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1.  An observational study of patient versus parental perceptions of health-related quality of life in children and adolescents with a chronic pain condition: who should the clinician believe? 
Background
Previous pediatric studies have observed a cross-informant variance in patient self-reported health-related quality of life (HRQoL) versus parent proxy-reported HRQoL. This study assessed in older children and adolescents with a variety of chronic pain conditions: 1) the consistency and agreement between pediatric patients’ self-report and their parents’ proxy-report of their child’s HRQoL; 2) whether this patient-parent agreement is dependent on additional demographic and clinical factors; and 3) the relationship between pediatric patient HRQoL and parental reported HRQoL.
Methods
The 99 enrolled patients (mean age 13.2 years, 71% female, 81% Caucasian) and an accompanying parent completed the PedsQLTM 4.0 and 36-Item Short-Form Health Survey Version 2 (SF-36v2) at the time of their initial appointment in a pediatric chronic pain medicine clinic. Patients’ and parents’ total, physical, and psychosocial HRQoL scores were analyzed via an intra-class correlation coefficient, Spearman’s correlation coefficient, Wilcoxon signed rank test, and Bland-Altman plot. A multivariable linear regression model was used to evaluate the association between clinical and demographic variables and the difference in patient and proxy scores for the Total Scale Score on the PedsQL™.
Results
With the exception of the psychosocial health domain, there were no statistically significant differences between pediatric patients’ self-report and their parents’ proxy-report of their child’s HRQoL. However, clinically significant patient-parent variation in pediatric HRQoL was observed. Differences in patient-parent proxy PedsQL™ Total Scale Score Scores were not significantly associated with patient age, gender, race, intensity and duration of patient’s pain, household income, parental marital status, and the parent’s own HRQoL on the SF-36v2. No significant relationship existed among patients’ self-reported HRQoL (PedsQL™), parental proxy-reports of the child’s HRQoL, and parents’ own self-reported HRQoL on the SF-36v2.
Conclusions
We observed clinically significant variation between pediatric chronic pain patients’ self-reports and their parents’ proxy-reports of their child’s HRQoL. While whenever possible the pediatric chronic pain patient’s own perspective should be directly solicited, equal attention and merit should be given to the parent’s proxy-report of HRQoL. To do otherwise will obviate the opportunity to use any discordance as the basis for a therapeutic discussion about the contributing dynamic with in parent-child dyad.
doi:10.1186/1477-7525-10-85
PMCID: PMC3478968  PMID: 22824550
Health-related quality of life; Chronic pain; Pediatric; Children; Adolescents; Proxy-report; Child-parent agreement
2.  Persistent pain in a community-based sample of children and adolescents: Sex differences in psychological constructs 
The prevalence of persistent and recurrent pain among children and adolescents has important economic, social and psychological repercussions. The impact of chronic pain in children extends beyond the affected individuals – more than one-third of parents of children with pain report clinically significant levels of stress and depression. Although many pain-related psychological factors have been examined in chronic pediatric pain populations, much of that research involved clinical samples. Community-based research, however, is necessary to uncover the way pain is experienced by youth, regardless of whether treatment is sought or is available. This study aimed to ascertain the lifetime prevalence of pediatric pain in a Canadian community-based sample, and to explore age and sex differences in children who report persistent pain and those who do not with respect to several constructs believed to play important roles in the development and maintenance of persistent pain.
BACKGROUND:
Very few studies have investigated the psychological factors associated with the pain experiences of children and adolescents in community samples.
OBJECTIVES:
To examine the lifetime prevalence of, and psychological variables associated with, persistent pain in a community sample of children and adolescents, and to explore differences according to sex, age and pain history.
METHODS:
Participants completed the Childhood Anxiety Sensitivity Index (CASI), the Child Pain Anxiety Symptoms Scale (CPASS), the Multidimensional Anxiety Scale for Children-10 (MASC-10), the Pain Catastrophizing Scale for Children (PCS-C) and a pain history questionnaire that assessed chronicity and pain frequency. After research ethics board approval, informed consent/assent was obtained from 1022 individuals recruited to participate in a study conducted at the Ontario Science Centre (Toronto, Ontario).
RESULTS:
Of the 1006 participants (54% female, mean [± SD] age 11.6±2.7 years) who provided complete data, 27% reported having experienced pain that lasted for three months or longer. A 2×2×2 (pain history, age and sex) multivariate ANOVA was conducted, with the total scores on the CASI, the CPASS, the MASC-10 and the PCS-C as dependent variables. Girls with a history of persistent pain expressed higher levels of anxiety sensitivity (P<0.001) and pain catastrophizing (P<0.001) than both girls without a pain history and boys regardless of pain history. This same pattern of results was found for anxiety and pain anxiety in the older, but not the younger, age group.
CONCLUSIONS:
Boys and girls appear to differ in terms of how age and pain history relate to the expression of pain-related psychological variables. Given the prevalence of persistent pain found in the study, more research is needed regarding the developmental implications of persistent pain in childhood and adolescence.
PMCID: PMC3206778  PMID: 22059200
Children; Persistent pain; Psychosocial factors; Sex differences
3.  Repeated primary care consultations for non-specific physical symptoms in children in UK: a cohort study 
BMC Family Practice  2014;15(1):195.
Background
Non-specific physical symptoms (NSPS), such as headache and abdominal pain, are common reasons for children to consult primary care. NSPS represent a significant burden not only on society, but also on health care services, through frequent physician consultations and referrals to secondary care. Research evidence suggests a positive relationship between health and consulting behavior of parents and their children, but research on whether repeated physician consultations for NSPS in children is influenced by parental consultations for NSPS is lacking. The aim was to measure the frequency of repeated physician consultations for NSPS in children, and investigate whether this is influenced by maternal consultations for NSPS.
Methods
A cohort study of children registered with primary care practices contributing to the Consultation in Primary Care Archive database. Participants were child-mother pairs registered between January 2007 and December 2010. The cohort comprised all children (n = 1437) aged 2 to 16 years who consulted a physician for NSPS in 2009. Mothers’ consultations for NSPS were measured between 2007 and 2008. Main outcome measures were repetition and frequency of consultations for NSPS in children (consultations for NSPS in both 2009 and 2010).
Results
Overall, 27% of children had repeated consultations for NSPS. The three most common repeated consultations were for back pain, constipation and abdominal pain. Exposure to maternal consultation for NSPS was associated with 21% increase in consultation frequency for NSPS (adjusted incidence rate ratio 1.21; 95% CI 1.12, 1.31). After adjusting for child age and maternal age, maternal consultation for NSPS was associated with an increased risk of repeated consultations for NSPS in children (relative risk 1.41; 95% CI 1.16, 1.73). This association was also significant for specific NSPS groups including painful, gastrointestinal, and neurologic symptoms.
Conclusions
Repeated consultation for NSPS is common among children. It is important for primary care physicians and secondary care clinicians, managing children referred from primary care for NSPS, to be aware that consultation for NSPS in mothers is a risk factor for repeated consultations for NSPS among children. More research is needed to uncover exactly how parental health influences health and consulting behavior of children.
doi:10.1186/s12875-014-0195-4
PMCID: PMC4261613  PMID: 25477255
4.  A Novel Tool for the Assessment of Pain: Validation in Low Back Pain 
PLoS Medicine  2009;6(4):e1000047.
Joachim Scholz and colleagues develop and validate an assessment tool that distinguishes between radicular and axial low back pain.
Background
Adequate pain assessment is critical for evaluating the efficacy of analgesic treatment in clinical practice and during the development of new therapies. Yet the currently used scores of global pain intensity fail to reflect the diversity of pain manifestations and the complexity of underlying biological mechanisms. We have developed a tool for a standardized assessment of pain-related symptoms and signs that differentiates pain phenotypes independent of etiology.
Methods and Findings
Using a structured interview (16 questions) and a standardized bedside examination (23 tests), we prospectively assessed symptoms and signs in 130 patients with peripheral neuropathic pain caused by diabetic polyneuropathy, postherpetic neuralgia, or radicular low back pain (LBP), and in 57 patients with non-neuropathic (axial) LBP. A hierarchical cluster analysis revealed distinct association patterns of symptoms and signs (pain subtypes) that characterized six subgroups of patients with neuropathic pain and two subgroups of patients with non-neuropathic pain. Using a classification tree analysis, we identified the most discriminatory assessment items for the identification of pain subtypes. We combined these six interview questions and ten physical tests in a pain assessment tool that we named Standardized Evaluation of Pain (StEP). We validated StEP for the distinction between radicular and axial LBP in an independent group of 137 patients. StEP identified patients with radicular pain with high sensitivity (92%; 95% confidence interval [CI] 83%–97%) and specificity (97%; 95% CI 89%–100%). The diagnostic accuracy of StEP exceeded that of a dedicated screening tool for neuropathic pain and spinal magnetic resonance imaging. In addition, we were able to reproduce subtypes of radicular and axial LBP, underscoring the utility of StEP for discerning distinct constellations of symptoms and signs.
Conclusions
We present a novel method of identifying pain subtypes that we believe reflect underlying pain mechanisms. We demonstrate that this new approach to pain assessment helps separate radicular from axial back pain. Beyond diagnostic utility, a standardized differentiation of pain subtypes that is independent of disease etiology may offer a unique opportunity to improve targeted analgesic treatment.
Editors' Summary
Background
Pain, although unpleasant, is essential for survival. Whenever the body is damaged, nerve cells detecting the injury send an electrical message via the spinal cord to the brain and, as a result, action is taken to prevent further damage. Usually pain is short-lived, but sometimes it continues for weeks, months, or years. Long-lasting (chronic) pain can be caused by an ongoing, often inflammatory condition (for example, arthritis) or by damage to the nervous system itself—experts call this “neuropathic” pain. Damage to the brain or spinal cord causes central neuropathic pain; damage to the nerves that convey information from distant parts of the body to the spinal cord causes peripheral neuropathic pain. One example of peripheral neuropathic pain is “radicular” low back pain (also called sciatica). This is pain that radiates from the back into the legs. By contrast, axial back pain (the most common type of low back pain) is confined to the lower back and is non-neuropathic.
Why Was This Study Done?
Chronic pain is very common—nearly 10% of American adults have frequent back pain, for example—and there are many treatments for it, including rest, regulated exercise (physical therapy), pain-killing drugs (analgesics), and surgery. However, the best treatment for any individual depends on the exact nature of their pain, so it is important to assess their pain carefully before starting treatment. This is usually done by scoring overall pain intensity, but this assessment does not reflect the characteristics of the pain (for example, whether it occurs spontaneously or in response to external stimuli) or the complex biological processes involved in pain generation. An assessment designed to take such factors into account might improve treatment outcomes and could be useful in the development of new therapies. In this study, the researchers develop and test a new, standardized tool for the assessment of chronic pain that, by examining many symptoms and signs, aims to distinguish between pain subtypes.
What Did the Researchers Do and Find?
One hundred thirty patients with several types of peripheral neuropathic pain and 57 patients with non-neuropathic (axial) low back pain completed a structured interview of 16 questions and a standardized bedside examination of 23 tests. Patients were asked, for example, to choose words that described their pain from a list provided by the researchers and to grade the intensity of particular aspects of their pain from zero (no pain) to ten (the maximum imaginable pain). Bedside tests included measurements of responses to light touch, pinprick, and vibration—chronic pain often alters responses to harmless stimuli. Using “hierarchical cluster analysis,” the researchers identified six subgroups of patients with neuropathic pain and two subgroups of patients with non-neuropathic pain based on the patterns of symptoms and signs revealed by the interviews and physical tests. They then used “classification tree analysis” to identify the six questions and ten physical tests that discriminated best between pain subtypes and combined these items into a tool for a Standardized Evaluation of Pain (StEP). Finally, the researchers asked whether StEP, which took 10–15 minutes, could identify patients with radicular back pain and discriminate them from those with axial back pain in an independent group of 137 patients with chronic low back pain. StEP, they report, accurately diagnosed these two conditions and was well accepted by the patients.
What Do These Findings Mean?
These findings indicate that a standardized assessment of pain-related signs and symptoms can provide a simple, quick diagnostic procedure that distinguishes between radicular (neuropathic) and axial (non-neuropathic) low back pain. This distinction is crucial because these types of back pain are best treated in different ways. In addition, the findings suggest that it might be possible to identify additional pain subtypes using StEP. Because these subtypes may represent conditions in which different pain mechanisms are acting, classifying patients in this way might eventually enable physicians to tailor treatments for chronic pain to the specific needs of individual patients rather than, as at present, largely guessing which of the available treatments is likely to work best.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000047.
This study is further discussed in a PLoS Medicine Perspective by Giorgio Cruccu and and Andrea Truini
The US National Institute of Neurological Disorders and Stroke provides a primer on pain in English and Spanish
In its 2006 report on the health status of the US, the National Center for Health Statistics provides a special feature on the epidemiology of pain, including back pain
The Pain Treatment Topics Web site is a resource, sponsored partly by associations and manufacturers, that provides information on all aspects of pain and its treatment for health care professionals and their patients
Medline Plus provides a brief description of pain and of back pain and links to further information on both topics (in English and Spanish)
The MedlinePlus Medical Encyclopedia also has a page on low back pain (in English and Spanish)
doi:10.1371/journal.pmed.1000047
PMCID: PMC2661253  PMID: 19360087
5.  Patterns and predictors of health service utilization in adolescents with pain: comparison between a community and a clinical pain sample 
There is limited research describing the patterns of healthcare utilization in adolescents with chronic pain. This study describes healthcare utilization in a clinical chronic pain sample, and compares the patterns of service use of this group to a community sample with intermittent pain complaints. We also investigated demographic and clinical factors that predicted healthcare visits and medication use in the clinical sample. Data on 117 adolescents (aged 12-18; n=59 clinical pain sample, n=58 community) were collected. Caregivers and adolescents reported on sociodemographics, medical visits, current medications, pain, activity limitations, and depression. As hypothesized, the clinical pain sample had higher rates of healthcare consultation on all types of medical visits (general, specialty care, complementary medicine, mental health, OT/PT), and higher medication use compared to the community sample. Regression analyses revealed that higher annual income, greater pain frequency, and higher levels of caregiver reported activity limitations were associated with a greater number of healthcare visits for the total sample. Within the clinical pain sample, higher pain frequency and greater activity limitations (caregiver-report) predicted more specialty care visits. Additionally, higher income and greater levels of depressive symptoms predicted a higher number of prescribed medications.
Perspective
This study contributes to the limited available data on health service and medication use in a clinical chronic pain sample versus a community sample of adolescents. We also identify clinical factors (pain frequency, parent-reported activity limitations, depressive symptoms) and demographic factors (gender, income) associated with healthcare utilization.
doi:10.1016/j.jpain.2010.12.011
PMCID: PMC3130816  PMID: 21481647
adolescent; chronic pain; health service use; activity limitations
6.  Pubertal status moderates the association between mother and child laboratory pain tolerance 
BACKGROUND:
There is limited information regarding the relationship between parent and child responses to laboratory pain induction in the absence of experimental manipulation.
OBJECTIVES:
To assess the association between responses to cold and pressure pain tasks in 133 nonclinical mothers and children (mean age 13.0 years; 70 girls), and the moderating effects of child sex and pubertal status on these mother-child relationships.
METHODS:
Mothers and children independently completed the cold and pressure pain tasks. Multiple linear regression analyses examined the association between mothers’ and children’s laboratory pain responses. The moderating effects of child sex and pubertal status were tested in the linear models by examining the interaction among mother laboratory pain responses, and child sex and pubertal status.
RESULTS:
Mothers’ cold pain anticipatory anxiety and pressure pain intensity were associated with children’s pressure pain anticipatory anxiety. Mothers’ pressure pain tolerance was associated with children’s pain tolerance for both the cold and pressure pain tasks. Mothers’ cold pain tolerance was associated with children’s pressure pain tolerance. Pubertal status moderated two of the three significant mother-child pain tolerance relationships, such that the associations held for early pubertal but not for late pubertal children. Sex did not moderate mother-child pain associations.
CONCLUSIONS:
The results indicate that mother-child pain relationships are centred primarily on pain avoidance behaviour, particularly among prepubertal children. These findings may inform interventions focused on pain behaviours, with a particular emphasis on mothers of prepubertal children, to reduce acute pain responses in their children.
PMCID: PMC3938339  PMID: 24367794
Adolescents; Children; Cold pressor task; Experimental pain; Parents
7.  Care-seeking behaviour of adolescents with knee pain: a population-based study among 504 adolescents 
Background
Knee pain is common during adolescence. Adolescents and their parents may think that knee pain is benign and self-limiting and therefore avoid seeking medical care. However, long-term prognosis of knee pain is not favourable and treatment seems to offer greater reductions in pain compared to a “wait-and-see” approach. The purpose of this study was to describe the determinants of care-seeking behaviour among adolescents with current knee pain and investigate what types of treatment are initiated.
Methods
An online questionnaire was forwarded to 2,846 adolescents aged 15–19 in four upper secondary schools. The questionnaire contained questions on age, gender, height, weight, currently painful body regions, frequency of knee pain, health-related quality of life measured by the EuroQol 5-dimensions, sports participation and if they had sought medical care. Adolescents who reported current knee pain at least monthly or more frequently were telephoned. The adolescents were asked about pain duration, onset of knee pain (traumatic or insidious) and if they were currently being treated for their knee pain.
Results
504 adolescents currently reported at least monthly knee pain. 59% of these had sought medical care and 18% were currently under medical treatment . A longer pain duration and higher pain severity increased the odds of seeking medical care. Females with traumatic onset of knee pain were more likely to have sought medical care than females with insidious onset of knee pain. Females with traumatic onset of knee pain and increased pain severity were more likely to be undergoing medical treatment. The most frequently reported treatments were the combination of exercises and orthotics (68% of those undergoing medical treatment).
Conclusion
Females with insidious onset of knee pain do not seek medical care as often as those with traumatic onset and adolescents of both genders with insidious onset are less likely to be under medical treatment. These findings are important as knee pain with insidious onset has similar consequences as knee pain with traumatic onset regarding pain severity, pain duration and reductions in health-related quality of life.
doi:10.1186/1471-2474-14-225
PMCID: PMC3729825  PMID: 23899043
Adolescents; Knee pain; Care-seeking; Treatment
8.  Sex Differences in the Association Between Cortisol Concentrations and Laboratory Pain Responses in Healthy Children 
Gender medicine  2009;6(Suppl 2):193-207.
Background
Research in adult populations has highlighted sex differences in cortisol concentrations and laboratory pain responses, with men exhibiting higher cortisol concentrations and reduced pain responses compared with women. Yet, less is known about the relationship of cortisol concentrations to pain in children.
Objective
This study examined associations between sex, cortisol, and pain responses to laboratory pain tasks in children.
Methods
Salivary cortisol samples from subjects aged 8 to 18 years were obtained at baseline after entering the laboratory (SCb), after the completion of all pain tasks (SC1), and at the end of the session (SC2), 20 minutes later. Blood cortisol samples were also taken after completion of the pain tasks (BC1) and at the end of the session (BC2), 20 minutes later. Subjects completed 3 counterbalanced laboratory pain tasks: pressure, heat, and cold pressor tasks. Pain measures included pain tolerance, and self-reported pain intensity and unpleasantness for all 3 tasks.
Results
The study included 235 healthy children and adolescents (119 boys, 116 girls; mean age, 12.7 years; range, 8–18 years; 109 [46.4%] were in early puberty; 94 [40.0%] white). Salivary and blood cortisol levels were highly correlated with each other. Salivary cortisol levels for the total sample and for boys and girls declined significantly from SCb to SC1 (P < 0.01), although there were no significant changes from SC1 to SC2. No significant sex differences in salivary or blood cortisol levels were evident at any assessment point. Separate examination of the cortisol–laboratory pain response relationships by sex (controlling for age and time of day) suggested different sex-specific patterns. Higher cortisol levels were associated with lower pain reactivity (ie, increased pressure tolerance) among boys compared with girls at SC1, SC2, and BC1 (SC1: r = 0.338, P = 0.003; SC2: r = 0.271, P = 0.020; and BC1: r = 0.261, P = 0.026). However, higher cortisol levels were related to higher pain response (ie, increased cold intensity [BC2: r = 0.229, P = 0.048] and unpleasantness [BC1: r = 0.237, P = 0.041]) in girls compared with boys.
Conclusions
These findings suggest important sex differences in cortisol–pain relationships in children and adolescents. Cortisol levels were positively associated with increased pain tolerance in boys and increased pain sensitivity in girls.
doi:10.1016/j.genm.2009.03.001
PMCID: PMC3486740  PMID: 19406369
pain; children; cortisol; sex differences
9.  Assessing Causality in the Association between Child Adiposity and Physical Activity Levels: A Mendelian Randomization Analysis 
PLoS Medicine  2014;11(3):e1001618.
Here, Timpson and colleagues performed a Mendelian Randomization analysis to determine whether childhood adiposity causally influences levels of physical activity. The results suggest that increased adiposity causes a reduction in physical activity in children; however, this study does not exclude lower physical activity also leading to increasing adiposity.
Please see later in the article for the Editors' Summary
Background
Cross-sectional studies have shown that objectively measured physical activity is associated with childhood adiposity, and a strong inverse dose–response association with body mass index (BMI) has been found. However, few studies have explored the extent to which this association reflects reverse causation. We aimed to determine whether childhood adiposity causally influences levels of physical activity using genetic variants reliably associated with adiposity to estimate causal effects.
Methods and Findings
The Avon Longitudinal Study of Parents and Children collected data on objectively assessed activity levels of 4,296 children at age 11 y with recorded BMI and genotypic data. We used 32 established genetic correlates of BMI combined in a weighted allelic score as an instrumental variable for adiposity to estimate the causal effect of adiposity on activity.
In observational analysis, a 3.3 kg/m2 (one standard deviation) higher BMI was associated with 22.3 (95% CI, 17.0, 27.6) movement counts/min less total physical activity (p = 1.6×10−16), 2.6 (2.1, 3.1) min/d less moderate-to-vigorous-intensity activity (p = 3.7×10−29), and 3.5 (1.5, 5.5) min/d more sedentary time (p = 5.0×10−4). In Mendelian randomization analyses, the same difference in BMI was associated with 32.4 (0.9, 63.9) movement counts/min less total physical activity (p = 0.04) (∼5.3% of the mean counts/minute), 2.8 (0.1, 5.5) min/d less moderate-to-vigorous-intensity activity (p = 0.04), and 13.2 (1.3, 25.2) min/d more sedentary time (p = 0.03). There was no strong evidence for a difference between variable estimates from observational estimates. Similar results were obtained using fat mass index. Low power and poor instrumentation of activity limited causal analysis of the influence of physical activity on BMI.
Conclusions
Our results suggest that increased adiposity causes a reduction in physical activity in children and support research into the targeting of BMI in efforts to increase childhood activity levels. Importantly, this does not exclude lower physical activity also leading to increased adiposity, i.e., bidirectional causation.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The World Health Organization estimates that globally at least 42 million children under the age of five are obese. The World Health Organization recommends that all children undertake at least one hour of physical activity daily, on the basis that increased physical activity will reduce or prevent excessive weight gain in children and adolescents. In practice, while numerous studies have shown that body mass index (BMI) shows a strong inverse correlation with physical activity (i.e., active children are thinner than sedentary ones), exercise programs specifically targeted at obese children have had only very limited success in reducing weight. The reasons for this are not clear, although environmental factors such as watching television and lack of exercise facilities are traditionally blamed.
Why Was This Study Done?
One of the reasons why obese children do not lose weight through exercise might be that being fat in itself leads to a decrease in physical activity. This is termed reverse causation, i.e., obesity causes sedentary behavior, rather than the other way around. The potential influence of environmental factors (e.g., lack of opportunity to exercise) makes it difficult to prove this argument. Recent research has demonstrated that specific genotypes are related to obesity in children. Specific variations within the DNA of individual genes (single nucleotide polymorphisms, or SNPs) are more common in obese individuals and predispose to greater adiposity across the weight distribution. While adiposity itself can be influenced by many environmental factors that complicate the interpretation of observed associations, at the population level, genetic variation is not related to the same factors, and over the life course cannot be changed. Investigations that exploit these properties of genetic associations to inform the interpretation of observed associations are termed Mendelian randomization studies. This research technique is used to reduce the influence of confounding environmental factors on an observed clinical condition. The authors of this study use Mendelian randomization to determine whether a genetic tendency towards high BMI and fat mass is correlated with reduced levels of physical activity in a large cohort of children.
What Did the Researchers Do and Find?
The researchers looked at a cohort of children from a large long-term health research project (the Avon Longitudinal Study of Parents and Children). BMI and total body fat were recorded. Total daily activity was measured via a small movement-counting device. In addition, the participants underwent genotyping to detect the presence of several SNPs known to be linked to obesity. For each child a total BMI allelic score was determined based on the number of obesity-related genetic variants carried by that individual. The association between obesity and reduced physical activity was then studied in two ways. Direct correlation between actual BMI and physical activity was measured (observational data). Separately, the link between BMI allelic score and physical activity was also determined (Mendelian randomization or instrumental variable analysis). The observational data showed that boys were more active than girls and had lower BMI. Across both sexes, a higher-than-average BMI was associated with lower daily activity. In genetic analyses, allelic score had a positive correlation with BMI, with one particular SNP being most strongly linked to high BMI and total fat mass. A high allelic score for BMI was also correlated with lower levels of daily physical activity. The authors conclude that children who are obese and have an inherent predisposition to high BMI also have a propensity to reduced levels of physical activity, which may compound their weight gain.
What Do These Findings Mean?
This study provides evidence that being fat is in itself a risk factor for low activity levels, separately from external environmental influences. This may be an example of “reverse causation,” i.e., high BMI causes a reduction in physical activity. Alternatively, there may be a bidirectional causality, so that those with a genetic predisposition to high fat mass exercise less, leading to higher BMI, and so on, in a vicious circle. A significant limitation of the study is that validated allelic scores for physical activity are not available. Thus, it is not possible to determine whether individuals with a high allelic score for BMI also have a propensity to exercise less, or whether it is simply the circumstance of being overweight that discourages activity. This study does suggest that trying to persuade obese children to lose weight by exercising more is likely to be ineffective unless additional strategies to reduce BMI, such as strict diet control, are also implemented.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001618.
The US Centers for Disease Control and Prevention provides obesity-related statistics, details of prevention programs, and an overview on public health strategy in the United States
A more worldwide view is given by the World Health Organization
The UK National Health Service website gives information on physical activity guidelines for different age groups
The International Obesity Task Force is a network of organizations that seeks to alert the world to the growing health crisis threatened by soaring levels of obesity
MedlinePlus—which brings together authoritative information from the US National Library of Medicine, National Institutes of Health, and other government agencies and health-related organizations—has a page on obesity
Additional information on the Avon Longitudinal Study of Parents and Children is available
The British Medical Journal has an article that describes Mendelian randomization
doi:10.1371/journal.pmed.1001618
PMCID: PMC3958348  PMID: 24642734
10.  Parent and child anxiety sensitivity: Relationship to children’s experimental pain responsivity 
Anxiety sensitivity (AS) or fear of anxiety sensations has been linked to childhood learning history for somatic symptoms, suggesting that parental AS may impact children’s responses to pain. Using structural equation modeling (SEM), we tested a conceptual model in which parent AS predicted child AS, which in turn predicted a hypothesized latent construct consisting of children’s pain intensity ratings for three laboratory pain tasks (cold pressor, thermal heat and pressure). This conceptual model was tested in 211 non-clinical parent-child pairs (104 girls, mean age = 12.4 years; 178 mothers). Our model was supported in girls only indicating that the sex of the child moderated the hypothesized relationships. Thus, parent AS was related to child laboratory pain intensity via its contribution to child AS in girls but not in boys. In girls, 42% of the effect of parent AS on laboratory pain intensity was explained via child AS. In boys, there was no clear link between parent AS and child AS, although child AS was predictive of experimental pain intensity across sex. Our results are consistent with the notion that parent AS may operate via healthy girls’ own fear of anxiety symptoms to influence their responses to laboratory pain stimuli.
Perspective-The present study highlights sex differences in the links among parent and child anxiety sensitivity (AS; fear of anxiety sensations) and children’s experimental pain responses. Among girls, childhood learning history related to somatic symptoms may be a particularly salient factor in the development of AS and pain responsivity.
doi:10.1016/j.jpain.2005.12.004
PMCID: PMC1540407  PMID: 16632321
anxiety sensitivity; laboratory pain; children; adolescents; parent; sex differences
11.  Parents' responses to symptoms of respiratory tract infection in their children 
Abstract
Background
Little is known about the determinants of parental response when children appear to have a respiratory tract infection (RTI). Our objective was to identify what factors predict that parents will seek medical consultation.
Methods
In a prospective cohort study we consecutively recruited 400 children aged 2 months to 12 years from the urban, largely middle-class, primary-care practices of 7 pediatricians in Toronto. Baseline demographic data were collected and the children followed by telephone inquiry until an RTI developed or 6 months elapsed. Data about any medical consultation for the RTI were collected. The parents completed a questionnaire on clinical features and parental interpretations and concerns. Potential predictors of consultation were organized into 4 domains: family factors, principal complaints, functional burden of illness (determined with a validated measure, the Canadian Acute Respiratory Illness and Flu Scale [CARIFS]) and parental interpretation of the illness. Key variables for each domain were derived by endorsement, correlation and combination, and univariate association with the outcome (medical consultation). A model was created to identify independent predictors of consultation.
Results
Of the 383 children (96%) for whom the study was completed, 275 (72%) had symptoms of an RTI within 6 months after recruitment. Medical consultation was sought for 140 (56%) of the 251 for whom further data were available. The questionnaire data and follow up were complete for 197 (78%) of the 251. Children with earaches compared to children without were more likely to be taken to a physician (odds ratio [OR] 10.2; 95% confidence interval [CI] 2.8–37.4), as were children with high fever (temperature > 40°C) compared to children with no fever or fever ≤ 40°C (OR 3.2; 95% CI 1.2–8.6). Parents who rated their children as having a complaint that was severe or persisting for more than 24 hours were more likely to see a physician than parents who rated their children as having no complaints (OR 8.5; 95% CI 2.3–32.0). Parental concern that the illness had an unusual course, with prolonged duration or deterioration (OR 5.7; 95% CI 1.3–24.8), that the child had a specific illness (OR 2.9; 95% CI 1.1–7.7) or that specific treatment was needed (OR 5.0; 95% CI 1.1–23.1), compared to children with no illnesses or need for treatment, also predicted consultation with a physician. Parents' postsecondary education (OR 4.0; 95% CI 1.1–14.6), compared to parents with less than postsecondary education, was the only parental factor that independently predicted taking a child to see a physician. Child's age 48 months or less was the only child factor that independently predicted physician consultation (0–6 months, OR 9.2, 95% CI 1.4–58.1; 7–12 months, OR 17.3, 95% CI 2.0–147.2; 13–24 months, OR 9.2, 95% CI 1.3–63.6; 25–48 months, OR 5.2, 95% CI 0.8–34.4). Neither family demographics nor functional burden of illness predicted consultation.
Interpretation
Generally, parents choose reasonable criteria for seeking physician advice. However, their perceptions and interpretations may be based in part on limited understanding of some factors. Further research is necessary to determine how these findings can be used to improve anticipatory guidance to parents and better address parental concerns.
PMCID: PMC139314  PMID: 12515781
12.  Expression of pain among Mi’kmaq children in one Atlantic Canadian community: a qualitative study 
CMAJ Open  2014;2(3):E133-E138.
Background
First Nation children have the highest rates of pain-related conditions among Canadian children, yet there is little research on how this population expresses its pain or how and whether the pain is successfully treated. The aim of this study was to understand how Mi’kmaq children express pain and how others interpret it.
Methods
We conducted a qualitative ethnographic study in a large Canadian Mi’kmaq community using interviews and conversation sessions. Participants included children and youth (n = 76), parents (n = 12) teachers (n = 7), elders (n = 6) and health care professionals (n = 13).
Results
Interpretive descriptive analysis was used and themes regarding pain expression, care seeking and pain management were identified. Pain expression included stoicism and hiding behaviour, and, when pain was discussed, it was via storytelling and descriptive language, such as similes. Participants reported feeling unheard, stereotyped and frustrated when they sought pain care. Frustration led to avoidance of seeking further care, perceptions of racism and repeat visits because of unsuccessful previous treatment. Participants voiced concerns about the utility of the numeric and faces pain scales to describe pain meaningfully. Positive encounters occurred when participants felt respected and heard.
Interpretation
Mi’kmaq children are stoic and often hide their pain. Community members feel frustrated and discriminated against when their pain is not identified, and conventional pain assessment tools may not be useful. If clinicians consider cultural context, build trust and allow for additional time to assess pain via storytelling or word descriptions as well as a family-centred approach, better pain care may occur.
doi:10.9778/cmajo.20130086
PMCID: PMC4117360  PMID: 25114895
13.  Health-related quality of life in girls and boys with juvenile idiopathic arthritis: self- and parental reports in a cross-sectional study 
Background
Juvenile Idiopathic Arthritis (JIA) affects children and adolescents with both short-term and long-term disability. These children also report lower health-related quality of life (HRQOL) compared to their healthy peers. However, there seems to be some discrepancies between self- and parent-reports, and gender differences need to be further studied. This study aims to describe HRQOL in girls and boys with JIA, and to explore gender differences in self-reports compared to parent-reports of HRQOL in children with JIA.
Methods
Fifty-three children and adolescents with JIA (70% girls and 30% boys) with a median age of 14 years (8–18 years), and their parents, participated in this cross-sectional study in Sweden. Data was systematically collected prior to ordinary visits at a Pediatric outpatient clinic, during a period of 16 months (2009–2010). Disability was assessed with the Childhood Health Assessment Questionnaire (CHAQ), and disease activity by physicians’ assessments and Erythrocyte Sedimentation Rate (ESR). The Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL) was used to assess self- and parent-reports of HRQOL in the child.
Results
In this sample of children with generally low disease activity and mild to moderate disability, more than half of the children experienced suboptimal HRQOL, equally in girls and boys. Significant differences between self- and parent-reports of child HRQOL were most evident among girls, with lower parent-reports regarding the girl’s physical- and psychosocial health as well as in the total HRQOL score. Except for the social functioning subscale, where parents’ reports were higher compared to their sons, there were no significant differences between boys- and parent-reports.
Conclusions
More than half of the girls and boys experienced suboptimal HRQOL in this sample, with no gender differences. However, there were differences between self- and parent-reports of child HRQOL, with most significant differences found among the girls. Thus, differences between self- and parent-reports of child HRQOL must be taken into account in clinical settings, especially among girls with JIA.
doi:10.1186/1546-0096-10-33
PMCID: PMC3523024  PMID: 22985358
Adolescent; Child; Gender; Parents; Pediatrics; Questionnaire
14.  Relationship of child perceptions of maternal pain to children's laboratory and non-laboratory pain 
Previous research has established links between parent and child pain. Yet little is known about sex-specific parent-child pain relationships in a non-clinical population. A sample of 186 children aged 8–18 years (49% female) provided information on maternal and self bodily-pain, assessed by asking children about the presence and location of bodily pain experienced. Children also completed three laboratory pain tasks and reported on cold pressor pain intensity, pressure pain intensity and heat pain intensity. The presence of child-reported maternal pain was consistently correlated with daughters’ bodily and laboratory pain, but not with sons’ pain in bivariate analyses. Multivariate analyses controlling for child age and maternal psychological distress indicated that children of mothers with bodily pain reported more total bodily pain sites as well as greater pressure and cold pain intensity, relative to children of mothers without bodily pain. For cold pain intensity, these results differed for boys vs. girls, in that daughters reporting maternal pain evidenced significantly higher cold pain intensity compared to daughters not reporting maternal pain. No such differences were found for boys. The findings suggest that children’s perceptions of maternal pain may play a role in influencing children’s own experience of pain and that maternal pain models may affect boys and girls differently.
PMCID: PMC2642517  PMID: 18592057
pain; sex differences; social learning; children
15.  Relationship of child perceptions of maternal pain to children’s laboratory and nonlaboratory pain 
Previous research has established links between parent and child pain. However, little is known about sex-specific parent-child pain relationships in a nonclinical population. A sample of 186 children aged eight to 18 years (49% female) provided information on maternal and self bodily pain, assessed by asking children about the presence and location of bodily pain experienced. Children also completed three laboratory pain tasks and reported on cold pressor pain intensity, pressure pain intensity and heat pain intensity. The presence of child-reported maternal pain was consistently correlated with daughters’ bodily and laboratory pain, but not with sons’ pain in bivariate analyses. Multivariate analyses controlling for child age and maternal psychological distress indicated that children of mothers with bodily pain reported more total bodily pain sites as well as greater pressure and cold pain intensity, relative to children of mothers without bodily pain. For cold pain intensity, these results differed for boys versus girls, in that daughters reporting maternal pain evidenced significantly higher cold pain intensity compared with daughters not reporting maternal pain. No such differences were found for boys. The findings suggest that children’s perceptions of maternal pain may play a role in influencing children’s own experience of pain, and that maternal pain models may affect boys and girls differently.
PMCID: PMC2642517  PMID: 18592057
Children; Pain; Sex differences; Social learning
16.  Preliminary validation of a self-efficacy scale for child functioning despite chronic pain (child and parent versions) 
Pain  2006;125(1-2):35-42.
Despite frequent targeting of health beliefs in pediatric chronic pain treatment interventions, there are currently no reliable and valid self-efficacy measures for children with chronic pain and their parents. The current study examined the psychometric properties of parent and child versions of a self-efficacy measure related to the child functioning normally when in pain. Pediatric pain patients, 9–18 years of age, and a caregiver completed questionnaires before an initial tertiary care clinic appointment. The 67 patients in our sample had an average of 1.7 pain locations, including abdominal pain (43.3%), headaches (50.7%), body pain (25.4%), back pain (23.9%), limb pain (20.9%), and/or chest pain (9.0%). Reliability for the new measures was excellent; the Cronbach's alpha was .89 for the 7 child items and .90 for the 7 parent items. Strong evidence for construct validity was also obtained as 23 of the 27 hypothesized correlations were confirmed. As predicted, parent and child ratings of increased self-efficacy for the child functioning normally when in pain were significantly correlated with each other, and to parent reports of fewer problems functioning due to physical or emotional problems; parent reports of fewer somatic, behavioral or emotional symptoms; parent reports of increased self-esteem, and unrelated to child pain, age and gender. Additionally, child ratings of increased self-efficacy were significantly correlated with child reports of increased self-esteem and fewer somatic symptoms. Replication with a larger sample size, more complex modeling, and prospective studies are indicated.
doi:10.1016/j.pain.2006.04.026
PMCID: PMC2394279  PMID: 16740360
Pediatric chronic pain; Self-efficacy; Health belief measures
17.  How Well Do Clinical Pain Assessment Tools Reflect Pain in Infants? 
PLoS Medicine  2008;5(6):e129.
Background
Pain in infancy is poorly understood, and medical staff often have difficulty assessing whether an infant is in pain. Current pain assessment tools rely on behavioural and physiological measures, such as change in facial expression, which may not accurately reflect pain experience. Our ability to measure cortical pain responses in young infants gives us the first opportunity to evaluate pain assessment tools with respect to the sensory input and establish whether the resultant pain scores reflect cortical pain processing.
Methods and Findings
Cortical haemodynamic activity was measured in infants, aged 25–43 wk postmenstrual, using near-infrared spectroscopy following a clinically required heel lance and compared to the magnitude of the premature infant pain profile (PIPP) score in the same infant to the same stimulus (n = 12, 33 test occasions). Overall, there was good correlation between the PIPP score and the level of cortical activity (regression coefficient = 0.72, 95% confidence interval [CI] limits 0.32–1.11, p = 0.001; correlation coefficient = 0.57). Of the different PIPP components, facial expression correlated best with cortical activity (regression coefficient = 1.26, 95% CI limits 0.84–1.67, p < 0.0001; correlation coefficient = 0.74) (n = 12, 33 test occasions). Cortical pain responses were still recorded in some infants who did not display a change in facial expression.
Conclusions
While painful stimulation generally evokes parallel cortical and behavioural responses in infants, pain may be processed at the cortical level without producing detectable behavioural changes. As a result, an infant with a low pain score based on behavioural assessment tools alone may not be pain free.
Rebeccah Slater and colleagues show that although painful stimulation generally evokes parallel cortical and behavioral responses in infants, pain may produce cortical responses without detectable behavioral changes.
Editors' Summary
Background.
Pain is a sensory and emotional experience. It is normally triggered by messages transmitted from specialized receptors (nociceptors) in the body to integrative centers in the spinal cord and brainstem and on to the brain, where it undergoes higher sensory and cognitive analysis, allowing the body to respond appropriately to the stimuli. While the experience of pain may be considered to be unpleasant, it is a useful tool in communicating to us and to others that there is something wrong with our bodies. Ultimately, these responses help restrict further damage to the body and start the process of healing.
In a clinical setting, the ability to communicate about pain allows an individual to seek strategies to ease the pain, such as taking analgesics. Being unable to effectively communicate one's experience of pain leaves the individual vulnerable to prolonged suffering. One such vulnerable group is infants.
Ignored and untreated pain in infants has been shown to have immediate and long-term effects as a result of structural and physiological changes within the nervous system. For example, the body responds to untreated pain by increased release of stress hormones, which may be associated with increased morbidity and mortality in the short term. Long-term effects of pain may include altered pain perception, chronic pain syndromes, and somatic complaints such as sleep disturbances, feeding problems, and inability to self-regulate in response to internal and external stressors. It has been proposed that attention deficit disorders, learning disorders, and behavioral problems in later childhood may be linked to repetitive pain in the preterm infant.
Why Was This Study Done?
Until as recently as the 1990s, newborns in some clinical centres underwent surgery with minimal anesthesia. Also, newborns received little or no pain management postoperatively or for painful procedures such as lumbar punctures or circumcisions. Since then, there has been growing awareness amongst clinicians that pain may be experienced from the earliest stages of postnatal life and that inadequate analgesia may lead to the type of long-term consequences mentioned above. However, gauging how much pain infants and young children are experiencing remains a substantial challenge. The researchers in this study wanted to assess the association between cortical pain responses in young infants and currently used tools for the assessment of pain in these infants. These current tools are based on behavioral and physiological measures, such as change in facial expression, and it is possible that these tools do not give an adequate measure of pain especially in infants born preterm.
What Did the Researchers Do and Find?
Twelve clinically stable infants were studied on 33 occasions when they required a heel lance to obtain a blood sample for a clinical reason. The researchers examined the relationship between brain activity and a clinical pain score, calculated using the premature infant pain profile (PIPP) in response to a painful event. Activity in the somatosensory cortex was measured noninvasively by near-infrared spectroscopy, which measures brain regional changes in oxygenated and deoxygenated hemoglobin concentration. The PIPP is a well-established pain score that ascribes a value to infant behavior such as change in facial expression.
They found that changes in brain activity in response to a painful stimulus were related to the PIPP scores. These changes were more strongly linked to the behavioral components of the PIPP, e.g., facial expression, than physiological components, e.g., heart rate. They also found that a positive brain response could occur in the absence of any facial expression.
What Do These Findings Mean?
Behaviors to communicate pain require motor responses to sensory and emotional stimuli. The maturity of this complex system in infants is not clearly understood. The results of this study raise further awareness of the ability of infants to experience pain and highlight the possibility that pain assessment based on behavioral tools alone may underestimate the pain response in infants.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050129.
Important papers on pain in human neonates are discussed in the open access Paediatric Pain Letter with links to original articles
The Institute of Child Health in London has a Web site describing a three-year international project on improving the assessment of pain in hospitalized children, with many useful links
The International Association for the Study of Pain (IASP) provides accurate and up-to-date information and links about pain mechanisms and treatment
doi:10.1371/journal.pmed.0050129
PMCID: PMC2504041  PMID: 18578562
18.  Psychological interventions for parents of children and adolescents with chronic illness 
Background
Psychological therapies have been developed for parents of children and adolescents with a chronic illness. Such therapies include parent only or parent and child/adolescent, and are designed to treat parent behaviour, parent mental health, child behaviour/disability, child mental health, child symptoms and/or family functioning. No comprehensive, meta-analytic reviews have been published in this area.
Objectives
To evaluate the effectiveness of psychological therapies that include coping strategies for parents of children/adolescents with chronic illnesses (painful conditions, cancer, diabetes mellitus, asthma, traumatic brain injury, inflammatory bowel diseases, skin diseases or gynaecological disorders). The therapy will aim to improve parent behaviour, parent mental health, child behaviour/disability, child mental health, child symptoms and family functioning.
Search methods
We searched CENTRAL, MEDLINE, EMBASE and PsyclNFO for randomised controlled trials (RCTs) of psychological interventions that included parents of children and adolescents with a chronic illness. The initial search was from inception of these databases to June 2011 and we conducted a follow-up search from June 2011 to March 2012. We identified additional studies from the reference list of retrieved papers and from discussion with investigators.
Selection criteria
Included studies were RCTs of psychological interventions that delivered treatment to parents of children and adolescents (under 19 years of age) with a chronic illness compared to active control, wait list control or treatment as usual. We excluded studies if the parent component was a coaching intervention, the aim of the intervention was health prevention/promotion, the comparator was a pharmacological treatment, the child/adolescent had an illness not listed above or the study included children with more than one type of chronic illness. Further to this, we excluded studies when the sample size of either comparator group was fewer than 10 at post-treatment.
Data collection and analysis
We included 35 RCTs involving a total of 2723 primary trial participants. Two review authors extracted data from 26 studies. We analysed data using two categories. First, we analysed data by each medical condition across all treatment classes at two time points (immediately post-treatment and the first available follow-up). Second, we analysed data by each treatment class (cognitive behavioural therapy (CBT), family therapy (FT), problem solving therapy (PST) and multisystemic therapy (MST)) across all medical conditions at two time points (immediately post-treatment and the first available follow-up). We assessed treatment effectiveness on six possible outcomes: parent behaviour, parent mental health, child behaviour/disability, child mental health, child symptoms and family functioning.
Main results
Across all treatment types, psychological therapies that included parents significantly improved child symptoms for painful conditions immediately post-treatment. Across all medical conditions, cognitive behavioural therapy (CBT) significantly improved child symptoms and problem solving therapy significantly improved parent behaviour and parent mental health immediately post-treatment. There were no other effects at post-treatment or follow-up. The risk of bias of included studies is described.
Authors' conclusions
There is no evidence on the effectiveness of psychological therapies that include parents in most outcome domains of functioning, for a large number of common chronic illnesses in children. There is good evidence for the effectiveness of including parents in psychological therapies that reduce pain in children with painful conditions. There is also good evidence for the effectiveness of CBT that includes parents for improving the primary symptom complaints when available data were included from chronic illness conditions. Finally, there is good evidence for the effectiveness of problem solving therapy delivered to parents on improving parent problem solving skills and parent mental health. All effects are immediately post-treatment. There are no significant findings for any treatment effects in any condition at follow-up.
doi:10.1002/14651858.CD009660.pub2
PMCID: PMC3551454  PMID: 22895990
19.  A Systematic Review of Studies That Aim to Determine Which Outcomes to Measure in Clinical Trials in Children  
PLoS Medicine  2008;5(4):e96.
Background
In clinical trials the selection of appropriate outcomes is crucial to the assessment of whether one intervention is better than another. Selection of inappropriate outcomes can compromise the utility of a trial. However, the process of selecting the most suitable outcomes to include can be complex. Our aim was to systematically review studies that address the process of selecting outcomes or outcome domains to measure in clinical trials in children.
Methods and Findings
We searched Cochrane databases (no date restrictions) in December 2006; and MEDLINE (1950 to 2006), CINAHL (1982 to 2006), and SCOPUS (1966 to 2006) in January 2007 for studies of the selection of outcomes for use in clinical trials in children. We also asked a group of experts in paediatric clinical research to refer us to any other relevant studies. From these articles we extracted data on the clinical condition of interest, description of the method used to select outcomes, the people involved in the selection process, the outcomes selected, and limitations of the method as defined by the authors. The literature search identified 8,889 potentially relevant abstracts. Of these, 70 were retrieved, and 25 were included in the review. These studies described the work of 13 collaborations representing various paediatric specialties including critical care, gastroenterology, haematology, psychiatry, neurology, respiratory paediatrics, rheumatology, neonatal medicine, and dentistry. Two groups utilised the Delphi technique, one used the nominal group technique, and one used both methods to reach a consensus about which outcomes should be measured in clinical trials. Other groups used semistructured discussion, and one group used a questionnaire-based survey. The collaborations involved clinical experts, research experts, and industry representatives. Three groups involved parents of children affected by the particular condition.
Conclusions
Very few studies address the appropriate choice of outcomes for clinical research with children, and in most paediatric specialties no research has been undertaken. Among the studies we did assess, very few involved parents or children in selecting outcomes that should be measured, and none directly involved children. Research should be undertaken to identify the best way to involve parents and children in assessing which outcomes should be measured in clinical trials.
Ian Sinha and colleagues show, in a systematic review of published studies, that there are very few studies that address the appropriate choice of outcomes for clinical research with children.
Editors' Summary
Background.
When adult patients are given a drug for a disease by their doctors, they can be sure that its benefits and harms will have been carefully studied in clinical trials. Clinical researchers will have asked how well the drug does when compared to other drugs by giving groups of patients the various treatments and determining several “outcomes.” These are measurements carefully chosen in advance by clinical experts that ensure that trials provide as much information as possible about how effectively a drug deals with a specific disease and whether it has any other effects on patients' health and daily life. The situation is very different, however, for pediatric (child) patients. About three-quarters of the drugs given to children are “off-label”—they have not been specifically tested in children. The assumption used to be that children are just small people who can safely take drugs tested in adults provided the dose is scaled down. However, it is now known that children's bodies handle many drugs differently from adult bodies and that a safe dose for an adult can sometimes kill a child even after scaling down for body size. Consequently, regulatory bodies in the US, Europe, and elsewhere now require clinical trials to be done in children and drugs for pediatric use to be specifically licensed.
Why Was This Study Done?
Because children are not small adults, the methodology used to design trials involving children needs to be adapted from that used to design trials in adult patients. In particular, the process of selecting the outcomes to include in pediatric trials needs to take into account the differences between adults and children. For example, because children's brains are still developing, it may be important to include outcome measures that will detect any effect that drugs have on intellectual development. In this study, therefore, the researchers undertook a systematic review of the medical literature to discover how much is known about the best way to select outcomes in clinical trials in children.
What Did the Researchers Do and Find?
The researchers used a predefined search strategy to identify all the studies published since 1950 that examined the selection of outcomes in clinical trials in children. They also asked experts in pediatric clinical research for details of relevant studies. Only 25 studies, which covered several pediatric specialties and were published by 13 collaborative groups, met the strict eligibility criteria laid down by the researchers for their systematic review. Several approaches previously used to choose outcomes in clinical trials in adults were used in these studies to select outcomes. Two groups used the “Delphi” technique, in which opinions are sought from individuals, collated, and fed back to the individuals to generate discussion and a final, consensus agreement. One group used the “nominal group technique,” which involves the use of structured face-to-face discussions to develop a solution to a problem followed by a vote. Another group used both methods. The remaining groups (except one that used a questionnaire) used semistructured discussion meetings or workshops to decide on outcomes. Although most of the groups included clinical experts, people doing research on the specific clinical condition under investigation, and industry representatives, only three groups asked parents about which outcomes should be included in the trials, and none asked children directly.
What Do These Findings Mean?
These findings indicate that very few studies have addressed the selection of appropriate outcomes for clinical research in children. Indeed, in many pediatric specialties no research has been done on this important topic. Importantly, some of the studies included in this systematic review clearly show that it is inappropriate to use the outcomes used in adult clinical trials in pediatric populations. Overall, although the studies identified in this review provide some useful information on the selection of outcomes in clinical trials in children, further research is urgently needed to ensure that this process is made easier and more uniform. In particular, much more research must be done to determine the best way to involve children and their parents in the selection of outcomes.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050096.
A related PLoSMedicine Perspective article is available
The European Medicines Agency provides information about the regulation of medicines for children in Europe
The US Food and Drug Administration Office of Pediatric Therapeutics provides similar information for the US
The UK Medicines and Healthcare products Regulatory Agency also provides information on why medicines need to be tested in children
The UK Medicines for Children Research Network aims to facilitate the conduct of clinical trials of medicines for children
The James Lind Alliance has been established in the UK to increase patient involvement in medical research issues such as outcome selection in clinical trials
doi:10.1371/journal.pmed.0050096
PMCID: PMC2346505  PMID: 18447577
20.  Weight Status, Parent Reaction, and Self-Concept in Five-Year-Old Girls 
Pediatrics  2001;107(1):46-53.
Objective
This study examined the relationship between weight status and self-concept in a sample of preschool-aged girls and whether parental concern about child overweight or restriction of access to food are associated with negative self-evaluations among girls.
Method
Participants were 197 5-year-old girls and their parents. Girls’ weight status (weight for height percentile) was calculated based on height and weight measurements. Girls’ self-concept was assessed using an individually administered questionnaire. Parents’ concern about their child’s weight status and restriction of their child’s access to food were assessed using a self-report questionnaire.
Results
Girls with higher weight status reported lower body esteem and lower perceived cognitive ability than did girls with lower weight status. Independent of girl’s weight status, higher paternal concern about child overweight was associated with lower perceived physical ability among girls; higher maternal concern about child overweight was associated with lower perceived physical and cognitive ability among girls. Finally, higher maternal restriction of girls’ access to foods was associated with lower perceived physical and cognitive ability among girls with higher weight status but not among girls with lower weight status.
Conclusions
At least as early as age 5 years, lower self-concept is noted among girls with higher weight status. In addition, parents’ concern about their child’s weight status and restriction of access to food are associated with negative self-evaluations among girls. Public health programs that raise parental awareness of childhood overweight without also providing constructive and blame-free alternatives for addressing child weight problems may be detrimental to children’s mental health.
doi:10.1542/peds.107.1.46
PMCID: PMC2533130  PMID: 11134433
21.  Mortality after Parental Death in Childhood: A Nationwide Cohort Study from Three Nordic Countries 
PLoS Medicine  2014;11(7):e1001679.
Jiong Li and colleagues examine mortality rates in children who lost a parent before 18 years old compared with those who did not using population-based data from Denmark, Sweden, and Finland.
Please see later in the article for the Editors' Summary
Background
Bereavement by spousal death and child death in adulthood has been shown to lead to an increased risk of mortality. Maternal death in infancy or parental death in early childhood may have an impact on mortality but evidence has been limited to short-term or selected causes of death. Little is known about long-term or cause-specific mortality after parental death in childhood.
Methods and Findings
This cohort study included all persons born in Denmark from 1968 to 2008 (n = 2,789,807) and in Sweden from 1973 to 2006 (n = 3,380,301), and a random sample of 89.3% of all born in Finland from 1987 to 2007 (n = 1,131,905). A total of 189,094 persons were included in the exposed cohort when they lost a parent before 18 years old. Log-linear Poisson regression was used to estimate mortality rate ratio (MRR). Parental death was associated with a 50% increased all-cause mortality (MRR = 1.50, 95% CI 1.43–1.58). The risks were increased for most specific cause groups and the highest MRRs were observed when the cause of child death and the cause of parental death were in the same category. Parental unnatural death was associated with a higher mortality risk (MRR = 1.84, 95% CI 1.71–2.00) than parental natural death (MRR = 1.33, 95% CI 1.24–1.41). The magnitude of the associations varied according to type of death and age at bereavement over different follow-up periods. The main limitation of the study is the lack of data on post-bereavement information on the quality of the parent-child relationship, lifestyles, and common physical environment.
Conclusions
Parental death in childhood or adolescence is associated with increased all-cause mortality into early adulthood. Since an increased mortality reflects both genetic susceptibility and long-term impacts of parental death on health and social well-being, our findings have implications in clinical responses and public health strategies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
When someone close dies, it is normal to grieve, to mourn the loss of that individual. Initially, people who have lost a loved one often feel numb and disorientated and find it hard to grasp what has happened. Later, people may feel angry or guilty, and may be overwhelmed by feelings of sadness and despair. They may become depressed or anxious and may even feel suicidal. People who are grieving can also have physical reactions to their loss such as sleep problems, changes in appetite, and illness. How long bereavement—the period of grief and mourning after a death—lasts and how badly it affects an individual depends on the relationship between the individual and the deceased person, on whether the death was expected, and on how much support the mourner receives from relatives, friends, and professionals.
Why Was This Study Done?
The loss of a life-partner or of a child is associated with an increased risk of death (mortality), and there is also some evidence that the death of a parent during childhood leads to an increased mortality risk in the short term. However, little is known about the long-term impact on mortality of early parental loss or whether the impact varies with the type of death—a natural death from illness or an unnatural death from external causes such as an accident—or with the specific cause of death. A better understanding of the impact of early bereavement on mortality is needed to ensure that bereaved children receive appropriate health and social support after a parent's death. Here, the researchers undertake a nationwide cohort study in three Nordic countries to investigate long-term and cause-specific mortality after parental death in childhood. A cohort study compares the occurrence of an event (here, death) in a group of individuals who have been exposed to a particular variable (here, early parental loss) with the occurrence of the same event in an unexposed cohort.
What Did the Researchers Do and Find?
The researchers obtained data on everyone born in Denmark from 1968 to 2008 and in Sweden from 1973 to 2006, and on most people born in Finland from 1987 to 2007 (more than 7 million individuals in total) from national registries. They identified 189,094 individuals who had lost a parent between the age of 6 months and 18 years. They then estimated the mortality rate ratio (MRR) associated with parental death during childhood or adolescence by comparing the number of deaths in this exposed cohort (after excluding children who died on the same day as a parent or shortly after from the same cause) and in the unexposed cohort. Compared with the unexposed cohort, the exposed cohort had 50% higher all-cause mortality (MRR = 1.50). The risk of mortality in the exposed cohort was increased for most major categories of cause of death but the highest MRRs were seen when the cause of death in children, adolescents, and young adults during follow-up and the cause of parental death were in the same category. Notably, parental unnatural death was associated with a higher mortality risk (MRR = 1.84) than parental natural death (MRR = 1.33). Finally, the exposed cohort had increased all-cause MRRs well into early adulthood irrespective of child age at parental death, and the magnitude of MRRs differed by child age at parental death and by type of death.
What Do These Findings Mean?
These findings show that in three high-income Nordic countries parental death during childhood and adolescence is associated with an increased risk of all-cause mortality into early adulthood, irrespective of sex and age at bereavement and after accounting for baseline characteristics such as socioeconomic status. Part of this association may be due to “confounding” factors—the people who lost a parent during childhood may have shared other unknown characteristics that increased their risk of death. Because the study was undertaken in high-income countries, these findings are unlikely to be the result of a lack of material or health care needs. Rather, the increased mortality among the exposed group reflects both genetic susceptibility and the long-term impacts of parental death on health and social well-being. Given that increased mortality probably only represents the tip of the iceberg of the adverse effects of early bereavement, these findings highlight the need to provide long-term health and social support to bereaved children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001679.
The UK National Health Service Choices website provides information about bereavement, including personal stories; it also provides information about children and bereavement and about young people and bereavement, including links to not-for-profit organizations that support children through bereavement
The US National Cancer Institute has detailed information about dealing with bereavement for the public and for health professionals that includes a section on children and grief (in English and Spanish)
The US National Alliance for Grieving Children promotes awareness of the needs of children and teens grieving a death and provides education and resources for anyone who wants to support them
MedlinePlus provides links to other resources about bereavement (in English and Spanish)
doi:10.1371/journal.pmed.1001679
PMCID: PMC4106717  PMID: 25051501
22.  Obesity in children and adolescents with chronic pain: Associations with pain and activity limitations 
The Clinical journal of pain  2010;26(8):705-711.
Objectives
Obesity is associated with functional disability in adults with chronic pain, but less is known about obesity among youth with chronic pain. The purpose of this study was to 1) identify the prevalence of overweight and obesity in children and adolescents receiving treatment for chronic pain, and 2) examine associations between Body Mass Index (BMI), pain intensity, and activity limitations in this population.
Methods
Data was obtained from records of 118 patients, ages 8 to 18, seen in a multidisciplinary pediatric pain clinic. Information about age, gender, pain problem, duration and severity, medical diagnoses, medications, height and weight were collected from medical records and intake questionnaires. The CDC’s pediatric BMI calculator was used to obtain percentile and category (underweight, healthy weight, overweight, obese). Children and parents completed the Child Activity Limitations Interview-21 (CALI-21), a self-report measure of activity limitations.
Results
A significantly higher rate of overweight and obesity was observed among youth with chronic pain compared to a normative sample. BMI percentile was predictive of concurrent limitations in vigorous activities, according to parent report.
Discussion
BMI percentile and weight status may contribute to activity limitations among children and adolescents with chronic pain. Weight status is an important factor to consider in the context of treatment of chronic pain and disability in children and adolescents.
doi:10.1097/AJP.0b013e3181e601fa
PMCID: PMC2939953  PMID: 20664337
obesity; Body Mass Index (BMI); activity; pediatric; chronic pain
23.  Parent experiences of inpatient pediatric care in relation to health care delivery and sociodemographic characteristics: results of a Norwegian national survey 
Background
The national survey of parent experiences with inpatient pediatric care contribute to the Norwegian system of health care quality indicators. This article reports on the statistical association between parent experiences of inpatient pediatric care and aspects of health care delivery, child health status and health outcome as assessed by the parents, and the parents’ sociodemographic characteristics.
Methods
6,160 parents of children who were inpatients at one of Norway’s 20 pediatric departments in 2005 were contacted to take part in a survey that included the Parent Experience of Pediatric Care questionnaire. It includes 25 items that form six scales measuring parent experiences: doctor services, hospital facilities, information discharge, information about examinations and tests, nursing services and organization. The six scales were analyzed using OLS-regression.
Results
3,308 (53.8%) responded. Mean scores ranged from 62.81 (organization) to 72.80 (hospital facilities) on a 0–100 scale where 100 is the best possible experience. Disappointment with staff, unexpected waiting, information regarding new medication, whether the staff were successful in easing the child’s pain, incorrect treatment and number of previous admissions had a statistically significant association with at least five of the PEPC scale scores. Disappointment with staff had the strongest association. Most sociodemographic characteristics had weak or no associations with parent experiences.
Conclusions
The complete relief of the child’s pain, reducing unexpected waiting and disappointment with staff, and providing good information about new medication are aspects of health care that should be considered in initiatives designed to improve parent experiences. In the Norwegian context parent experiences vary little by parents’ sociodemographic characteristics.
doi:10.1186/1472-6963-13-512
PMCID: PMC3866943  PMID: 24325153
Parent experiences; Parent satisfaction; Quality of care; Inpatient pediatric care; Norway
24.  Relationship Between Resting Blood Pressure and Laboratory-Induced Pain Among Healthy Children 
Gender Medicine  2011;8(6):388-398.
Background
Adult studies have demonstrated that increased resting blood pressure (BP) levels correlate with decreased pain sensitivity. However, few studies have examined the relationship between BP and experimental pain sensitivity among children.
Objectives
This study investigated the association between resting BP levels and experimental pain tolerance, intensity, and unpleasantness in healthy children. We also explored whether these BP–pain relationships were age and gender dependent.
Methods
Participants underwent separate 4-trial blocks of cutaneous pressure and thermal pain stimuli, and 1 trial of a cold pain stimulus in counterbalanced order.
Results
A total of 235 healthy children (49.6% female; mean age 12.7 [2.9] years; age range 8–18 years) participated. The study revealed specific gender-based BP–pain relationships. Girls with higher resting systolic BP levels were found to have lower thermal intensity ratings than girls with lower resting systolic BP levels; this relationship was stronger among adolescent girls than among younger girls. Among young girls (8–11 years), those with higher resting diastolic BP (DBP) levels were found to have lower cold intensity and unpleasantness as well as lower thermal intensity ratings than did young girls with lower resting DBP levels; these DBP–pain response relationships were not seen among adolescent girls.
Conclusions
Age, rather than resting BP, was predictive of laboratory pain ratings in boys. The findings suggest that the relationship between BP and experimental pain is age and gender dependent. These aspects of cardiovascular relationships to pain in males and females need further attention to understand their clinical importance.
doi:10.1016/j.genm.2011.07.002
PMCID: PMC3319441  PMID: 22035675
blood pressure; children; gender differences; laboratory pain
25.  Exploring salivary cortisol and recurrent pain in mid-adolescents living in two homes 
BMC psychology  2014;2(1):46.
Background
Each year, around 50.000 children in Sweden experience a separation between their parents. Joint physical custody (JPC), where the child alternates homes between the parents for about equal amount of time, has become a common living arrangement after parental separation. Children in two homes could benefit from everyday contact with both parents and access to both parents’ financial resources. However, children could experience stress from being constantly moving and potentially exposed to parental conflicts. Still, studies on JPC and biological functioning related to stress, are lacking. The aim of this study was to investigate how living arrangements (intact family/JPC) relate to HPA-axis activity and recurrent pain in mid-adolescents.
Methods
Mid-adolescents (106 girls and 51 boys) provided demographic details, self-reports of recurrent pain (headache, stomachache, neck/shoulder and back pain) and salivary samples. Salivary cortisol samples were collected: 1) immediately at awakening, 2) +30 minutes, 3) +60 minutes, and 4) at 8 p.m. The cortisol awakening response (CAR) was computed using an established formula. Additionally, the diurnal decline between the waking and 8 p.m. samples was computed.
Results
Hierarchical multiple regressions showed that living arrangements (intact family/JPC) was not associated with morning cortisol (CAR), the diurnal cortisol decline or with recurrent pain. However, sex was a significant predictor of both cortisol measures and recurrent pain with girls exhibiting a higher cortisol awakening response and a greater diurnal decline value as well as reporting more recurrent pain than did boys.
Conclusions
Living arrangements were not associated with HPA-axis activity or recurrent pain in this group of well-functioning mid-adolescents. Although this study is the first to investigate how living arrangements relate to HPA-axis functioning and additional studies are needed, the tentative findings suggest that these mid-adolescents have adapted to their living arrangements and that other factors play a more pertinent role for HPA-functioning and subjective health.
doi:10.1186/s40359-014-0046-z
PMCID: PMC4269984  PMID: 25566390
HPA-axis activity; Cortisol; Mid-adolescence; Recurrent pain; Joint physical custody

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