Pilot study to evaluate the safety and effectiveness of etidronate treatment for arterial calcification due to deficiency of CD73 (ACDC).

BACKGROUND: Arterial calcification due to deficiency of CD73 (ACDC; OMIM 211800) is a rare genetic disease resulting in calcium deposits in arteries and small joints causing claudication, resting pain, severe joint pain, and deformities. Currently, there are no standard treatments for ACDC. Our previous work identified etidronate as a potential targeted ACDC treatment, using in vitro and in vivo disease models with patient-derived cells. In this study, we test the safety and effectiveness of etidronate in attenuating the progression of lower-extremity arterial calcification and vascular blood flow based on the computed tomography (CT) calcium score and ankle-brachial index (ABI). METHODS: Seven adult patients with a confirmed genetic diagnosis of ACDC were enrolled in an open-label, nonrandomized, single-arm pilot study for etidronate treatment. They took etidronate daily for 14 days every 3 months and were examined at the NIH Clinical Center bi-annually for 3 years. They received a baseline evaluation as well as yearly follow up after treatment. Study visits included imaging studies, exercise tolerance tests with ABIs, clinical blood and urine testing, and full dental exams. RESULTS: Etidronate treatment appeared to have slowed the progression of further vascular calcification in lower extremities as measured by CT but did not have an effect in reversing vascular and/or periarticular joint calcifications in our small ACDC cohort. CONCLUSIONS: Etidronate was found to be safe and well tolerated by our patients and, despite the small sample size, appeared to show an effect in slowing the progression of calcification in our ACDC patient cohort.(ClinicalTrials.gov Identifier NCT01585402).

Palliative care referral criteria and application in pediatric illness care: A scoping review.

BACKGROUND: Specialty pediatric palliative care services can help to address unmet care needs for children with complex and serious illness. Current guidelines support the identification of unmet palliative care needs; however, it is unknown how these guidelines or other clinical characteristics influence pediatric palliative care referral in research and practice. AIM: To evaluate the identification and application of palliative care referral criteria in pediatric illness care and research. DESIGN: A scoping review with a content analysis approach to summarize results. DATA SOURCES: Five electronic databases (PubMed, CINAHL, PsycINFO, SCOPUS, and Academic Search Premier) were used to identify peer-reviewed literature published in English between January 2010 and September 2021. RESULTS: We included 37 articles focused on the referral of pediatric patients to palliative care teams. The identified categories of referral criteria were: disease-related; symptom-related; treatment communication; psychosocial, emotional, and spiritual support; acute care needs; end-of-life care needs; care management needs; and self-referrals for pediatric palliative care services. We identified two validated instruments to facilitate palliative care referral and seven articles which described population-specific interventions to improve palliative care access. Nineteen articles implemented a retrospective health record review approach that consistently identified palliative care needs with varying rates of service use. CONCLUSIONS: The literature demonstrates inconsistent methods for identifying and referring children and adolescents with unmet palliative care needs. Prospective cohort studies and clinical trials would inform more consistent pediatric palliative care referral practices. More research is needed on palliative care referral and outcomes in community-focused pediatrics.

Symptoms and daily experiences reported by children with cancer using a game-based app.

PURPOSE: Mobile health (mHealth) resources, including apps, are emerging as resources to support children in tracking symptoms and other health-related data. The purpose of this study was to describe symptoms and daily experiences reported by elementary school-age children receiving treatment for cancer using the newly developed Color Me Healthy app. DESIGN AND METHODS: Participants in this descriptive study were children 6-12 years of age, who were receiving cancer treatment at a free-standing children's hospital in the Intermountain West of the United States. Children were requested to use the app for at least five days between clinical visits. Children's app-reported data were extracted from individual user accounts for analysis. Quantitative data were summarized descriptively. Qualitative data were summarized using qualitative content analysis. RESULTS: Nineteen children (6-12 years; median 8 years; 7 females) completed 107 days of app use. All children reported symptoms at least once, and 14 reported at least one day with a symptom of moderate or greater severity. Daily experiences reported through the app reflected children's engagement in usual childhood experiences while also describing life with cancer, including symptoms. CONCLUSIONS: Elementary school-age children are capable of self-reporting symptoms using a symptom reporting app, providing preliminary evidence for the potential benefits and clinical relevance of mHealth resources to support health outcomes within this population. PRACTICE IMPLICATIONS: Clinicians should anticipate and support ongoing symptom management needs between clinical visits. Children's self-reported data can promote a person-centered approach to symptom assessment and management.

Multifocal calcific periarthritis with distinctive clinical and radiological features in patients with CD73 deficiency.

OBJECTIVES: Arterial calcification due to deficiency of CD73 (ACDC) is a hereditary autosomal recessive ectopic mineralization syndrome caused by loss-of-function mutations in the ecto-5'-nucleotidase gene. Periarticular calcification has been reported but the clinical characterization of arthritis as well as the microstructure and chemical composition of periarticular calcifications and SF crystals has not been systematically investigated. METHODS: Eight ACDC patients underwent extensive rheumatological and radiological evaluation over a period of 11 years. Periarticular and synovial biopsies were obtained from four patients. Characterization of crystal composition was evaluated by compensated polarized light microscopy, Alizarin Red staining for synovial fluid along with X-ray diffraction and X-ray micro tomosynthesis scanner for periarticular calcification. RESULTS: Arthritis in ACDC patients has a clinical presentation of mixed erosive-degenerative joint changes with a median onset of articular symptoms at 17 years of age and progresses over time to the development of fixed deformities and functional limitations of small peripheral joints with, eventually, larger joint and distinct axial involvement later in life. We have identified calcium pyrophosphate and calcium hydroxyapatite (CHA) crystals in SF specimens and determined that CHA crystals are the principal component of periarticular calcifications. CONCLUSION: This is the largest study in ACDC patients to describe erosive peripheral arthropathy and axial enthesopathic calcifications over a period of 11 years and the first to identify the composition of periarticular calcifications and SF crystals. ACDC should be considered among the genetic causes of early-onset OA, as musculoskeletal disease signs may often precede vascular symptoms.

Investigating key predictors of persistent low back pain: A focus on psychological stress.

AIM: To investigate the degree to which psychological stress, self-reported pain scores, and pain sensitivity during an acute state of low back pain (LBP) predict the development of persistent LBP trajectories. BACKGROUND: Identifying which factors influence LBP trajectories is critical to understand why some individuals experience persistent LBP and to illuminate areas for nursing intervention. METHODS: A secondary data analysis of a prospective study examining trajectories of LBP was conducted. The sample was comprised of 217 adults with acute-onset LBP recruited from the community and followed over 24 weeks. Variables of interest included demographic data, perceived stress scores, self-reported pain scores, and somatosensory characteristics collected within the first 4 weeks of LBP onset. The data were analyzed using non-parametric bivariate comparisons and a semi-parametric Cox proportional hazards model with interval-censoring. RESULTS: Individuals with higher psychological stress scores were less likely to experience pain resolution (Hazard ratio [HR] = 0.555, 95% confidence interval [CI] = 0.36-0.85, p = 0.02). After adjustment for covariates in the final model, the analysis revealed household income (HR = 2.79, 95% CI [1.63-4.67], p < 0.001) to be the dominant predictor of LBP persistence in this sample. CONCLUSION: Heightened psychological stress and pain severity as well as decreased pressure pain thresholds were indicated as influential factors of LBP trajectories. Household income was identified as the dominant predictor, demonstrating that individuals with a higher household income were more likely to resolve their pain. Strategies which integrate assessment of stress, self-reported pain scores, pain sensitivity, and social determinants for patients experiencing pain are needed to advance nursing care.

Deconstructing Pain Disability through Concept Analysis.

OBJECTIVE: Pain disability is a complex and challenging problem that impacts the daily lives of individuals living with persistent pain. Although this concept is measured throughout pain populations, conceptual clarity is needed to identify the defining characteristics and further understand what comprises this experience for clinical translation. DESIGN: We completed a concept analysis to identify major attributes and provide a broad framework of pain disability for improved recognition throughout the discipline of nursing. DATA SOURCES: Literature searches in PubMed, CINAHL, PsychINFO, and Scopus identified 39 relevant cross-disciplinary articles published between January 1990 and November 2017. REVIEW/ANALYSIS METHODS: We implemented Avant and Walker's method of concept analysis to establish the attributes, antecedents, and consequences of pain disability. RESULTS: Two major attributes of pain disability are discussed, including (1) physical and/or psychological responses leading to a functional loss; and (2) the degree of ability to fulfill role expectations. The antecedent to the development of pain disability is a painful trigger. Three leading consequences are identified as suffering, pain reactivity, and secondary loss. CONCLUSIONS: Pain disability is a fluid concept that is characterized by the subjective experiences of the individual. A new conceptualization of pain disability is offered as the inability to maintain role expectations due to the result of a painful trigger and subsequent physical and/or psychosocial dysfunction.

Informing Parents as Caregivers With a Symptom Assessment App Developed for Children With Cancer.

Background: Mobile health technologies can assist children to communicate their symptom experiences in a developmentally appropriate format. However, few investigations have examined how mHealth resources may also assist parents in their caregiver role. The purpose of this study was to explore how a symptom assessment app designed for school-age children with cancer could further inform parents as caregivers. Methods: Nineteen parents (18 mothers; median 35 years old, range 26-48 years) of children (6-12 years of age) receiving cancer treatment participated in the feasibility/acceptability trial of a game-based symptom assessment app. Acceptability interviews with parents were completed after each child's trial with the app. We completed a secondary analysis of the parent interviews using thematic analysis to examine how the app could support parents in their caregiving role. Results: Parents perceived the app to (1) elicit the child's voice about his/her symptom experience; (2) provide a supportive and safe environment for the child to report symptoms; and (3) create an opportunity to facilitate communication between the child, parent, and clinical team. Parents expressed a willingness for their child to represent his/her experience with the app so that they could make informed decisions regarding symptom care. Discussion: Perceived benefits of the app extended to parents as they described developing further insight into their child's cancer experience. The knowledge gained allowed parents the potential to enhance symptom communication and supportive care strategies. Future research should further evaluate how mHealth tools facilitate shared symptom management between children receiving treatment for cancer and their caregivers.

Communication of pain by school-age children with cancer using a game-based symptom assessment app: A secondary analysis.

PURPOSE: To evaluate the self-reported pain experiences of school-age children with cancer participating in a feasibility trial of a game-based symptom assessment app. METHOD: Nineteen children (median: 8 years, range 6-12 years old) receiving cancer treatment were recruited to complete five days of symptom tracking between clinical visits using a symptom assessment app. Children could report pain as a general symptom with the ability to further localize pain on an avatar. Children could also describe symptoms in response to the app's free-text questions or the app's diary. Descriptive statistics characterized reports of pain frequency, severity, bother, and location. Free-text responses were examined for pain-related statements and analyzed using content analysis. RESULTS: All 19 children documented pain on at least one day of app reporting between clinical visits. Pain was most frequently recorded as of mild severity and mild bother. Participants localized pain most frequently to the head, followed by the stomach, chest, extremities, and mouth. Eleven children documented 32 qualitative statements which included rich descriptions of pain-related topics (i.e., "my port hurts a little") and location (i.e., "my vision aching"). CONCLUSIONS: These results demonstrate that school-age children with cancer are willing to describe their ambulatory pain experiences on a game-based mobile app through quantitative reports and by using narrative descriptions. Additionally, these findings can potentially guide clinicians in using multiple approaches to elicit a clinically meaningful evaluation of pain in this population.

A Role for Global DNA Methylation Level and IL2 Expression in the Transition From Acute to Chronic Low Back Pain.

Objectives: The transition from acute low back pain (aLBP) to chronic LBP (cLBP) results from a variety of factors, including epigenetic modifications of DNA. The aim of this study was to (1) compare global DNA (gDNA) methylation and histone acetylation at LBP onset between the aLBP and cLBP participants, (2) compare mRNA expression of genes with known roles in the transduction, maintenance, and/or modulation of pain between the aLBP and cLBP participants, (3) compare somatosensory function and pain ratings in our participants, and (4) determine if the aforementioned measurements were associated. Methods: A total of 220 participants were recruited for this prospective observational study following recent onset of an episode of LBP. We retained 45 individuals whose gDNA was of sufficient quality for analysis. The final sample included 14 participants whose pain resolved within 6 weeks of onset (aLBP),15 participants that reported pain for 6 months (cLBP), and 16 healthy controls. Participants were subjected to quantitative sensory testing (QST), blood was drawn via venipuncture, gDNA isolated, and global DNA methylation and histone acetylation, as well as mRNA expression of 84 candidate genes, were measured. Results: Individuals that develop cLBP display multimodal somatosensory hypersensitivity relative to aLBP participants. cLBP participants also had significantly lower global DNA methylation, which was negatively correlated with interleukin-2 (IL2) mRNA expression. Discussion: cLBP is characterized by somatosensory hypersensitivity, lower global DNA methylation, and higher IL2 expression level compared to those whose pain will resolve quickly (aLBP). These results suggest potential diagnostic and therapeutic relevance for global DNA methylation and IL2 expression in the pathology underlying the transition from acute to chronic LBP.

A Systematic Review of Biological Mechanisms and Chronic Pain Outcomes During Stress Reduction Interventions.

BACKGROUND: Nonpharmacologic stress reduction interventions provide an opportunity to modify chronic pain trajectories; however, the biological mechanisms underlying these interventions are poorly understood. OBJECTIVES: To examine clinical literature published in 2012-2018 with the goals of (1) identifying which biological mechanisms or biomarkers are currently being measured in nonpharmacologic stress reduction intervention studies for individuals with chronic pain and (2) evaluating the evidence to determine whether these stress reduction interventions lead to changes in (a) pain outcomes and/or (b) measured biomarkers. DATA SOURCES: Scientific articles in the electronic databases PubMed/Medline, Cumulative Index of Nursing and Allied Health Literature, PsychINFO, and SCOPUS following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. STUDY SELECTION: Randomized controlled trials and quasi-experimental studies that recruited subjects with a chronic pain condition, examined a relationship between a nonpharmacologic stress reduction intervention and pain-related outcome(s), and included measurement of a biomarker. RESULTS: The 13 articles that met inclusion criteria spanned four nonpharmacologic stress reduction categories: mindfulness-based stress reduction, physical exercise, manual therapies, and biofeedback. Methods for studying biomarkers included measuring biological samples, neurological function, and autonomic control. Although all studies investigated both biological measures and pain outcomes, only three demonstrated an association between the biomarker(s) and pain-related outcomes. CONCLUSIONS: The results of this review highlight the complex nature of stress-pain relationships and the lack of rigorous clinical research identifying specific stress-related biological factors that modulate pain outcomes. Stress reduction interventions remain a favorable method for symptom management in patients living with chronic pain, but consistency in study measures and design is needed for robust evaluation.

Forced Enlightenment: A Metasynthesis of Experiences During Childhood Cancer Survivorship.

BACKGROUND: Childhood cancer survivorship can be described as a lifelong experience that requires vigilant follow-up care and continual support. Although there is growing qualitative and quantitative literature on this experience, articles focusing on qualitative synthesis are lacking. Qualitative metasynthesis can further facilitate the knowledge of survivorship experiences to inform care. OBJECTIVE: The aim of this qualitative metasynthesis was to investigate the experiences of childhood cancer survivors and develop an integrated understanding of the survivorship experience. METHODS: The method of qualitative meta-ethnography guided this research. Data extracted from the studies were directly compared through reciprocal translation. RESULTS: A total of 18 qualitative articles met the inclusion criteria. The authors identified 4 key metaphors, including Transcendence, Lingering Shadows, Fortifying Bonds, and Ongoing Acclimation. The metaphors are brought together by 3 essential concepts that drive the survivorship experience: (1) recognition of wisdom gained, (2) acknowledgment of vulnerabilities, and (3) actions taken to manage present and future. Together, these metaphors and essential concepts make up the global theme "Forced Enlightenment." CONCLUSION: This metasynthesis illuminates the complex nature of the childhood cancer survivorship experience, in which survivors work to grow beyond their treatment experience while inevitably being tied to it. Next steps should include further exploration of individual metaphors and validation of forced enlightenment as an experience. IMPLICATIONS FOR PRACTICE: Each of the metaphors may be used to guide the development of nursing interventions. Translation to clinical practice should focus on prioritizing coping and adaptation skills during cancer treatment, which can be carried through survivorship.

Morphology and chemical identity of periarticular and vascular calcification in a patient with the rare genetic disease of arterial calcification due to deficiency of CD73 (ACDC).

A 54-year old female patient with the genetic disease of arterial calcification due to deficiency of CD73 was studied under the Undiagnosed Disease Program of the National Institutes of Health. She presented with symptoms of claudication in her 40s and later developed arthritic symptoms, ectopic calcification in her left hand and severe arterial calcifications of the lower extremities. Since little was known about the composition of the calcifications in arterial calcification due to deficiency of CD73, we investigated their chemical identity and microscopic morphology in this patient with imaging and x-ray diffraction analysis. We found that, microscopically, the bulk calcifications consisted of fragments of either solid or porous internal structure. Both periarticular and arterial calcifications were primarily hydroxyapatite crystals of the same crystalline anisotropy, but different crystalline grain sizes. This was consistent with the presence of hydroxyapatite crystals along with birefringent calcium pyrophosphate dihydrate crystals in the synovial fluid of the patients by polarized light microscopy. The result suggests that tissue calcification in both locations follow a similar biochemical mechanism caused by an increase in extracellular tissue-nonspecific alkaline phosphatase activity.

Contribution of COMT and BDNF Genotype and Expression to the Risk of Transition From Acute to Chronic Low Back Pain.

OBJECTIVES: A number of factors, including heritability and the environment, contribute to risk of transition from acute low back pain to chronic low back pain (CLBP). The aim of this study was to (1) compare somatosensory function and pain ratings at low back pain (LBP) onset between the acute low back pain and CLBP conditions and (2) evaluate associations between BDNF and COMT polymorphisms and expression levels at LBP onset to acute and chronic pain burden and risk for transition to the chronic pain state. METHODS: In this longitudinal study, 220 participants were enrolled following recent onset of LBP and data were collected until the LBP resolved or until the end of the study at 6 months. Forty-two participants' pain resolved before 6 weeks from onset and 42 participants continued to have pain at 6 months. Patient-reported pain burden, somatosensory function (quantitative sensory testing), and blood samples were collected at each study visit. RESULTS: CLBP is associated with greater pain burden and somatosensory hypersensitivity at the time of LBP onset. COMT rs4680 genotype (GG) was associated with acute cold pain sensitivity and with the risk for transition to CLBP while COMT expression was independently associated with risk for transition. DISCUSSION: CLBP was characterized by higher reported pain burden and augmented hypersensitivity at LBP onset. COMT expression and genotype were associated with acute pain burden and likelihood of transition to CLBP.