAS), the first enzyme of the heme biosynthesis pathway, catalyses the pyridoxal 5'-phosphate-dependent condensation between glycine and succinyl-CoA to yield 5-aminolevulinic acid (5-amino-4-oxopentanoate). A three-dimensional structural model of Rhodobacter spheroides ALAS has been constructed and used to identify amino acid residues at the active site that are likely to be important for the recognition of glycine, the only amino acid substrate. Several residues have been investigated by site-directed mutagenesis and enzyme variants have been generated that are able to use alanine, serine or threonine. A three-dimensional structure model of 5-aminolevulinic acid synthase from human erythrocytes (ALAS 2) has also been constructed and used to map a range of naturally occurring human mutants that give rise to X-linked sideroblastic anemia. A number of these anemias respond favourably to vitamin B(6) (pyridoxine) therapy, whereas others are either partially responsive or completely refractory. Detailed investigations with selected human mutants have highlighted the importance of arginine-517 that is implicated in glycine carboxyl group binding.

Functional abdominal pain (FAP) is associated with significant anxiety and impairment. Prior investigations of child anxiety in youth with FAP are generally limited by small sample sizes, based on child report, and use lengthy diagnostic tools. It is unknown whether a brief anxiety-screening tool is feasible, whether parent and child reports of anxiety are congruent, and whether parent and child agreement of child anxiety corresponds to increased impairment. The purpose of this investigation was to examine anxiety characteristics in youth with FAP using parent and child reports. Parent-child agreement of child anxiety symptoms was examined in relation to pain and disability.One hundred patients with FAP (8-18 years of age) recruited from pediatric gastroenterology clinics completed measures of pain intensity (Numeric Rating Scale) and disability (Functional Disability Inventory). Patients and caregivers both completed a measure of child anxiety characteristics (Screen for Child Anxiety and Related Disorders).Clinically significant anxiety symptoms were more commonly reported by youth (54%) than their parents (30%). Panic/somatic symptoms, generalized anxiety, and separation anxiety were most commonly endorsed by patients, whereas generalized anxiety, separation anxiety, and school avoidance were most commonly reported by parents. The majority (65%) of parents and children agreed on the presence (26%) or absence (39%) of clinically significant anxiety. Parent-child agreement of clinically significant anxiety was related to increased impairment.A brief screening instrument of parent and child reports of anxiety can provide clinically relevant information for comprehensive treatment planning in children with FAP.

Due to a high incidence of anterior cruciate ligament (ACL) re-injury in alpine ski racers, this study aims to assess functional asymmetry in the countermovement jump (CMJ), squat jump (SJ), and leg muscle mass in elite ski racers with and without anterior cruciate ligament reconstruction (ACL-R). Elite alpine skiers with ACL-R (n = 9; 26.2 ± 11.8 months post-op) and uninjured skiers (n = 9) participated in neuromuscular screening. Vertical ground reaction force during the CMJ and SJ was assessed using dual force plate methodology to obtain phase-specific bilateral asymmetry indices (AIs) for kinetic impulse (CMJ and SJ phase-specific kinetic impulse AI). Dual x-ray absorptiometry scanning was used to assess asymmetry in lower body muscle mass. Compared with controls, ACL-R skiers had increased AI in muscle mass (P 0.001), kinetic impulse AI in the CMJ concentric phase (P 0.05), and the final phase of the SJ (P 0.05). Positive associations were observed between muscle mass and AI in the CMJ concentric phase (r = 0.57, P 0.01) as well as in the late SJ phase (r = 0.66, P 0.01). Future research is required to assess the role of the CMJ and SJ phase-specific kinetic impulse AI as a part of a multifaceted approach for improving outcome following ACL-R in elite ski racers.

OBJECTIVE: This prospective longitudinal study examined the long-term physical and psychosocial outcomes of adolescents with juvenile-onset fibromyalgia (JFM), compared with healthy control subjects, into early adulthood. METHODS: Adolescent patients with JFM initially seen at a pediatric rheumatology clinic (n = 94) and age- and gender-matched healthy control subjects (n = 33) completed online measures of demographic characteristics, pain, physical functioning, mood symptoms, and health care utilization at ∼6 years’ follow-up (mean age: 21 years). A standard in-person tender-point examination was conducted. RESULTS: Patients with JFM had significantly higher pain (P < .001), poorer physical function (P < .001), greater anxiety (P < .001) and depressive symptoms (P < .001), and more medical visits (P < .001)than control subjects. The majority (>80%) of JFM patients continued to experience fibromyalgia symptoms into early adulthood, and 51.1% of the JFM sample met American College of Rheumatology criteria for adult fibromyalgia at follow-up. Patients with JFM were more likely than control subjects to be married and less likely to obtain a college education. CONCLUSIONS: Adolescent patients with JFM have a high likelihood of continued fibromyalgia symptoms into young adulthood. Those who met criteria for fibromyalgia in adulthood exhibited the highest levels of physical and emotional impairment. Emerging differences in educational attainment and marital status were also found in the JFM group. JFM is likely to be a long-term condition for many patients, and this study for the first time describes the wide-ranging impact of JFM on a variety of physical and psychosocial outcomes that seem to diverge from their same-age peers.

5-Aminolaevulinate dehydratase (ALAD) is a homo-octameric metallo-enzyme that catalyses the formation of porphobilinogen from 5-aminolaevulinic acid. The structure of the yeast enzyme has been solved to 2.3 A resolution, revealing that each subunit adopts a TIM barrel fold with a 39 residue N-terminal arm. Pairs of monomers wrap their arms around each other to form compact dimers and these associate to form a 422 symmetric octamer. All eight active sites are on the surface of the octamer and possess two lysine residues (210 and 263), one of which, Lys 263, forms a Schiff base link to the substrate. The two lysine side chains are close to two zinc binding sites one of which is formed by three cysteine residues (133, 135 and 143) while the other involves Cys 234 and His 142. ALAD has features at its active site that are common to both metallo- and Schiff base-aldolases and therefore represents an intriguing combination of both classes of enzyme. Lead ions, which inhibit ALAD potently, replace the zinc bound to the enzyme's unique triple-cysteine site.

Porphobilinogen deaminase (PBG-D), an early enzyme of the tetrapyrrole biosynthetic pathway, catalyzes the formation of a tetrapyrrole chain, preuroporphyrinogen, from four molecules of porphobilinogen (PBG). The PBG-D apoenzyme is responsible for the autocatalytic synthesis and covalent attachment of a dipyrromethane cofactor at its active site. In this paper an efficient method for the purification of Escherichia coli PBG-D apoenzyme using an affinity chromatography resin is reported. Circular dichroism (CD) spectra of apoenzyme and holoenzyme were recorded and significant differences in both the backbone and aromatic region of the spectra were observed. The differences in the spectra allowed the reconstitution of holoenzyme from purified apoenzyme with PBG and preuroporphyrinogen in solution to be monitored separately by CD. Apoenzyme incubated with preuroporhyrinogen gave a CD spectrum that was much more like the CD spectrum of holoenzyme than apoenzyme incubated with PBG. The results showed clearly that the cofactor was generated much more rapidly from preuroporphyrinogen than from PBG. Changes in the CD spectrum associated with the aromatic side-chain region, in particular the contribution assigned to phenylalanine-62, were found to correlate well with the activity of the reconstituted enzyme. Phenylalanine-62 is located in close proximity to the cofactor and acts as a sensitive probe to active-site changes. The stability of the holoenzyme and apoenzyme were compared with respect to both heat and susceptibility to proteolysis. The results were consistent with a model for the apoenzyme in which, in the absence of the cofactor, the three domains of the protein are held less rigidly together, thereby making the protein more susceptible to heat denaturation and proteolysis. The CD spectrum of the holoenzyme was found to be similar at both pH 5.1 and 7.4, suggesting that the crystal structure, determined at pH 5.1, is likely to be similar at physiological pH values.

Emergency room and hospital discharge data have been used to describe the risk factors and public health impact of dog bites. These data sets are based on financial charges for severe bites and underestimates dog bite burdens within communities. This study expands both the source of information and risk factor data collected to provide demographic analysis of dog bite injury risk factors reported in Bay County, Florida in 2009-2010. Extended data for dog bites reported by various sources from January 1, 2009 to December 31, 2010 were collected by Florida Department of Health in Bay County. Data collected included bite victim's age and gender, primary reported cause of bite, setting, dog's restraint status and relationship between the victim and the dog. A total of 799 bites were reported. Most bites (55%) were reported first by healthcare practitioners, particularly bites involving children

Cytomegalovirus (CMV) is often present in bronchoalveolar lavage (BAL) fluid of immunosuppressed patients without CMV pneumonitis. The amount of viral DNA within BAL cells of patients with definite CMV pneumonitis and of viral shedders was quantitated by polymerase chain reaction (PCR) and the extent of CMV gene expression within BAL cells was defined by reverse transcription - PCR. No viral DNA was detected in 6 viral shedders, and 12 had low copy numbers (mean, 72 copies/10(5) BAL cells; median, 20) compared with numbers in pneumonitis patients (267,580 and 57,000, respectively). When CMV intranuclear inclusions were absent within BAL cells of patients with pneumonitis, copy numbers (mean, 9362; median, 7110) were still significantly higher than among shedders. Expression of viral glycoprotein H mRNA was detected in BAL cells of all 11 pneumonitis patients tested but in 0 of 18 viral shedders. Thus, high-grade infection and viral replication within BAL cells are integral features of CMV pneumonitis but not viral shedding.

A system for the automatic analysis of 24-well plates used in antibody assays to measles virus has been designed and developed based on digitising the information on the plate through a CCD camera, displaying the image and then analysing it using image processing methods. The system is being used in the analysis of sera from individuals vaccinated against measles and has been compared with the previous method where the plates were assessed by eye. The results from both methods are very similar although the manual method consisted of counting numbers of plaques (clear areas in the cells of the plate) and the automatic method measured plaque area. The automatic method is much faster than the original method and prevents operator fatigue. It does not deal, at present, with anomalies such as partially filled wells but could be developed to do so by incorporating intelligence into the system.

The pharmacokinetics of 2,000 mg of sulfadiazine administered twice daily (BID) versus those of 1,000 mg administered four times a day were compared in eight human immunodeficiency virus-infected patients. No differences in pharmacokinetic parameters were detected between the regimens. These data provide a pharmacokinetic rationale for BID dosing of sulfadiazine for the treatment and suppression of toxoplasmosis.

Functional abdominal pain (FAP) is a common pediatric disorder associated with impairment in functioning that may persist for the long term. Anxiety is common in youth with FAP, and may be an important factor in predicting youth who are at greatest risk for increased impairment because of pain symptoms. In this article, we examine the relation between anxiety and impairment in youth with FAP. Furthermore, we explore various biopsychosocial factors (eg, neurobiological substrates, coping strategies, social factors) that may be implicated in the relation among FAP, anxiety, and increased impairment. Finally, we propose physician guidelines for screening and treatment of youth with FAP and co-occurring anxiety. Youth with FAP and co-occurring anxiety may benefit from cognitive-behavioral therapy in the context of multidisciplinary care.

Trauma is a leading cause of morbidity and mortality in the U.S., and substance abuse makes an enormous contribution to this problem as well as to the increased cost of health care. A substance abuse consultation (SAC) team was developed to evaluate and intervene with trauma victims who are suspected of having problems with alcohol and/or other drugs. This study was undertaken to determine the effectiveness of this service.This study is a retrospective review of 100 consecutive trauma admissions who were felt to be at high risk for substance abuse and were referred to the SAC team for evaluation and intervention. This study was undertaken in a tertiary care teaching hospital in a cooperative effort between the trauma center and the addictions program.All 100 patients were diagnosed with psychoactive substance use disorders and 78 were referred for alcohol and other drug rehabilitation. Of these patients, 62% accepted a referral for drug and alcohol treatment.From these preliminary data, it appears that a SAC team may be effective in intervening with hospitalized trauma patients who have alcohol and other drug problems.

The UL97 phosphotransferase coding sequences of clinical cytomegalovirus (CMV) isolates, 10 resistant and 11 sensitive to ganciclovir, were compared to define mutations associated with drug resistance. In each ganciclovir-resistant isolate, a mutation was found that resulted in an amino acid substitution at codon 460 (4 isolates), codon 594 (2 isolates), or codon 595 (4 isolates). No sensitive isolate carried any of these mutations. Marker transfer studies showed that each mutation was capable of conferring ganciclovir resistance to the laboratory CMV strain AD169. Rapid diagnostic tests based on DNA amplification and restriction enzyme analysis were developed for these mutations. Specific mutant DNAs were detected when they constituted at least 10% of the population in the specimen. Several mutations in UL97 appear to be common markers for ganciclovir resistance, and their detection may be a rapid alternative to conventional cell culture susceptibility testing.

A technique is described for quantitation of the human cytomegalovirus (HCMV) glycoprotein H (gH) gene in cells using a quantitative-competitive polymerase chain reaction (QC-PCR). Two recombinant DNA molecules, differing in size due to a 92-bp deletion within the HCMV gH sequence, were used in co-amplification studies to construct a standard curve from which the copy number of the gH gene present in clinical samples could be interpolated. The use of primers labeled with a fluorescent dye allowed direct detection of the amplified products by measuring the amount of fluorescence emitted by each specific PCR fragment with an automated DNA sequencer coupled to a software program. This system was validated subsequently using bronchoalveolar lavage cells obtained from immunocompromised patients and found to be highly sensitive and reproducible over a range of 5-50,000 HCMV gH copies. This rapid procedure could easily be applied to study the pathogenesis of HCMV infection, identify the patients at high risk of developing HCMV disease, and monitor the effects of antiviral therapy at the molecular level.

Seven patients were evaluated at a mean duration of 8·4 yr after sustaining inhalational injury associated with burns. At the time of re-examination, the patients were asymptomatic and had normal chest X-rays, and arterial blood gases. Three of the seven patients had abnormally elevated serum calcitonin levels. The spirometry (FEV1) measurements showed an inverse trend to that of the serum calcitonin levels. The elevated calcitonin levels had an abnormal predominance of the procalcitonin component as assessed by several region specific antisera. The serum calcitonin also showed a significant correlation with the hormone level which had been obtained at the time of prior discharge from the hospital (r = 0·91).Although there appears to be no or minimal chronic pulmonary sequela to inhalational injury in burns by pulmonary testing, we speculate that the hyperprocalcitonemia in some of the patients may reflect a long-term hyperplastic response of the bronchio-epithelial pulmonary neuroendocrine cells. The potential significance of this and other lung-associated endocrine markers is discussed.

With the advent of accountable care organizations, bundled payments, value-based purchasing, and penalties for preventable hospital readmission, tight connections and collaboration across the care continuum will become critical to achieve successful patient outcomes and to reduce the cost of care delivery. Lehigh Valley Health Network (LVHN), the largest provider of health services in eastern Pennsylvania, set out on a journey to build collaborative relationships with skilled nursing facilities (SNFs) in their eastern Pennsylvania community. LVHN desired SNF partners with mutual interests in improving quality of care and lowering costs of delivery where possible. Recognizing that not all SNFs are alike, LVHN developed a Collaborative Partner Prioritization Tool to assess and prioritize skilled nursing facilities in an effort to determine those that would make the best collaborators. SNFs were reviewed based on their volume of mutual patients, quality of care delivery, and their perceived willingness to align with LVHN. Six variables were used to assess these facilities, including (1) patient discharge destination volume by SNF; (2) 30-day all-cause readmission rate to an LVHN hospital; (3) Medicare’s Nursing Home Compare 5-Star Overall Rating; (4) the health network affiliation of the SNF’s medical director; (5) the level of LVHN-employed or -affiliated physician presence at the SNF; and (6) the SNF’s current participation in LVHN-sponsored programs and meetings. Through use of the Collaborative Partner Prioritization Tool, it was discovered that roughly 70% of LVHN patients who required skilled nursing care following their inpatient stay received care at 1 of 20 SNFs. Of these, 5 facilities performed well on the 6-variable assessment, deeming them the “Tier 1 Facilities” to initially focus collaborative efforts. LVHN has strategically deployed physician resources and has increased physician presence at these “Tier 1 SNFs.” These facilities have also gained remote read-only access to LVHN’s inpatient electronic medical record and have had opportunity to participate in LVHN-sponsored programs. Special projects have been co-developed with several SNFs, including a telemedicine-based Parkinson’s disease program to increase patient access to a neurologist specially trained in movement disorders. The Collaborative Partner Prioritization Tool has become a powerful tool when used for prioritization of relationships and allocation of LVHN physicians and resources. Collaboration with strong SNF partners has offered a shared opportunity to improve quality of care, reduce costs, and prepare for the many policies affecting the health care industry. Future outcomes of this work will include quality metrics, such as readmissions, patient satisfaction with care, time for decision to admit, and overall costs of care. The data and metrics used to define the prioritization tool will continue to be adapted as the post-acute market and hospital-SNF relationships continue to evolve.

Circulating leukocytes are important in dissemination of cytomegalovirus (CMV) infection in humans. In the mouse model of murine CMV infection (MCMV), it has been shown that infection peaks on days 5 to 7 after experimental infection, when 0.01 to 0.1% of the circulating leukocytes contain viral DNA. In our laboratory, MCMV DNA was detected by in situ hybridization predominantly in the mononuclear cells on day 6 after acute infection. Infectious virus was recovered from day 6 mononuclear fractions in 16 of 16 mice compared with that from day 6 polymorphonuclear fractions in 4 of 16 mice. An eclipse phenomenon was noted in the blood leukocytes by quantitative blot hybridization: the amount of MCMV DNA present was small on day 2, diminished on days 3 and 4, and then increased markedly on days 5 and 6 in both the mononuclear and polymorphonuclear fractions immediately following viral augmentation in the liver and spleen. MCMV immediate-early and glycoprotein B (late) transcripts were present in pooled mononuclear fractions only on day 6 of acute infection but not in pooled polymorphonuclear fractions. Collectively, these data demonstrate that (i) circulating leukocytes, predominantly mononuclear, are involved in dissemination of MCMV; (ii) a primary viremia with dissemination of MCMV to reticuloendothelial organs (liver and spleen) occurs and is followed by viral amplification and a subsequent, more intense secondary viremia; and (iii) immediate-early viral mRNA and glycoprotein B mRNA transcripts are detectable only during peak infection on day 6 in mononuclear leukocytes but not in polymorphonuclear leukocytes.

The Functional Disability Inventory (FDI) is a well-established and commonly used measure of physical functioning and disability in youth with chronic pain. Further validation of the measure has been called for, in particular, examination of the clinical utility and factor structure of the measure. To address this need, we utilized a large multicenter dataset of pediatric patients with chronic pain who had completed the FDI and other measures assessing pain and emotional functioning. Clinical reference points to allow for interpretation of raw scores were developed to enhance clinical utility of the measure and exploratory factor analysis was performed to examine its factor structure. Participants included 1300 youth ages 8 to 18 years (M=14.2 years; 76% female) with chronic pain. Examination of the distribution of FDI scores and validation with measures of depressive symptoms and pain intensity yielded three distinct categories of disability: No/Minimal Disability, Moderate Disability and Severe Disability. Factor analysis of FDI scores revealed a two-factor solution representing vigorous Physical Activities and non-physically strenuous Daily Activities. The three-level classification system and factor structure were further explored via comparison across the four most commonly encountered pain conditions in clinical settings (head, back, abdominal and widespread pain). Our findings provide important new information regarding the clinical utility and validity of the FDI. This will greatly enhance the interpretability of scores for research and clinical use in a wide range of pediatric pain conditions. In particular these findings will facilitate use of the FDI as an outcome measure in future clinical trials.

A three-dimensional computer modelling system has been developed for use in biology, and is currently running on a Sun3 computer. The data originate as a series of two-dimensional micrographs which are digitised via a TV camera. The two-dimensional images are used to select features of interest and to construct a three-dimensional model. This model can be viewed in vector or solid format, it can be rotated about three orthogonal axes and can be viewed in three dimensions as a stereo pair or an anaglyph. The system has been used in a large number of projects over the past 10-15 years, for example, to examine physiological and nerve structures. The time-consuming part of the process is the selection of features, which involves a high level of biological expertise. Present developments are concerned with reduction of the time spent in feature recognition and involve the introduction of expert systems together with human-computer interaction to deal with problems of identification.

Ischemic necrosis of the upper extremities caused by invasive mucormycosis developed in a patient with soil contamination of severe burn wounds. An arteriogram of the arm showed complete obstruction of blood flow in the forearm. Histologic specimens showed nonseptate branching hyphae obliterating the arterial lumens. Cutaneous mucormycosis affects patients who are immunocompromised, including victims of multiple trauma and burns. This case represents a previously undescribed clinical presentation in a patient with major burns. Because of its lethal nature, mucormycosis in a patient with burns must be treated with aggressive surgical debridement, including amputation, and with parentral amphotericin B at the earliest sign of cutaneous presence.

Objective To describe school absences in adolescents with Juvenile Primary Fibromyalgia Syndrome (JPFS) and examine the relationship between school absenteeism, pain, psychiatric symptoms, and maternal pain history. Methods Adolescents with JPFS (N ¼ 102; mean age 14.96 years) completed measures of pain and depressive symptoms, and completed a psychiatric interview. Parents provided information about the adolescents’ school absences, type of schooling, and parental pain history. School attendance reports were obtained directly from schools. Results Over 12% of adolescents with JPFS were homeschooled. Those enrolled in regular school missed 2.9 days per month on average, with one-third of participants missing more than 3 days per month. Pain and maternal pain history were not related to school absenteeism. However, depressive symptoms were significantly associated with school absences. Conclusion Many adolescents with JPFS experience difficulties with regular school attendance. Long-term risks associated with school absenteeism and the importance of addressing psychological factors are discussed.