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Adolescence is a sensitive period for both brain development and the emergence of chronic pain particularly in females. However, the brain mechanisms supporting pain perception during adolescence remain unclear. This study compares perceptual and brain responses to pain in female adolescents and adults to characterize pain processing in the developing brain. Thirty adolescent (ages 13-17 years) and 30 adult (ages 35-55 years) females underwent a functional magnetic resonance imaging scan involving acute pain. Participants received 12 ten-second noxious pressure stimuli that were applied to the left thumbnail at 2.5 and 4 kg/cm 2 , and rated pain intensity and unpleasantness on a visual analogue scale. We found a significant group-by-stimulus intensity interaction on pain ratings. Compared with adults, adolescents reported greater pain intensity and unpleasantness in response to 2.5 kg/cm 2 but not 4 kg/cm 2 . Adolescents showed greater medial-lateral prefrontal cortex and supramarginal gyrus activation in response to 2.5 kg/cm 2 and greater medial prefrontal cortex and rostral anterior cingulate responses to 4 kg/cm 2 . Adolescents showed greater pain-evoked responses in the neurologic pain signature and greater activation in the default mode and ventral attention networks. Also, the amygdala and associated regions played a stronger role in predicting pain intensity in adolescents, and activity in default mode and ventral attention regions more strongly mediated the relationship between stimulus intensity and pain ratings. This study provides first evidence of greater low-pain sensitivity and pain-evoked brain responses in female adolescents (vs adult women) in regions important for nociceptive, affective, and cognitive processing, which may be associated with differences in peripheral nociception.

Juvenile fibromyalgia is a common referral in pediatric rheumatology settings. Providing a clear diagnosis and explanation of altered pain processing offers reassurance that pain has a biologic basis and the symptoms are part of a recognized pain syndrome. Physicians should acknowledge the impact of chronic pain and associated symptoms on patient's lives and take time to understand contributing factors including stress, mood, inactivity, and lifestyle factors. The optimal treatment for juvenile fibromyalgia is multidisciplinary, focusing on education about juvenile fibromyalgia, along with physical therapy, cognitive behavioral therapy, sleep hygiene, healthy lifestyle habits, and medications for symptom management as appropriate.

Objectives A university-based randomized clinical study evaluated the 5-year performance of chairside-fabricated zirconia-reinforced lithium silicate (ZLS)-ceramic partial crowns. Material and methods Forty-five patients were restored with 61 chairside-fabricated ZLS-restorations (Cerec SW 4.2, Dentsply Sirona, Germany; Vita Suprinity, Vita Zahnfabrik, Germany). Deviating from the manufacturers’ recommendations, restorations with reduced minimum material thicknesses (MMT) were fabricated: group 1, MMT = 0.5–0.74 mm (n = 31); group 2, MMT = 0.75–1.0 mm (n = 30). For luting, a self-adhesive cement (SAC) or a total-etch technique with a composite cement (TEC) was applied. Statistical evaluation was performed by time-to-event analysis (Kaplan–Meier). Possible covariates of the survival (SVR) and success rates (SCR), evaluated in a Cox regression model, were MMT, restoration position (premolar/molar), and cementation technique (SAC vs. TEC). Results Forty patients (54 restorations, premolars, n = 23; molars, n = 31) participated in the 5-year follow-up. Five losses due to ceramic fractures occurred in group 1 (n = 28) (SVR: 83.0% [95% confidence interval (CI): 0.71–0.96]). Group 2 (n = 26) showed no losses (SVR: 100%). The success rate for partial crowns placed on premolars was 100% and 69% (95% CI: 0.54–0.84) for molar restorations. Recementation was required in 4 restorations with SAC (SCR: 86% [95% CI: 0.73–0.99]; SCR-DC: 100%). Restorations in group 2 showed a significantly reduced risk of material fracture hazard ratio (HR) = 0.09, p = 0.0292) compared with the restorations in group 1. Molar partial crowns showed an increased risk for a clinical intervention (HR = 5.26, p = 0.0222) compared to premolar restorations. Conclusions Material thickness and position of the restoration are risk factors influencing the survival and success rate of ZLS-ceramic partial crowns. Clinical relevance Observation of an MMT of at least 0.75–1.0 mm for ZLS-ceramics is essential to avoid material-related fractures. Clinical trial registration: German Clinical Trails Register (trial number: DRKS00005611)

The goal of the current study was to enhance the measurement of the pediatric chronic pain experience through a methodologically rigorous approach. This paper outlines the development and initial validation of a pain intensity measure for pediatric patients with chronic pain using Patient-Reported Outcomes Measurement Information System methodology. Measure development incorporated feedback from children with painful conditions. Based on input from pediatric participants and content experts, 4 candidate items assessing pain intensity were included for large scale testing. Children completed self-report items pertaining to their pain experience that were developed as part of a larger pool of new candidate Patient-Reported Outcomes Measurement Information System pediatric pain domain items as well as measures of pain interference, depressive symptoms, fatigue, pain behavior, pain intensity, and pain catastrophizing. The final sample for the large scale testing included N = 442 pediatric patients between the ages 8 to 18 years (Mean age = 13.54, Standard Deviation = 2.78; 71.27% female) experiencing chronic pain. Psychometric analysis resulted in a final measure that included 3 items with evidence of reliability (Cronbach alpha = .82) and convergent validity. The Likert format of the response options may be preferable to the traditional numeric rating scale for use in pediatric populations who experience chronic pain based on patients' feedback, which was directly utilized in designing the scale. Further, the inclusion of fewer and clinically meaningful response options should reduce ambiguity for young respondents. PERSPECTIVE: We have developed and evaluated a clinically sensitive and psychometrically precise 3-item pain intensity measure with Likert-type responses for self-report use among children and adolescents ages 8 to 18 years with chronic pain. Development of the item content and response options included input from children and adolescents with chronic pain. The development of pain intensity items with pediatric appropriate language, and labeled, fewer response options to yield maximal clinically meaningful information improves the precision of pain intensity measurement in children.

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.

ARTS (Sept4_i2) is a pro-apoptotic protein and a product of the Sept4 gene. ARTS acts upstream of mitochondria to initiate caspase activation. ARTS induces apoptosis by specifically binding XIAP and allowing de-repression of active caspases required for Mitochondrial Outer Membrane Permeabilzation (MOMP). Moreover, ARTS promotes apoptosis by inducing ubiquitin-mediated degradation of both major anti-apoptotic proteins XIAP and Bcl-2. In the resolution phase of inflammation, the infiltrating leukocytes, which execute the acute innate response, undergo apoptosis and are subsequently cleared by phagocytic macrophages (i.e. efferocytosis). In this course, macrophages undergo reprogramming from inflammatory, to anti-inflammatory, and eventually to resolving macrophages that leave the injury sites. Since engulfment of apoptotic leukocytes is a key signaling step in macrophage reprogramming and resolution of inflammation, we hypothesized that a failed apoptosis in leukocytes in vivo would result in an impaired resolution process. To test this hypothesis, we utilized the Sept4/ARTS-/- mice, which exhibit resistance to apoptosis in many cell types. During zymosan A-induced peritonitis, Sept4/ARTS-/- mice exhibited impaired resolution of inflammation, characterized by reduced neutrophil apoptosis, macrophage efferocytosis and expression of pro-resolving mediators. This was associated with increased pro-inflammatory cytokines and reduced anti-inflammatory cytokines, secreted by resolution-phase macrophages. Moreover, ARTS overexpression in leukocytes in vitro promoted an anti-inflammatory behavior. Overall, our results suggest that ARTS is a key master-regulator necessary for neutrophil apoptosis, macrophage efferocytosis and reprogramming to the pro-resolving phenotype during the resolution of inflammation.

Accurate characterization of the human immunodeficiency virus (HIV) reservoir is imperative to develop an effective cure. HIV was measured in antiretroviral therapy-suppressed individuals using the intact proviral DNA assay (IPDA), along with assays for total or integrated HIV DNA, and inducible HIV RNA or p24. Intact provirus correlated with total and integrated HIV.

Supplemental Digital Content is available in the text, Background: A declining selenium (Se) status constitutes a characteristic of critical illness and may affect disease course and survival. The dynamics of trauma-induced changes in biomarkers of Se status are poorly characterized, and an association with multiple organ failure (MOF) and mortality can be hypothesized. It was the aim of this study to investigate Se and selenoprotein P (SELENOP) concentrations in major trauma patients during the early posttraumatic period. Patients and Methods: Twenty-four patients after major trauma (ISS ≥16) were included at our level one trauma center. Se supplementation ever during the 90-day observation period was defined as an exclusion criterion. Serum samples were drawn within less than 60 min after trauma, and after 6 h, 12 h, 24 h, 48 h, and 72 h. Serum Se was analyzed by X-ray fluorescence and SELENOP concentrations by ELISA. The data were correlated to clinical parameters, occurrence of MOF defined by MOF and APACHE II score, lung injury defined by Horowitz index and clinical outcome (90-days survival). Results: Serum Se and SELENOP concentrations of the trauma patients were significantly below the average of healthy European subjects (mean ±SD; Se, 41.2±8.1 vs. 84.7±23.3 μg/L, P

The purpose of this study was to explore the perspective of renal dietitians regarding plant-based diets for chronic kidney disease (CKD) management and evaluate the acceptability of a hypothetical plant-based dietary prescription aiming for the consumption of 30 unique plant foods per week. This study used an exploratory mixed methods design. Forty-six renal dietitians participated in either an online survey (n = 35) or an in-depth interview (n = 11). Dietitians perceived that plant-based diets could address multiple clinical concerns relevant to CKD. Forty percent of survey respondents reported the hypothetical dietary prescription was realistic for people with CKD, 34.3% were unsure, and 25.7% perceived it as unrealistic. Strengths of the hypothetical prescription included shifting the focus to whole foods and using practical resources like recipes. Limited staffing, time, and follow-up opportunities with patients, as well as differing nutrition philosophies were the most commonly reported challenges to implementation; while a supportive multidisciplinary team was identified as an important enabler. To increase patient acceptance of plant-based dietary approaches, education about plant food benefits was recommended, as was implementing small, incremental dietary changes. Successful implementation of plant-based diets is perceived to require frequent patient contact and ongoing education and support by a dietitian. Buy-in from the multidisciplinary team was also considered imperative.

Objective: Juvenile fibromyalgia (FM) is a prevalent chronic pain condition affecting children and adolescents worldwide during a critical period of brain development. To date, no published studies have addressed the pathophysiology of juvenile FM. This study was undertaken to characterize gray matter volume (GMV) alterations in juvenile FM patients for the first time, and to investigate their functional and clinical relevance. Methods: Thirty-four female adolescents with juvenile FM and 38 healthy adolescents underwent a structural magnetic resonance imaging examination and completed questionnaires assessing core juvenile FM symptoms. Using voxel-based morphometry, we assessed between-group GMV differences and associations between GMV and functional disability, fatigue, and pain interference in juvenile FM. We also studied whether validated brain patterns predicting pain, cognitive control, or negative emotion were amplified/attenuated in juvenile FM patients and whether structural alterations reported in adult FM were replicated in adolescents with juvenile FM. Results: Compared to controls, juvenile FM patients showed GMV reductions in the anterior midcingulate cortex (aMCC) region (family-wise error corrected P [PFWE-corr ] = 0.04; estimated with threshold-free cluster enhancement [TFCE]; n = 72) associated with pain. Within the juvenile FM group, patients reporting higher functional disability had larger GMV in inferior frontal regions (PFWE-corr = 0.006; TFCE estimated; n = 34) linked to affective, self-referential, and language-related processes. Last, GMV reductions in juvenile FM showed partial overlap with findings in adult FM, specifically for the anterior/posterior cingulate cortices (P = 0.02 and P = 0.03, respectively; n = 72). Conclusion: Pain-related aMCC reductions may be a structural hallmark of juvenile FM, whereas alterations in regions involved in emotional, self-referential, and language-related processes may predict disease impact on patients' well-being. The partial overlap between juvenile and adult FM findings strengthens the importance of early symptom identification and intervention to prevent the transition to adult forms of the disease.

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of inherited disorders of connective tissue. EDS hypermobility type (EDS-HT), characterized by joint hypermobility, is most common and increasingly recognized in pediatrics. Treatment involves protecting joints, preventing injuries, and managing symptoms/comorbidities. Pediatric EDS-HT patients often see multiple medical providers; however, data on healthcare utilization (HCU) in this population are lacking. This retrospective, electronic chart review examines HCU data 1 year prior and subsequent to a new diagnosis of EDS-HT using Villefranche criteria. Demographics, diagnoses, and HCU (office visits, therapies, hospital encounters/procedures, and tests) were obtained for N = 102 youth attending a Connective Tissue Disorder Clinic over a 21-month timeframe. After EDS-HT diagnosis, HCU patterns shifted to reflect greater involvement of therapy (physical, psychological, and occupational) and symptom management. More genetics, rheumatology, and orthopedics visits occurred prediagnosis, and more physical therapy, pain management, cardiology, and neurology visits occurred postdiagnosis. Testing and hospital encounter/procedure frequencies did not change. Overall, the pattern of HCU changed from diagnostic to treatment, in accordance with evidence-based EDS-HT care. Understanding HCU patterns of pediatric patients with EDS-HT can elucidate patient interaction with the health care system, with the potential to inform and improve the standard of care.

We describe the development and analysis of a new teletherapy modality that, through a novel approach to targeted radiation delivery, has the potential to provide greater conformality than conventional photon-based treatments. The proposed system uses an X-ray lens to reflect photons from a conventional X-ray tube toward a focal spot. The resulting dose distributions have a highly localized peak dose, with lower doses in the converging radiation cone. Physical principles governing the design of this system are presented, along with a series of measurements analyzing various characteristics of the converging beam. The beam was designed to be nearly monoenergetic (~ 59 keV), with an energy bandwidth of approximately 10 keV allowing for treatment energies lower than conventional therapies. The focal spot was measured to be approximately 2.5 cm long and 4 mm wide. Mounting the proposed X-ray delivery system on a robotic arm would allow sub-millimeter accuracy in focal spot positioning, resulting in highly conformal dose distribution via the optimal placement of individual focal spots within the target volume. Aspects of this novel radiation beam are discussed considering their possible clinical application as a treatment approach that takes maximum advantage of the unique properties afforded by converging X-ray beam therapy.

A child maltreatment history is reported more frequently among adults with chronic pain compared with the general population; unfortunately, studies have primarily relied upon retrospective maltreatment reports by adults with chronic pain. This prospective study assessed pain symptoms in a cohort of young adult women with a documented history of child maltreatment, compared with a matched cohort of women who did not experience childhood maltreatment. Young women (N = 477) were recruited between ages 14 to 17 years and followed annually to age 19. Of these women, 57% experienced maltreatment (ie, physical, sexual, or emotional abuse, neglect; n = 273) substantiated by child welfare record. Maltreated women were demographically matched to nonmaltreated women, also confirmed by child welfare record. In adolescence, post-traumatic stress was assessed. Women were contacted as young adults (Mage = 24.76; n = 383) and surveyed about their pain experiences, including the presence of pain in the past week, pain severity (0-10), and number of body areas with pain. Mediation path analyses examining the impact of maltreatment and adolescent post-traumatic stress on young adult pain were estimated through structural equation modeling. As adults, women who had experienced child maltreatment reported higher pain intensity, a greater number of pain locations, and were more likely to experience pain in the previous week than nonmaltreated women. Adolescent post-traumatic stress partially explained the effects of maltreatment on pain. Young adult women who experienced child maltreatment are at higher risk of pain, particularly when they also experienced post-traumatic stress as adolescents.

Background To develop and test the feasibility and initial effectiveness of the Treatment and Education Approach for Childhood-onset Lupus (TEACH) protocol, a 6-session cognitive behavioral therapy (CBT) intervention for adolescents and young adults (AYA) with childhood-onset systemic lupus erythematosus (cSLE). Methods Females with cSLE (n = 14; ages 13–19 years, M = 16.21 years) presenting to a pediatric rheumatology clinic subsequently completed the protocol, which was iteratively modified based on participant/interventionist feedback. Upon intervention completion, participants provided qualitative data on feasibility, acceptability, potential modifications, and perceived effectiveness of the program via a semi-structured interview, which was analyzed for shared themes. Participants also completed measures of fatigue, psychological distress, and pain intensity before and after the intervention. Nonparametric statistics were conducted to examine changes in outcome measures following the intervention. Results During the study, several protocol modifications were employed to better address the unique needs of individuals with cSLE (e.g., separate content for adolescents versus young adults). Results suggest that TEACH is feasible, acceptable, and potentially effective in the management of cSLE symptoms. Following the intervention, there was a statistically significant reduction in fatigue (Z = − 2.81, p

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: Abdominal pain is a common presenting complaint in youth seeking medical care and can be debilitating. Therefore, it is important to understand the impact of pain on functioning using a clinically sensitive approach. In recent years, the National Institutes of Health has established a common core of psychometrically precise measures through the Patient-Reported Outcomes Measurement Information System (PROMIS) initiative. The Pediatric PROMIS-Pain Interference (PPPI) scale was developed to measure pain-related interference, drawing from existing legacy measures. However, its clinical validity has not been thoroughly established in clinical populations. The current study sought to develop clinical cut-points and investigate the validity of the PPPI in a large sample (N = 5,281) of youth presenting to gastroenterological care with abdominal pain symptoms. METHODS: Convergent validity of the PPPI was investigated. Quartile and tertile groupings of the PPPI were calculated and compared to cut-points derived from healthy populations and mixed convenience samples on clinical outcomes via multivariate analyses of variance (MANOVAs). RESULTS: There was good evidence of convergent validity. The tertile solution was superior in classifying different levels of pain-related outcomes as compared to other cut-points. The tertile solution suggested the following PPPI groupings: minimal (≤ 51), moderate (52–59), and severe (≥ 60). DISCUSSION: Results suggest the PPPI is a valid measure with clinically meaningful cut-points to assess pain-related interference in youth with abdominal pain.

Background Juvenile-onset Fibromyalgia (JFM) is a chronic pain condition characterized by widespread musculoskeletal pain, fatigue, sleep difficulties, mood concerns, and other associated symptoms. Although diagnosed in childhood, JFM often persists into adulthood can result in continued physical, social, and psychological impairment. The purpose of this qualitative study was to identify themes of risk and resilience for long-term outcomes among young adults diagnosed with JFM in childhood. Methods The sample included 13 young adults (ages 26–34) who had been diagnosed with JFM in adolescence. Focus groups were used to elicit qualitative information about living with JFM and perceived challenges and buffering factors impacting their adjustment. Results The majority of participants (80%, N = 12) continued to meet criteria for fibromyalgia (FM). An iterative, thematic analysis revealed themes of resilience (e.g., greater acceptance, re-setting expectations, active coping, addressing mental health) and risk (e.g., lack of information, stigma, isolation, negative healthcare experiences). Conclusion Results suggest the need for longer follow-up of youth with JFM as they transition to adulthood with multidisciplinary care and more attention to education about JFM and associated symptoms such as fatigue, as well as ongoing support for coping and mental health needs. A holistic approach to care during the transition years could be beneficial to minimize impact of JFM on long-term functioning.

Objectives To evaluate the feasibility of a stepped care model, and establish the effect of a tailored cognitive behavioral therapy, the Aim to Decrease Anxiety and Pain Treatment (ADAPT), compared with standard medical treatment as usual on pain-related outcomes and anxiety. Study design Eligible patients between the ages of 9 and 14 years with functional abdominal pain disorders (n = 139) received enhanced usual care during their medical visit to a gastroenterologist. Those that failed to respond to enhanced usual care were randomized to receive either a tailored cognitive behavioral therapy (ADAPT) plus medical treatment as usual, or medical treatment as usual only. ADAPT dose (4 sessions of pain management or 6 sessions of pain and anxiety management) was based on presence of clinically significant anxiety. Outcomes included feasibility, based on recruitment and retention rates. Response to ADAPT plus medical treatment as usual vs medical treatment as usual on pain-related outcomes and anxiety measures was also investigated using a structural equation modeling equivalent of a MANCOVA. Anxiety levels and ADAPT dose as moderators of treatment effects were also explored. Results Based on recruitment and retention rates, stepped care was feasible. Enhanced usual care was effective for only 8% of youth. Participants randomized to ADAPT plus medical treatment as usual showed significantly greater improvements in pain-related disability, but not pain levels, and greater improvements in anxiety symptoms compared with those randomized to medical treatment as usual only. Anxiety and ADAPT treatment dose did not moderate the effect of treatment on disability nor pain. Conclusions Tailoring care based on patient need may be optimal for maximizing the use of limited psychotherapeutic resources while enhancing care. Trial registration ClinicalTrials.gov : NCT03134950 .

Summary Background & aims Enteral nutrition (EN) and parenteral nutrition (PN) enriched with omega-3 polyunsaturated fatty acids (PUFA) have beneficial effects in critical illness. This study aimed to assess the combined effect of EN and supplemental PN enriched with omega-3 PUFA on blood oxygenation in intensive care unit (ICU) patients. Methods Single-center, prospective, randomized, controlled, double-blind, phase III trial conducted from 10/2013 to 11/2017. A total of 100 ICU patients (18–85 years, APACHE II score > 15) requiring mechanical ventilation were randomly assigned to received combined EN and PN either with omega-3 PUFA (omega-3 group) or without (control group) for up to 28 days. Primary endpoint: ‘change of PaO2/FiO2 from day (D) 1 to D4’. Secondary endpoints: lung function parameters, ICU complications, length of hospital stay, days free of ICU care/ventilation/sedation/catecholamine treatment, mortality, erythrocyte fatty acid composition, inflammatory parameters. Safety parameters: standard laboratory assessment, vital signs, physical examination, SOFA score, adverse events. Results Combined EN and PN covered energy requirements to more than 80%. Blood oxygenation (ΔPaO2/FiO2 from D1 to D4: −1.3 ± 83.7, n = 42, and 13.3 ± 86.1, n = 39, in omega-3 and control group, respectively, p = 0.7795) and other lung function parameters did not differ between groups but days free of catecholamine treatment were significantly higher in the omega-3 group (~4 days, p = 0.0481). On D6, significantly more patients in the omega-3 group tolerated EN alone (51.0% vs. 29.8%, p = 0.0342). Eicosapentaenoic acid (EPA) content in erythrocytes was significantly increased in the omega-3 group at last observation compared with the control group (ΔEPA: 0.928 ± 0.808% vs. −0.024 ± 0.190%, p Conclusions Enteral and supplemental PN both enriched with omega-3 PUFA did not improve lung function but allowed earlier weaning from catecholamine treatment and PN. Supplemental PN succeeded to adequately cover energy requirements in critically ill patients. Trial registration www.clinicaltrials.gov, registration number: NCT01162928 .

Antiretroviral therapy is able to effectively control but not eradicate HIV infection, which can persist, leading to the need for lifelong therapy. The existence of latently HIV-infected cells is a major barrier to the eradication of chronic HIV infection. Histone deacetylase inhibitors (HDACis), small molecules licensed for oncology indications, have shown the ability to produce HIV transcripts in vitro and in vivo. The pharmacologic parameters that drive optimal HIV latency reversal in vivo are unknown and could be influenced by such factors as the HDACi binding kinetics, concentration of compound, and duration of exposure. This study evaluates how these parameters affect HIV latency reversal for a series of novel HDACis that differ in their enzymatic on and off rates. Varying cellular exposure, using automated washout methods of HDACi in a Jurkat cell model of HIV latency, led to the investigation of the relationship between pharmacokinetic (PK) properties, target engagement (TE), and pharmacodynamic (PD) responses. Using an automated robotic platform enabled miniaturization of a suspension cell-based washout assay that required multiple manipulations over the 48 h duration of the assay. Quantification of histone acetylation (TE) revealed that HDACis showed early peaks and differences in the durability of response between different investigated HDACis. By expanding the sample times, the shift between TE and PD, as measured by green fluorescent protein, could be fully characterized. The comprehensive data set generated by automating the assays described here was used to establish a PK/PD model for HDACi-induced HIV latency reversal.

Supplemental Digital Content is Available in the Text. Updating a core outcome set for pediatric chronic pain interventions using an accepted framework and methodology will advance care for children with chronic pain., Appropriate outcome measures and high-quality intervention trials are critical to advancing care for children with chronic pain. Our aim was to update a core outcome set for pediatric chronic pain interventions. The first phase involved collecting providers', patients', and parents' perspectives about treatment of pediatric chronic pain to understand clinically meaningful outcomes to be routinely measured. The second phase was to reach consensus of mandatory and optional outcome domains following the OMERACT framework. A modified Delphi study with 2 rounds was conducted including 3 stakeholder groups: children with chronic pain (n = 93), their parents (n = 90), and health care providers who treat youth with chronic pain (n = 52). Quantitative and qualitative data from round 1 of the Delphi study were summarized to identify important outcomes, which were condensed to a list of 10 outcome domains. Round 2 surveys were analyzed to determine the importance of the 10 domains and their relative ranking in each stakeholder group. A virtual consensus conference was held with the steering committee to reach consensus on a set of recommended outcome domains for pediatric chronic pain clinical trials. It was determined, by unanimous vote, that pain severity, pain interference with daily living, overall well-being, and adverse events, including death, would be considered mandatory domains to be assessed in all trials of any type of intervention. Emotional functioning, physical functioning, and sleep were important but optional domains. Last, the research agenda identifies several important emerging areas, including biomarkers. Future work includes selecting appropriate validated measures to assess each outcome domain.

Juvenile fibromyalgia (JFM) is a chronic and debilitating noninflammatory musculoskeletal pain syndrome that is typically diagnosed in adolescence. There are no specific medical tests or disease markers to diagnose the condition, and classification is based on patient report of pain and other associated symptoms after ruling out other underlying medical causes. JFM can be disabling in multiple life domains and therefore, a multidimensional assessment of JFM is recommended to gain a full picture of the extent of JFM symptoms along with their impact on physical and emotional functioning and quality of life. The following updated review outlines evidence-based measures useful in the assessment of school-age children and adolescents with JFM. New measures include 1) the Pain and Symptom Assessment Tool (PSAT) that offers a standardized tool for the classification of fibromyalgia in pediatric patients and 2) the Patient-Reported Outcomes Measurement Information System (PROMIS®) Pediatric Pain Interference, Anxiety, and Depression Scales. Updated information is presented on previously established measures that assess the impact of JFM on functioning and quality of life - the Functional Disability Inventory (FDI) and the Pediatric Quality of Life Inventory (PedsQL) 3.0 Rheumatology Module Pain and Hurt Scale, are also discussed. In general, there are increasing options for validated patient-reported outcome measures available to measure the spectrum of symptoms in JFM and assess impact on daily life. Greater consistency in identification of JFM and use of standardized assessment tools will undoubtedly lead to higher quality research much needed in this relatively understudied musculoskeletal pain condition.

We demonstrate that human immunodeficiency virus (HIV) gag p24 protein is more readily detected in gut and lymph node tissues than in blood CD4+ T cells and correlates better with CD4 count during antiretroviral therapy (ART). Gut p24 levels also measurably decline with ART in natural controllers. During ART, gut p24 expression is more strongly associated both with HIV-specific CD8+ T-cell frequency and plasma soluble CD14 levels than gut HIV RNA expression. This study supports using gag p24 as a marker of HIV expression in HIV+ tissues to study effects of viral persistence and to monitor efficacy of treatment in HIV-based clearance studies.

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.

The neutrophil granule protein lactoferrin is cleaved and accumulates in efferocytic macrophages as inflammation is resolved. Two peptides present within a resolution-associated 17 kDa fragment of lactoferrin promote the termination of inflammation in vivo by enhancing murine macrophage reprogramming. Here, we report that these two bioactive tripeptides, phenylalanine-lysine-aspartic acid and phenylalanine-lysine-glutamic acid (FKD and FKE, respectively), inhibit ERK and cJun activation following human macrophage exposure to LPS. In addition, these peptides at low concentrations (1&ndash, 10 &mu, M) modulate human macrophage reprogramming to an anti-inflammatory/pro-resolving phenotype. This was reflected by inhibition of LPS-induced TNF-&alpha, and IL-6 secretion and increased IL-10 levels. Moreover, we found naturally occurring FKE analogs (FKECH and FKECHLA) can recapitulate the activity of the short peptide in regulating macrophage cytokine secretion, whereas a reversed EKF peptide was inert in this respect. Curiously, FKD and FKE also regulated cytokine production by bone marrow-derived mouse macrophages, but in a very different fashion than their effect on human macrophages. Thus, lactoferrin peptides limit pro-inflammatory signaling and cytokine production by LPS-activated human macrophages and thereby enhance the resolution of inflammation.

Genetic counseling is a communication process whereby an individual or family obtains information about a genetic condition, is helped to understand the implications and significance of the condition, and is given resources to help with coping and management. It is a continuous process involving lasting supportive relationships between the family and the genetic professional. Genetic counselors are master's level-trained health-care professionals who work closely with pediatricians and pediatric subspecialists alike. Genetic counselors can be a source of information about genetic conditions, risk assessment for disease, and genetic testing. Although most of a genetic counselor's job is patient care and education, genetic counselors also serve as resources to educate health professionals about genetics.

Objectives To evaluate the feasibility and acceptability of the Aim to Decrease Anxiety and Pain Treatment (ADAPT), a brief, on-line and in-person behavioral intervention targeting pain and anxiety in youth with functional abdominal pain disorders (FAPDs). Methods Patients were recruited from several outpatient pediatric gastroenterology clinics. Nine participants (ages 9-13) completed the full protocol. Thematic analysis of detailed qualitative feedback was obtained via semistructured patient and caregiver interviews after treatment was conducted. Feasibility and preliminary outcomes were examined using nonparametric tests. Results Preliminary results indicate that the ADAPT treatment is feasible, acceptable, and potentially effective for youth with FAPD. Treatment completers reported that they enjoyed the program and used the skills to manage their pain and worry. Results also indicated that the majority of participants experienced a reduction in anxiety and several reported reductions in pain and functional disability levels. Conclusions Findings from this study suggest that targeting both pain and anxiety may positively impact outcomes in youth with FAPD. The ADAPT intervention has the potential to provide a cost effective and practical application of cognitive behavioral therapy using an innovative combination of in-person and technology-based platforms. Overall, the ADAPT intervention is a promising and innovative intervention to improve the outcomes of youth with FAPD.

Though phenotypic and target-based high-throughput screening approaches have been employed to discover new antibiotics, the identification of promising therapeutic candidates remains challenging. Each approach provides different information, and understanding their results can provide hypotheses for a mechanism of action (MoA) and reveal actionable chemical matter. Here, we describe a framework for identifying efficacy targets of bioactive compounds. High throughput biophysical profiling against a broad range of targets coupled with machine learning was employed to identify chemical features with predicted efficacy targets for a given phenotypic screen. We validate the approach on data from a set of 55 000 compounds in 24 historical internal antibacterial phenotypic screens and 636 bacterial targets screened in high-throughput biophysical binding assays. Models were built to reveal the relationships between phenotype, target, and chemotype, which recapitulated mechanisms for known antibacterials. We also prospectively identified novel inhibitors of dihydrofolate reductase with nanomolar antibacterial efficacy against Mycobacterium tuberculosis. Molecular modeling provided structural insight into target-ligand interactions underlying selective killing activity toward mycobacteria over human cells.

Objectives Reduced pain thresholds have been documented in adult fibromyalgia, but there are no quantitative studies of altered pain sensitivity in adolescents with juvenile fibromyalgia (JFM). The current study examined differences in pressure pain sensitivity between adolescent females with JFM and healthy controls. The relationship between levels of anxiety and pain were also examined. Methods A total of 34 JFM (15.4±1.4 y old) and 31 controls (14.5±1.3 y old) completed self-report measures of pain and anxiety. Pressure pain threshold was assessed (palm and forehead sites) with a hand-held algometer. Participants indicated the first sensation of pain and then rated the intensity of pain on a Numerical Rating Scale. Results Adolescents with JFM exhibited greater sensitivity to pressure pain compared with controls. While the difference between JFM and controls was only observed at the forehead, the intensity of pain produced by the pressure algometry at both sites was significantly higher in the JFM participants compared with controls. Correlations between clinical pain and anxiety were significant for the JFM group only. No relationships were observed between anxiety and pressure pain for either group. Discussion This study is a first step toward investigating mechanisms of altered pain processing in adolescents with JFM. Adolescents with JFM were found be more sensitive to pressure pain than their healthy peers, which suggests a propensity for sensitization of peripheral and/or central nociceptive information often reported in adult fibromyalgia, and which does not appear to be affected by anxiety.

We aimed to identify risk factors for persistently reduced health-related quality of life in childhood-onset lupus and describe a risk profile for persistently reduced health-related quality of life. At a tertiary rheumatology clinic, 50 childhood onset lupus patients were assessed twice, approximately six months apart. Measures of disease activity and patient-reported measures of health-related quality of life, pain, depressive symptoms, anxiety and disability were collected at each visit. At visits 1 and 2, respectively, clinically relevant fatigue was present in 66% and 56% of patients; clinically significant depressive symptoms in 26% and 24%; and clinically significant anxiety in 34% and 28%. Poorer health-related quality of life at follow-up was significantly predicted by higher fatigue and depressive symptoms at the initial visit. Using clinically relevant cut-offs for fatigue and depressive symptoms, patients were assigned to Low ( n = 27) or High Risk ( n = 23) groups. A profile of significantly greater pain, anxiety and coping difficulties was seen in the High Risk group. Routine assessment of fatigue and mood symptoms in youth with childhood-onset lupus could be helpful in identifying those at risk for persistently poor health-related quality of life. Integration of behavioral interventions to address fatigue and mood symptoms into medical care for such patients may be beneficial, but more research in this area is needed.

We compared headache frequency trajectories between clinical trial participants who received cognitive-behavioral therapy (CBT) and amitriptyline (CBT+A) or headache education (HE) and amitriptyline (HE+A) to determine if there was a differential time course of treatment response between the groups. One hundred thirty-five patients (age 10–17 years) diagnosed with chronic migraine participated, attending 8 one-hour one-on-one CBT or HE sessions with a trained psychologist for 8 weekly sessions, 2 sessions at weeks 12 and 16, and a post-treatment visit at week 20. Participants kept daily headache diaries and completed take-home assignments between visits. Data from daily headache diaries are presented for each day and according to 28-day periods. Trajectories of improvement indicate initial decrease in headache days began during the first month of treatment, for both groups, and continued to decrease throughout treatment. The CBT+A group had greater daily improvement than the HE+A group. A significantly greater proportion of the CBT+A group had a ≥50% reduction in headache days each month, and a significantly greater proportion of the CBT+A group had ≤4 headache days per month in months 3 through 5. Results indicate the trajectory of decrease in headache days is significantly better for patients receiving CBT+A versus HE+A. Perspective This article presents daily information about headache frequency over a 20-week clinical trial. Youth with chronic migraine who received CBT+A improved faster than those in the control group. Findings provide clinicians with evidence-based expectations for treatment response over time and ways of monitoring treatment success. Trial registration clinicaltrials.gov identifier NCT00389038 .

The Inborn Errors of Metabolism Collaborative (IBEMC) includes clinicians from 29 institutions collecting data to enhance understanding of metabolic conditions diagnosable by newborn screening. Data collected includes hospitalizations, test results, services, and long-term outcomes. Through evaluation of this data, we sought to determine how frequently genetic counseling had been provided, how often genetic testing was performed, and also determine the consanguinity rate in this population. A data query was performed with the following elements abstracted/analyzed: current age, metabolic condition, whether genetic counseling was provided (and by whom), whether genetic testing was performed, and consanguinity. Genetic counseling was provided to families 95.8% of the time and in 68.6% of cases by a genetic counselor. Genetic testing was performed on 68.0% of subjects, with usage highest for fatty-acid-oxidation disorders (85.1%). The rate of consanguinity was 2.38%. Within this large national collaborative there is a high frequency of genetic counseling, though in one-third of cases a genetic counselor has not been involved. Additionally, while metabolic conditions have historically been diagnosed biochemically, there is currently high utilization of molecular testing suggesting DNA testing is being incorporated into diagnostic assessments - especially for fatty-acid-oxidation disorders where the underlying genotype helps predict clinical presentation.

Pain behaviors are important indicators of functioning in chronic pain; however, no self-reported pain behavior instrument has been developed for pediatric populations. The purpose of this study was to create a brief pediatric measure of patient-reported pain behaviors as part of the Patient-Reported Outcome Measurement Information System (PROMIS). A pool of 47 candidate items for this measure had been previously developed through qualitative research. In this study, youth with chronic pain associated with juvenile fibromyalgia, juvenile idiopathic arthritis, or sickle cell disease (ages 8-18 years) from 3 pediatric centers completed all 47 candidate items for development of the pain behavior item bank along with established measures of pain interference, depressive symptoms, fatigue, average pain intensity, and pain catastrophizing. Caregivers reported on sociodemographic information and health history. Psychometric properties of the pain behavior items were examined using an item response theory framework with confirmatory factor analysis and examination of differential item functioning, internal consistency, and test information curves. Results were used along with expert consensus and alignment with the adult PROMIS pain behavior items to arrive at an 8-item pediatric pain behavior short form, and all 47 items were retained in a calibrated item bank. Confirmatory factor analysis and correlations with validated measures of pain, pain interference, and psychosocial functioning provided support for the short form's reliability and validity. The new PROMIS pediatric pain behavior scale provides a reliable, precise, and valid measure for future research on pain behavior in school-aged children with chronic pain.

In the triage of hits from a high-throughput screening campaign or during the optimization of a lead compound, it is relatively routine to test compounds at multiple concentrations to determine potency and maximal effect. Additional follow-up experiments, such as agonist shift, can be quite valuable in ascertaining compound mechanism of action (MOA). However, these experiments require cross-titration of a test compound with the activating ligand of the receptor requiring 100-200 data points, severely limiting the number tested in MOA assays in a screening triage. We describe a process to enhance the throughput of such cross-titration experiments through the integration of Hewlett Packard's D300 digital dispenser onto one of our robotics platforms to enable on-the-fly cross-titration of compounds in a 1536-well plate format. The process handles all the compound management and data tracking, as well as the biological assay. The process relies heavily on in-house-built software and hardware, and uses our proprietary control software for the platform. Using this system, we were able to automate the cross-titration of compounds for both positive and negative allosteric modulators of two different G protein-coupled receptors (GPCRs) using two distinct assay detection formats, IP1 and Ca

Background Chronic postsurgical pain (CPSP) affects half a million children annually in the United States, with dire socioeconomic consequences, including long-term disability into adulthood. The few studies of CPSP in children are limited by sample size, follow-up duration, non-homogeneity of surgical procedure and factors evaluated. Methods In a prospective study of 144 adolescents undergoing a single major surgery (spine fusion), we evaluated demographic, perioperative, surgical and psychosocial factors as predictors of a continuum of postsurgical pain: immediate, pain maintenance at 2–3 months (chronic pain/CP) and persistence of pain a year (persistent pain/PP) after surgery. Results We found an incidence of 37.8% and 41.8% for CP and PP. CP and acute pain were both significant predictors for developing PP (p-value

OBJECTIVES: This review outlines a conceptual framework adapted from the biopsychosocial model of pain to examine the relationship between adverse childhood events (ACEs) and chronic pain in youth in order to highlight the state of current research and guide future efforts. Methods: A review of the literature was performed in the areas of ACEs and health outcomes with general adult and pediatric populations in addition to studies within the pain literature. Potential relationships between ACEs, chronic pain, and its impact in youth are outlined and discussed. Results: The literature suggests an association between adverse outcomes of ACEs and chronic pain in children and adolescents although causal links have not been confirmed. However, ACEs are associated with multiple risk factors identified in the biopsychosocial model of pain, and may serve to exacerbate or confer heightened risk for pain and poor outcomes. Discussion: Adverse experiences in childhood may be associated with greater risk for the development/maintenance of chronic pain in youth. More research is needed on ACEs and how they uniquely affect the biopsychosocial mechanisms underlying chronic pain in children throughout the lifespan. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. Language: en

Randomized control trials (RCTs) have long been the gold standard for allowing causal inferences to be made regarding the efficacy of a treatment under investigation, but traditional RCT data analysis perspectives do not take into account a common reality: imperfect participant compliance to treatment. Recent advances in both maximum likelihood parameter estimation and mixture modeling methodology have enabled treatment effects to be estimated, in the presence of less than ideal levels of participant compliance, via a Complier Average Causal Effect (CACE) structural equation mixture model. CACE is described in contrast to "intent to treat" (ITT), "per protocol", and "as treated" RCT data analysis perspectives. CACE model assumptions, specification, estimation, and interpretation will all be demonstrated with simulated data generated from a randomized controlled trial of cognitive-behavioral therapy for Juvenile Fibromyalgia. CACE analysis model figures, linear model equations, and Mplus estimation syntax examples are all provided. Data needed to reproduce analyses in this article are available as supplemental materials (online only) in the Appendix of this article.

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.

The uptake of apoptotic polymorphonuclear cells (PMN) by macrophages is critical for timely resolution of inflammation. High-burden uptake of apoptotic cells is associated with loss of phagocytosis in resolution phase macrophages. Here, using a transcriptomic analysis of macrophage subsets, we show that non-phagocytic resolution phase macrophages express a distinct IFN-β-related gene signature in mice. We also report elevated levels of IFN-β in peritoneal and broncho-alveolar exudates in mice during the resolution of peritonitis and pneumonia, respectively. Elimination of endogenous IFN-β impairs, whereas treatment with exogenous IFN-β enhances, bacterial clearance, PMN apoptosis, efferocytosis and macrophage reprogramming. STAT3 signalling in response to IFN-β promotes apoptosis of human PMNs. Finally, uptake of apoptotic cells promotes loss of phagocytic capacity in macrophages alongside decreased surface expression of efferocytic receptors in vivo. Collectively, these results identify IFN-β produced by resolution phase macrophages as an effector cytokine in resolving bacterial inflammation., Clearance of apoptotic neutrophils by macrophages is important for the resolution of inflammation. Here, the authors show that interferon-β produced by resolution phase macrophages promotes neutrophil apoptosis and efferocytosis and induces macrophage reprogramming to a pro-resolving phenotype, thereby identifying IFN-β as a multi-pronged pro-resolution cytokine.

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.

OBJECTIVE: Anxiety is common in pediatric chronic pain and is related to a higher risk for poor outcomes; thus, there is a need for effective clinical screening methods to identify youth with chronic pain and co-occurring anxiety. The Screen for Child Anxiety Related Disorders (SCARED) is a validated measure that defines clinically significant anxiety using the traditional clinical cut-off, but in pain populations, may fail to screen in youth with subclinical anxiety that may also be at increased risk. Two studies aimed to devise a clinically meaningful approach to capture anxiety severity in pediatric chronic pain. METHODS: Study 1 (n=959) and Study 2 (n=207) were completed at two separate pediatric pain clinics, where the SCARED was administered along with measures of disability, activity limitations, pain intensity, quality of life, and pain catastrophizing. Groups with different levels of anxiety were compared on clinical outcomes via multivariate analyses of variance (MANOVAs) or independent samples T-tests. RESULTS: A tertile solution suggested the following anxiety groupings based on the SCARED: minimal (0–12), subclinical (13–24), and clinical (≥25). Across both studies, the tertile solution was generally superior in classifying different levels of pain-related outcomes. DISCUSSION: Future directions include testing the utility of this anxiety classification system to identify youth with subclinical levels of anxiety for early intervention focused on both pain and anxiety management.

// Keren Weidenfeld 1 , Sagi Schif-Zuck 1 , Hanan Abu-Tayeh 1 , Keunsoo Kang 2 , Ofra Kessler 3 , Marina Weissmann 3 , Gera Neufeld 3 , Dalit Barkan 1 1 Department of Human Biology, University of Haifa, Haifa, Israel 2 Department of Microbiology, Dankook University, Cheonan, Republic of Korea 3 Cancer Research and Vascular Biology Center, The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel Correspondence to: Dalit Barkan, email: dalitbrk@gmail.com Keywords: dormant tumor cells, breast cancer recurrence, cancer stem cells, epithelial mesenchymal transition, LOXL2 Received: January 24, 2016 Accepted: September 12, 2016 Published: September 19, 2016 ABSTRACT Recurrence of breast cancer disease years after treatment appears to arise from disseminated dormant tumor cells (DTC). The mechanisms underlying the outgrowth of DTC remain largely unknown. Here we demonstrate that dormant MCF-7 cells expressing LOXL2 acquire a cancer stem cell (CSC)-like phenotype, mediating their outgrowth in the 3D BME system that models tumor dormancy and outgrowth. Similarly, MCF-7-LOXL2 cells colonizing the lung transitioned from dormancy to metastatic outgrowth whereas MCF-7 cells remained dormant. Notably, epithelial to mesenchymal transition (EMT) of MCF-7-LOXL2 cells was required for their CSC-like properties and their transition to metastatic outgrowth. These findings were further supported by clinical data demonstrating that increase in LOXL2 mRNA levels correlates with increase in the mRNA levels of EMT and stem cells markers, and is also associated with decrease in relapse free survival of breast cancer patients. Notably, conditional hypoxia induced expression of endogenous LOXL2 in MCF-7 cells promoted EMT and the acquisition of a CSC-like phenotype, while knockdown of LOXL2 inhibited this transition. Overall, our results demonstrate that expression of LOXL2 endowed DTC with CSC-like phenotype driving their transition to metastatic outgrowth and this stem-like phenotype is dependent on EMT that can be driven by the tumor microenvironment.

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.

Adolescents with juvenile fibromyalgia (JFM) are typically sedentary despite recommendations for physical exercise, a key component of pain management. Interventions such as cognitive-behavior therapy (CBT) are beneficial but do not improve exercise participation. The objective of this study was to obtain preliminary information about the feasibility, safety, and acceptability of a new intervention--Fibromyalgia Integrative Training for Teens (FIT Teens), which combines CBT with specialized neuromuscular exercise training modified from evidence-based injury prevention protocols.Participants were 17 adolescent females (aged 12 to 18 y) with JFM. Of these, 11 completed the 8-week (16 sessions) FIT Teens program in a small-group format with 3 to 4 patients per group. Patients provided detailed qualitative feedback via individual semistructured interviews after treatment. Interview content was coded using thematic analysis. Interventionist feedback about treatment implementation was also obtained.The intervention was found to be feasible, well tolerated, and safe for JFM patients. Barriers to enrollment (50% of those approached) included difficulties with transportation or time conflicts. Treatment completers enjoyed the group format and reported increased self-efficacy, strength, and motivation to exercise. Participants also reported decreased pain and increased energy levels. Feedback from participants and interventionists was incorporated into a final treatment manual to be used in a future trial.Results of this study provided initial support for the new FIT Teens program. An integrative strategy of combining pain coping skills via CBT enhanced with tailored exercise specifically designed to improve confidence in movement and improving activity participation holds promise in the management of JFM.

As initial steps in a broader effort to develop and test pediatric pain behavior and pain quality item banks for the Patient-Reported Outcomes Measurement Information System (PROMIS), we used qualitative interview and item review methods to 1) evaluate the overall conceptual scope and content validity of the PROMIS pain domain framework among children with chronic/recurrent pain conditions, and 2) develop item candidates for further psychometric testing. To elicit the experiential and conceptual scope of pain outcomes across a variety of pediatric recurrent/chronic pain conditions, we conducted 32 semi-structured individual and 2 focus-group interviews with children and adolescents (8–17 years), and 32 individual and 2 focus-group interviews with parents of children with pain. Interviews with pain experts (10) explored the operational limits of pain measurement in children. For item bank development, we identified existing items from measures in the literature, grouped them by concept, removed redundancies, and modified the remaining items to match PROMIS formatting. New items were written as needed and cognitive debriefing was completed with the children and their parents, resulting in 98 pain behavior (47 self, 51 proxy), 54 quality, and 4 intensity items for further testing. Qualitative content analyses suggest that reportable pain outcomes that matter to children with pain are captured within and consistent with the pain domain framework in PROMIS. Perspective PROMIS pediatric pain behavior, quality, and intensity items were developed based on a theoretical framework of pain that was evaluated by multiple stakeholders in the measurement of pediatric pain, including researchers, clinicians, and children with pain and their parents, and the appropriateness of the framework was verified.

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