Müllerian Agenesis in a patient with Rubinstein-Taybi Syndrome: A Case Series and Review of the Overlapping Developmental Biologic Pathways.

BACKGROUND: Rubinstein-Taybi syndrome (RSTS) is a multi-system neurodevelopmental condition caused by deficiency of CREBBP (16p13.3) or EP300 (22q13.2). Müllerian agenesis, or Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, is defined as congenital agenesis of the uterus, cervix, and upper vagina without a definite genetic cause. INDEX CASE AND CASE SERIES: We present a 14-year-old female with RSTS type 1 (CREBBP, c.4395-2A>C) and MRKH, the first documented in the literature. Following presentation to Gynecology for anticipatory guidance regarding future menstrual suppression and follow-up of previously diagnosed labial adhesions, exam under anesthesia revealed a single urogenital opening with cystoscopy demonstrating a normal urethra and bladder. Laboratory evaluation was consistent with peripubertal female gonadotropins and estradiol, 46,XX karyotype, and normal microarray, and a pelvic MRI confirmed Müllerian agenesis. Given this case, we assessed our cohort of females with RSTS and found that 4 of 12 individuals also had Müllerian anomalies. CONCLUSION: Gynecologic evaluation should be a part of medical care for females with RSTS, particularly in individuals with delayed menarche or abnormal menstrual history, on the basis of the observed association between RSTS and Müllerian anomalies in this case series. Although several candidate genes and copy number variants are associated with MRKH, no candidate genes in close proximity to the 16p13.3 region have been identified to explain both RSTS and MRKH in the index patient. Due to the regulatory nature of CREBBP during embryonic development, we theorize that CREBBP may play a role in the migration of Müllerian structures during embryogenesis.

Early Measures of TBI Severity Poorly Predict Later Individual Impairment in a Rat Fluid Percussion Model.

BACKGROUND: Multiple measures of injury severity are suggested as common data elements in preclinical traumatic brain injury (TBI) research. The robustness of these measures in characterizing injury severity is unclear. In particular, it is not known how reliably they predict individual outcomes after experimental TBI. METHODS: We assessed several commonly used measures of initial injury severity for their ability to predict chronic cognitive outcomes in a rat lateral fluid percussion (LFPI) model of TBI. At the time of injury, we assessed reflex righting time, neurologic severity scores, and 24 h weight loss. Sixty days after LFPI, we evaluated working memory using a spontaneous alternation T-maze task. RESULTS: We found that righting time and weight loss had no correlation to chronic T-maze performance, while neurologic severity score correlated weakly. DISCUSSION: Taken together, our results indicate that commonly used early measures of injury severity do not robustly predict longer-term outcomes. This finding parallels the uncertainty in predicting individual outcomes in TBI clinical populations.

Behavioral and neuropsychiatric challenges across the lifespan in individuals with Rubinstein-Taybi syndrome.

Introduction: Rubinstein-Taybi syndrome (RSTS) is a rare congenital disorder characterized by developmental and intellectual disability, broadening of thumbs and halluces, and characteristic facial features. Pathogenic variants in CREBBP lead to RSTS type 1 (RSTS1) and in EP300 lead to RSTS type 2 (RSTS2). Individuals with RSTS can demonstrate a variety of behavioral and neuropsychiatric challenges, including anxiety, hyperactivity/inattention, self-injury, repetitive behaviors, and aggression. Behavioral challenges are consistently reported as one of the primary factors impacting quality of life. Despite the high prevalence and morbidity of behavioral and neuropsychiatric features of RSTS, a paucity of data exists regarding its natural history. Methods: To better understand the neurocognitive and behavioral challenges faced by individuals with RSTS, 71 caregivers of individuals with RSTS, ranging in age from one to 61 years, completed four questionnaires measuring obsessive compulsive disorder (OCD)-like symptoms, anxiety, challenging behaviors, and adaptive behavior and living skills. Results: Results revealed a high prevalence of neuropsychiatric and behavioral challenges across ages. We found specific challenging behaviors were worse in school age individuals. Scaled adaptive behavior and living skill scores differed across ages with an increased gap between typically developing peers becoming more apparent at older ages. Between types, individuals with RSTS2 had better adaptive behavior and living skills and less stereotypic behaviors but higher social phobia than individuals with RSTS1. Further, female individuals with RSTS1 appear to have increased hyperactivity. However, both groups had impairments in adaptive functioning compared to typically developing peers. Discussion: Our findings support and expand previous reports of a high prevalence of neuropsychiatric and behavioral challenges in individuals with RSTS. However, we are the first to report differences between types of RSTS. Further, age-related differences were seen with higher challenging behaviors within school-age individuals, which may improve over time, and lower adaptive behavioral skills compared to normative scales. Anticipation of these potential differential challenges across age is vital for proactive management for individuals with RSTS. Our study underscores the importance of enacting neuropsychiatric and behavioral screening earlier in childhood so appropriate management can be implemented. However, further longitudinal studies in larger cohorts are needed to understand better how behavioral and neuropsychiatric characteristics of RSTS evolve over the lifespan and differentially affect subpopulation groups.

Leftover Opioid Analgesics and Disposal Following Ambulatory Pediatric Surgeries in the Context of a Restrictive Opioid-Prescribing Policy.

BACKGROUND: Opioid analgesics are commonly prescribed for postoperative analgesia following pediatric surgery and often result in leftover opioid analgesics in the home. To reduce the volume of leftover opioids and overall community opioid burden, the State of Tennessee enacted a policy to reduce initial opioid prescribing to a 3-day supply for most acute pain incidents. We aimed to evaluate the extent of leftover opioid analgesics following pediatric ambulatory surgeries in the context of a state-mandated restrictive opioid-prescribing policy. We also aimed to evaluate opioid disposal rates, methods of disposal, and reasons for nondisposal. METHODS: Study personnel contacted the parents of 300 pediatric patients discharged with an opioid prescription following pediatric ambulatory surgery. Parents completed a retrospective telephone survey regarding opioid use and disposal. Data from the survey were combined with data from the medical record to evaluate proportion of opioid doses prescribed that were left over. RESULTS: The final analyzable sample of 185 patients (62% response rate) were prescribed a median of 12 opioid doses (interquartile range [IQR], 12-18), consumed 2 opioid doses (IQR, 0-4), and had 10 opioid doses left over (IQR, 7-13). Over 90% (n = 170 of 185) of parents reported they had leftover opioid analgesics, with 83% of prescribed doses left over. A significant proportion (29%, n = 54 of 185) of parents administered no prescribed opioids after surgery. Less than half (42%, n = 71 of 170) of parents disposed of the leftover opioid medication, most commonly by flushing down the toilet, pouring down the sink, or throwing in the garbage. Parents retaining leftover opioids (53%, n = 90 of 170) were most likely to keep them in an unlocked location (68%, n = 61 of 90). Parents described forgetfulness and worry that their child will experience pain in the future as primary reasons for not disposing of the leftover opioid medication. CONCLUSIONS: Despite Tennessee's policy aimed at reducing leftover opioids, a significant proportion of prescribed opioids were left over following pediatric ambulatory surgeries. A majority of parents did not engage in safe opioid disposal practices. Given the safety risks related to leftover opioids in the home, further interventions to improve disposal rates and tailor opioid prescribing are warranted after pediatric surgery.

"My Body Hates Me": A Qualitative Analysis of the Experience of Functional Nausea in Adolescent Girls and Their Mothers.

Nausea is a somatic sensation typically associated with the need to vomit in order to remove a toxin from the body. When nausea occurs in the absence of a specific structural cause or toxin, it is classified as a functional gastrointestinal disorder (FGID). Functional nausea was newly recognized in 2016 as a FGID in children and little is known about its prevalence, course or patient experiences. Nausea co-occurring with functional abdominal pain in childhood has been associated with long-term risk for anxiety and ongoing somatic symptoms into young adulthood. However, few studies have focused uniquely on the experience and impact of nausea on youth. The present study aimed to qualitatively understand the experiences of adolescent girls with functional nausea and their parents. Five mother-daughter dyads were recruited from a specialized pediatric gastroenterology clinic focused on nausea and completed semi-structured interviews. Interviews were transcribed and coded using interpretive phenomenological analysis (IPA). Four main themes emerged: nausea interference, body frustration, misunderstanding of symptoms, and maternal helplessness and guilt. These themes were similar to prior studies on the experiences of youth with chronic pain but also indicated unique challenges due to nausea, such as significant food restriction and subsequent weight loss.

Are endogenous opioid mechanisms involved in the effects of aerobic exercise training on chronic low back pain? A randomized controlled trial.

Aerobic exercise is believed to be an effective chronic low back pain (CLBP) intervention, although its mechanisms remain largely untested. This study evaluated whether endogenous opioid (EO) mechanisms contributed to the analgesic effects of an aerobic exercise intervention for CLBP. Individuals with CLBP were randomized to a 6-week, 18-session aerobic exercise intervention (n = 38) or usual activity control (n = 44). Before and after the intervention, participants underwent separate laboratory sessions to assess responses to evoked heat pain after receiving saline placebo or intravenous naloxone (opioid antagonist) in a double-blinded, crossover fashion. Chronic pain intensity and interference were assessed before and after the intervention. Endogenous opioid analgesia was indexed by naloxone-placebo condition differences in evoked pain responses (blockade effects). Relative to controls, exercise participants reported significantly greater pre-post intervention decreases in chronic pain intensity and interference (Ps < 0.04) and larger reductions in placebo condition evoked pain responsiveness (McGill Pain Questionnaire-Short Form [MPQ]-Total). At the group level, EO analgesia (MPQ-Total blockade effects) increased significantly pre-post intervention only among female exercisers (P = 0.03). Dose-response effects were suggested by a significant positive association in the exercise group between exercise intensity (based on meeting heart rate targets) and EO increases (MPQ-Present Pain Intensity; P = 0.04). Enhanced EO analgesia (MPQ-Total) was associated with a significantly greater improvement in average chronic pain intensity (P = 0.009). Aerobic exercise training in the absence of other interventions appears effective for CLBP management. Aerobic exercise-related enhancements in endogenous pain inhibition, in part EO-related, likely contribute to these benefits.