Developmental-Behavioral Pediatrics 13 Years After the First Board Certification: Evolving Subspecialty.

OBJECTIVE: To examine and define the evolving subspecialty of developmental-behavioral pediatrics (DBP) by analyzing workforce surveys presubspecialty and postsubspecialty certification. METHODS: In 2015, an electronic workforce survey was sent to the members of the American Academy of Pediatrics Section on DBP and Council on Children with Disabilities and the Society for DBP. Answers from the 1998 survey for respondents with subspecialty fellowship training were compared. RESULTS: Compared with the 1998 group of 265 DBPs, the 368 DBPs in the 2015 group were older, more female, and more diverse. In both groups, ≥80% evaluated and treated autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and developmental delays, but significantly (p < 0.001) fewer cared for children with physical disabilities (e.g., cerebral palsy [58% to 41%], multihandicapped [53% to 39%], neonatal follow-up [47% to 31%], and spina bifida [26% to 13%]) and other disorders (e.g., failure to thrive and obesity/eating disorders [27% to 15%]). Time for new patient and return visits remained the same (1.5 hours and 0.7 hours). Pediatric generalists and family practice physicians initiated most referrals; fewer 2015 DBPs (p < 0.001) reported school districts (83% to 70%) and more reported pediatric subspecialty (57% to 77%; p < 0.001) referrals. Acknowledgment of the need for more community DBP specialists increased from 66% to 80% (p < 0.001). CONCLUSION: Survey data indicated that the workforce is aging and changing. ADHD, ASD, and developmental delays are solidifying as the defining clinical focus of DBP. Current trends can identify training needs, facilitate recruitment, and advocate for system change to support the DBP workforce to respond to the great need.

Autism Spectrum Disorder Parent Report for Outcome Monitoring: A Preliminary Report of Development and Clinical Utility.

OBJECTIVE: Children with autism spectrum disorder (ASD) face challenges across many functional domains. A tool that gathers relevant clinical information before visits, emphasizing symptoms that are likely to change over development and inform clinical interventions, could improve health care quality, allowing for more patient-centered and efficient care. This study evaluated the clinical utility and preliminary psychometrics of the ASD Parent Report for Outcome Monitoring (ASD-PROM), a web-based measure assessing competence in core features of ASD, along with the breadth of concerns and comorbidities that frequently co-occur with ASD. METHODS: An interdisciplinary team drafted the ASD-PROM and made iterative revisions based on parent feedback. Parents of 62 children completed the ASD-PROM before their autism-specialty clinical visit, 53 completed the ASD-PROM twice, and 48 completed the Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) concurrently. Parents (n = 25) and clinicians (n = 13) completed postvisit surveys to assess utility (phase 1). The ASD-PROM was then released for general clinical use (phase 2). RESULTS: On a Likert scale (1 = very poorly, 10 = very well), parents found that ASD-PROM items described their child's abilities well (median = 8.0; interquartile range [IQR]: 7.0-9.5) and had a positive effect on care (median = 8.0; IQR: 7.0-10.0). Clinicians found the ASD-PROM effective in assessing parent-reported patient abilities (median = 9.0, IQR: 7.0-9.0) and felt the ASD-PROM helped make their care more patient-centered and efficient (both median = 8.0, IQR: 6.0-9.0). Two-week test-retest reliability was acceptable (0.95). ASD-PROM scores correlated positively with scores from similar domains on the Vineland-II (Pearson r 0.30-0.50, medium to large effects). CONCLUSION: The ASD-PROM is a freely available tool to gather information on developmental and behavioral functioning in children with ASD before autism-specialty clinical visits. Clinical utility and preliminary psychometrics are promising, although limitations (including a low response rate during clinical use and a need for additional in-depth assessments and potential resulting modifications to the tool) remain to be addressed. Ultimately, the ASD-PROM may help promote patient-centered and efficient care for children across a wide range of ages and developmental levels.

Practice guideline: Treatment for insomnia and disrupted sleep behavior in children and adolescents with autism spectrum disorder: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

OBJECTIVE: To review pharmacologic and nonpharmacologic strategies for treating sleep disturbances in children and adolescents with autism spectrum disorder (ASD) and to develop recommendations for addressing sleep disturbance in this population. METHODS: The guideline panel followed the American Academy of Neurology 2011 guideline development process, as amended. The systematic review included studies through December 2017. Recommendations were based on evidence, related evidence, principles of care, and inferences. MAJOR RECOMMENDATIONS LEVEL B: For children and adolescents with ASD and sleep disturbance, clinicians should assess for medications and coexisting conditions that could contribute to the sleep disturbance and should address identified issues. Clinicians should counsel parents regarding strategies for improved sleep habits with behavioral strategies as a first-line treatment approach for sleep disturbance either alone or in combination with pharmacologic or nutraceutical approaches. Clinicians should offer melatonin if behavioral strategies have not been helpful and contributing coexisting conditions and use of concomitant medications have been addressed, starting with a low dose. Clinicians should recommend using pharmaceutical-grade melatonin if available. Clinicians should counsel children, adolescents, and parents regarding potential adverse effects of melatonin use and the lack of long-term safety data. Clinicians should counsel that there is currently no evidence to support the routine use of weighted blankets or specialized mattress technology for improving disrupted sleep. If asked about weighted blankets, clinicians should counsel that the trial reported no serious adverse events with blanket use and that blankets could be a reasonable nonpharmacologic approach for some individuals.

Investigating Potential Biomarkers in Autism Spectrum Disorder.

BACKGROUND: Early identification and treatment of individuals with autism spectrum disorder (ASD) improves outcomes, but specific evidence needed to individualize treatment recommendations is lacking. Biomarkers that could be routinely measured within the clinical setting could potentially transform clinical care for patients with ASD. This demonstration project employed collection of biomarker data during regular autism specialty clinical visits and explored the relationship of biomarkers with clinical ASD symptoms. METHODS: Eighty-three children with ASD, aged 5-10 years, completed a multi-site feasibility study integrating the collection of biochemical (blood serotonin, urine melatonin sulfate excretion) and clinical (head circumference, dysmorphology exam, digit ratio, cognitive and behavioral function) biomarkers during routine ASD clinic visits. Parents completed a demographic survey and the Aberrant Behavior Checklist-Community. Cognitive function was determined by record review. Data analysis utilized Wilcoxon two-sample tests and Spearman correlations. RESULTS: Participants were 82% male, 63% White, 19% Hispanic, with a broad range of functioning. Group means indicated hyperserotonemia. In a single regression analysis adjusting for race and median household income, higher income was associated with higher levels of blood serotonin and urine melatonin sulfate excretion levels (p = 0.004 and p = 0.04, respectively). Melatonin correlated negatively with age (p = 0.048) and reported neurologic problems (p = 0.02). Dysmorphic status correlated with higher reported stereotyped behavior (p = 0.02) and inappropriate speech (p = 0.04). CONCLUSION: This demonstration project employed collection of multiple biomarkers, allowed for examination of associations between biochemical and clinical measures, and identified several findings that suggest direction for future studies. This clinical research model has promise for integrative biomarker research in individuals with complex, heterogeneous neurodevelopmental disorders such as ASD.

High-Functioning Autism, Severe Anxiety, and Bullying in a 26 Year Old.

CASE: Peter is a 26-year-old group home resident in Austria with a history of poor peer relationships, including being bullied, and previous diagnoses of attention-deficit hyperactivity disorder, Asperger syndrome, social anxiety, depression, and developmental coordination disorder. Consultation from our international neurodevelopmental team was requested for severe anxiety and avoidance of social interactions. He reported 4 or more spontaneous anxiety episodes per day. Anxiety triggers included returning to his group home from his vocational rehabilitation program each evening or returning to the group home after weekends at his parents' house. Each Sunday evening, in anticipation of returning to the group home, Peter engaged in tantrums, including screaming and throwing objects and suicidal threats without intent, but not direct aggression toward family members. He phoned his mother several times per day on weekdays.Peter's early history was significant for hyperactivity, impulsivity, aggression, and socially intrusive behavior; he repeated kindergarten and by first grade was characterized as motorically clumsy and "too much in [peers'] personal space." He played alone in kindergarten and had poor social boundaries; when older, he evidenced reduced social perception, and his family reported he did not notice when peers made fun of him. His language developed normally, but he had a "sophisticated style of speaking" and as an adult continued to have trouble understanding gestures, jokes, and social themes in movies.Between ages 7 and 11 years, Peter had been bullied and ostracized by male peers but did well academically, always got along well with adults, and preferred to play with girls. Exclusion by peers persisted through high school, at which time his independent functioning declined and he required his mother's assistance with organizing his materials. At age 15 years, Peter repeated a grade so that he could change classmates, and by the equivalent of his junior year, his grades deteriorated. He had several psychiatric admissions for depression and destructive outbursts (to avoid going to school) and was diagnosed with Asperger disorder. At age 18 years, Peter refused to return to school. He lived at home with his parents, only leaving the house to accompany them on errands, until placed in a group home for people with mental health disorders at age 20 years. At age 26 years, he is sharing a supported-living apartment with 2 young adults with chronic psychiatric disorders. He works in 3 highly structured sheltered workshops for a few hours each and becomes easily overwhelmed in unstructured situations and/or in situations in which he anticipates being reprimanded or letting someone down. Despite a strong interest in marine biology, anxiety prevents him from considering college.How would you proceed with diagnostic testing or intervention to help this young man?

Measuring the involvement in family life of children with autism spectrum disorder: A DBPNet study.

BACKGROUND: Children with Autism Spectrum Disorder (ASD) have social and communication deficits that impair their involvement in family life. No measures of child involvement in the family have been validated for the ASD population. AIM: To evaluate the validity of a measure of Family Involvement (FI) of children ages 5-12 with ASD. METHOD: Parents of children ages 5-12 with ASD (n = 114) completed FI items from the PROMIS® pediatric Family Relationships item bank in computerized adaptive testing (CAT) format, as well as measures of ASD symptom burden, parenting stress, and parental depression. Medical record review provided child intelligence or developmental quotient. A reference sample (n = 236) closely matching the ASD sample in age and gender was created from the national standardization sample, and underwent a simulated CAT. RESULTS: The CAT precisely and efficiently measured parent-reported FI of children with ASD. Average FI scores were lower among children with ASD (M = 46.3, SD = 7.1) than children in the reference sample (M = 52.5, SD = 9.1). A "dose response" decrease in FI was observed as ASD severity increased. Increased parenting stress was associated with lower FI. No relationship between FI and child IQ was found. CONCLUSION: The FI items captured FI among children ages 5-12 with ASD with acceptable precision. Reduced FI among children with ASD, particularly those with higher symptom severity, suggests validity of the items in this population.

Helping a Child with Autism Spectrum Disorder Cope with Divorce.

CASE: Aaron is an 11-year-old boy with autism spectrum disorder (ASD), with cognitive and language skills in the above-average range, whose parents have recently separated. Aaron's mother initiated the separation when she learned that Aaron's father had maintained a relationship with a woman with whom he has a 10-year-old daughter. When Aaron's mother discovered this relationship, she demanded that Aaron's father leave their home.Aaron's father has moved in with his long-term girlfriend and keeps in contact with Aaron by calling once a day. Neither Aaron's father nor mother has discussed the reason for their separation with Aaron. So far, they have explained their separation by telling Aaron that they are "taking a break."Aaron's mother has been deeply hurt by Aaron's father's infidelity and does not want to reconcile with him. Aaron's father recognizes this but would like to continue to have a close relationship with his son. He would also like Aaron to get to know his half-sister.Aaron's mother seeks guidance regarding how to talk to Aaron about the separation and his father's second family. Given Aaron's diagnosis of ASD, she is particularly concerned about his ability to cope with this unexpected change in circumstances. What is your advice?

A Workforce Survey on Developmental-Behavioral Pediatrics.

BACKGROUND AND OBJECTIVES: Developmental-behavioral conditions are common, affecting ∼15% of US children. The prevalence and complexity of these conditions are increasing despite long wait times and a limited pipeline of new providers. We surveyed a convenience sample of the developmental-behavioral pediatric (DBP) workforce to determine current practices, workforce trends, and future needs. METHODS: An electronic survey was e-mailed to 1568 members of the American Academy of Pediatrics Section on Developmental and Behavioral Pediatrics and Council on Children with Disabilities, the Society for Developmental and Behavioral Pediatrics, and the National Association of Pediatric Nurse Practitioners Developmental and Behavioral Mental Health Special Interest Group. RESULTS: The response rate was 48%. There were 411 fellowship-trained physicians, 147 nonfellowship-trained physicians, and 125 nurse practitioners; 61% were women, 79% were white, and 5% were Hispanic. Physicians had a mean of 29 years since medical school graduation, and one-third planned to retire in 3 to 5 years. Nurse practitioners were earlier in their careers. Respondents reported long wait times for new appointments, clinician burnout, increased patient complexity and up to 50% additional time spent per visit in nonreimbursed clinical-care activities. Female subspecialists spent more time per visit in billable and nonbillable components of clinical care. CONCLUSIONS: The DBP workforce struggles to meet current service demands, with long waits for appointments, increased complexity, and high volumes of nonreimbursed care. Sex-based practice differences must be considered in future planning. The viability of the DBP subspecialty requires strategies to maintain and expand the workforce, improve clinical efficiency, and prevent burnout.

Feasibility of Conducting Autism Biomarker Research in the Clinical Setting.

OBJECTIVE: Recruitment and completion of research activities during regular clinical care has the potential to increase research participation in complex neurodevelopmental disorders. We evaluated the feasibility, and effect on clinical care, of conducting biomarker research within a subspecialty clinical visit for autism spectrum disorder (ASD). METHODS: Children, aged 5 to 10 years, were recruited by providers in ASD clinics at 5 institutions. Biomarkers collected were growth measurements, head circumference, neurologic and dysmorphology examinations, digit ratio (2D:4D) measurement, and platelet serotonin and urinary melatonin sulfate excretion levels. Parents completed the Aberrant Behavior Checklist-Community and a medical/demographic questionnaire. Cognitive level was abstracted from the medical record. Parents and clinicians completed surveys on the effect of the study on the clinical visit. RESULTS: Eighty-three children and their caregivers participated. Factors limiting participation included difficulty reaching families by phone and parent concern about the study blood draw requirement. All children completed at least 4 of 7 planned research activities. Demographic factors, educational placement, and child behavior were not associated with completion of study activities. Lower nonverbal cognitive function was weakly associated with fewer activities completed. Forty-four percent of clinicians reported an effect of the research study on the clinical visit. However, neither parent-reported nor clinician-reported effect was associated with the degree of study activity completion. CONCLUSION: Recruiting study participants in the context of scheduled ASD clinical visits required significant effort. However, once recruited, participants completed most study activities, regardless of behavioral symptom severity. Research activities did not adversely affect the clinical visit.

Child and family characteristics associated with age of diagnosis of an autism spectrum disorder in a tertiary care setting.

OBJECTIVE: To identify child and family characteristics associated with age of diagnosis of autism spectrum disorder (ASD) in a tertiary care setting using objective, standardized assessments ensuring diagnostic validity and timing. METHODS: The authors conducted a chart review of children who received their initial ASD diagnosis from 2007 to 2011. Child variables included gender, birth order, cognitive functioning, and for children ≤36 months, language and adaptive assessments. Family variables included insurance, maternal age, maternal education, sibling or family member with ASD, and number of children in the house. Primary outcome was age of ASD diagnosis. The authors ran multiple regression models evaluating the impact of child and family variables on the total sample and on the subsample of children ≤36 months. RESULTS: Median age of diagnosis was 2.9 years (range, 15 mo-13.8 yr; n = 591). In the total sample, significant predictors of earlier age of diagnosis were later birth order, higher maternal education, fewer children in the house, and a sibling with ASD. In a separate analysis of children ≤36 months of age (n = 315) with additional data for language and adaptive assessments, significant predictors of younger age of diagnosis were higher cognitive and adaptive functioning, lower receptive and expressive language, and having a sibling with ASD. CONCLUSIONS: This study suggests that both family and child characteristics play an important role in the early identification of ASD and that predictive variables may vary based on a child's age. Future research should help to elucidate this finding so that screening measures and policies aimed at early identification can target the most predictive factors.

Methylphenidate and continuous spike and wave during sleep in a child with attention deficit hyperactivity disorder.

Attention-deficit/hyperactivity disorder is the most common neurobehavioral disorder in children and frequently associated with epilepsy. For patients with both conditions, methylphenidate remains a mainstay in the treatment of behavioral problems. Most studies demonstrate that methylphenidate is effective in treating children with well-controlled epilepsy, and that methylphenidate does not increase the risk of having seizures in patients with EEG abnormalities without epilepsy. However, in patients with active seizures, the results are somewhat contradictory. This article presents the case of a young girl with attention-deficit/hyperactivity disorder and behavioral problems on Depakote (valproic acid) who had an abnormal EEG with left centroparietal spikes but no history of electrographic seizures. She experienced a convulsion the day after her first dose of methylphenidate, and repeat EEG demonstrated continuous spike and slow wave during sleep. This case report suggests that children with continuous spike and slow wave during sleep may have a higher risk of developing seizures with methylphenidate treatment.

Clinical genetic testing for patients with autism spectrum disorders.

BACKGROUND: Multiple lines of evidence indicate a strong genetic contribution to autism spectrum disorders (ASDs). Current guidelines for clinical genetic testing recommend a G-banded karyotype to detect chromosomal abnormalities and fragile X DNA testing, but guidelines for chromosomal microarray analysis have not been established. PATIENTS AND METHODS: A cohort of 933 patients received clinical genetic testing for a diagnosis of ASD between January 2006 and December 2008. Clinical genetic testing included G-banded karyotype, fragile X testing, and chromosomal microarray (CMA) to test for submicroscopic genomic deletions and duplications. Diagnostic yield of clinically significant genetic changes was compared. RESULTS: Karyotype yielded abnormal results in 19 of 852 patients (2.23% [95% confidence interval (CI): 1.73%-2.73%]), fragile X testing was abnormal in 4 of 861 (0.46% [95% CI: 0.36%-0.56%]), and CMA identified deletions or duplications in 154 of 848 patients (18.2% [95% CI: 14.76%-21.64%]). CMA results for 59 of 848 patients (7.0% [95% CI: 5.5%-8.5%]) were considered abnormal, which includes variants associated with known genomic disorders or variants of possible significance. CMA results were normal in 10 of 852 patients (1.2%) with abnormal karyotype due to balanced rearrangements or unidentified marker chromosome. CMA with whole-genome coverage and CMA with targeted genomic regions detected clinically relevant copy-number changes in 7.3% (51 of 697) and 5.3% (8 of 151) of patients, respectively, both higher than karyotype. With the exception of recurrent deletion and duplication of chromosome 16p11.2 and 15q13.2q13.3, most copy-number changes were unique or identified in only a small subset of patients. CONCLUSIONS: CMA had the highest detection rate among clinically available genetic tests for patients with ASD. Interpretation of microarray data is complicated by the presence of both novel and recurrent copy-number variants of unknown significance. Despite these limitations, CMA should be considered as part of the initial diagnostic evaluation of patients with ASD.

Routine developmental screening implemented in urban primary care settings: more evidence of feasibility and effectiveness.

OBJECTIVES: The purpose of this study was to examine the feasibility and effectiveness of implementation of validated developmental screening by using the Parents' Evaluation of Developmental Status in 2 urban pediatric practices. DESIGN AND METHODS: We implemented the Parents' Evaluation of Developmental Status at Boston Children's Hospital Primary Care Center and at Joseph Smith Community Health Center as quality improvement initiatives. Each practice offered screening to all of the patients attending well-child care visits between 6 months and 8 years of age. The implementation process was investigated by using preimplementation and postimplementation surveys and a focus group of pediatric primary care providers. To assess outcomes, such as changes in identification rates and referrals for developmental and behavioral concerns, we reviewed medical charts of all of the 2- and 3-year-olds present at Children's Hospital Primary Care Center well-child care visits in the periods before and after screening implementation. RESULTS: Providers found routine screening easier than expected and feasible to conduct in a busy primary care setting. The practice change resulted in screening of 61.6% of eligible children. Compared with same-aged children before screening, after screening was implemented more behavioral concerns were detected in the 2-year-old group, and more children with developmental concerns were identified in the 3-year-old group. Referral rates for additional evaluation increased only for 3-year-olds, although the types of referrals (ie, audiology and early intervention) were consistent as those found before screening started. CONCLUSIONS: Implementation of validated screening by using the Parents' Evaluation of Developmental Status was feasible in large, urban settings. Effectiveness was demonstrated via chart review documenting an increased rate of identification of developmental and behavioral concerns. Perceived obstacles, such as the time requirement, should not prevent widespread adoption of screening.

Teaching paediatric residents about learning disorders: use of standardised case discussion versus multimedia computer tutorial.

BACKGROUND: We developed a standardised case-based educational exercise on the topic of childhood learning disorders, and a multimedia computerised adaptation of this exercise, as part of a national curriculum project based on the Bright Futures guidelines. OBJECTIVE: To explore resident perceptions of the facilitated case discussion (FCD) and the computerised tutorial (CT). DESIGN: Quasi-randomised comparison of two educational interventions. SETTING: Preclinic teaching conferences at a large urban children's hospital. PARTICIPANTS: A total of 46 paediatric residents years 1-3 assigned to either FCD (n = 21) or CT (n = 25). INTERVENTIONS: FCD residents met in groups of 8-12 with a trained facilitator for a structured case discussion, while CT residents worked in groups of 2-3 at a computer station linked to an interactive website. OUTCOME MEASURES: Participant responses during semistructured focus group interviews. ANALYSIS: Focus group transcripts, field notes and computer logs were analysed simultaneously using qualitative grounded theory methodology. RESULTS: Residents experienced CT as fun, offering flexibility, greater auditory and visual appeal and more opportunities for active learning. FCD allowed greater contact with expert faculty and made the material more relevant to clinical practice. FCD participants emphasised the clinical skills gleaned and stated that the learning experience would change their future patient management. Both groups reported that case discussion was more interactive than computer learning. Median time spent on learning was slightly shorter for the CT group. All groups of learners arrived at the correct final diagnosis. CONCLUSIONS: FCD and CT stimulate different types of learning among paediatric residents. Future studies are needed to determine how to integrate these two techniques to meet the learning needs of residents in diverse settings.

Factors associated with difficult toilet training.

OBJECTIVE: To identify temperament and behavioral patterns in children with difficult toilet training and to compare those children with same-aged toilet-trained children. METHODS: We compared 46 referred clinic patients who were difficult toilet trainers (DTT) with 62 comparison children (CC) using the Carey-McDevitt Behavioral Style Questionnaire, the Parenting Scale, and a questionnaire of toilet-training history. RESULTS: CC were more likely to have easy temperaments (odds ratio [OR]: 33.51). DTT were more likely to be less adaptable (OR: 3.12), more negative in mood (OR: 2.79), less persistent (OR: 2.97), and lower in approach (OR: 1.85). DTT were more likely than CC to be constipated (OR: 3.52), although 55% of CC were constipated. DTT were likely to hide to stool (74%) and to ask for pull-ups in which to leave stool (37%). Parenting styles did not differ between the groups. CONCLUSIONS: Although the referral population may be inherently biased, these data suggest that difficult toilet training is associated with difficult temperamental traits and constipation in affected children.

Understanding pediatric inner-city asthma: an explanatory model approach.

Explanatory models (EMs) for asthma among inner-city school-age children and their families were examined as a means of better understanding health behaviors. Children and parents were interviewed about their concepts of asthma etiology, asthma medications, and alternative therapies. Drawings were elicited from children to understand their beliefs about asthma. Nineteen children with 17 mothers from a variety of cultural backgrounds were interviewed. Among children, contagion was the primary EM for asthma etiology (53%). Twenty-five percent of children reported fear of dying from asthma, while fear of their child dying from asthma was reported by 76% of mothers. Mothers reported a variety of EMs, some culturally specific, but the majority reported biomedical concepts of etiology, pathophysiology, and triggers. Although 76% of mothers knew the names of more than one of their children's medications, 47% thought their child's medications all had similar functions. Thirty-five percent of families used herbal treatments and 35% incorporated religion into asthma treatment. Seventy-one percent of families had discontinued medications and 23% reported currently not giving anti-inflammatory medication. Reasons for discontinuing daily medications included fears of unknown side effects (53%), addiction (18%), tachyphylaxis (18%), and feeling that their child was being given too much medicine (23%). The traditional focus of asthma education is not sufficient to ensure adherence. Asthma education for children should address their views of etiology and fears about dying from asthma. Conversations with parents about their EMs and beliefs about medications and alternative therapies could assist in understanding and responding to parental concerns and choices about medications and help achieve better adherence.