Tofacitinib Therapy in Children and Young Adults With Pediatric-onset Medically Refractory Inflammatory Bowel Disease.

OBJECTIVES: Tofacitinib, a selective Janus kinase inhibitor, effectively induces and maintains remission in adults with inflammatory bowel disease (IBD), but data are limited in children. This study aimed to evaluate the efficacy and safety of tofacitinib for medically refractory pediatric-onset IBD. METHODS: This single-center retrospective study included subjects ages 21 years and younger who started tofacitinib for medically refractory IBD. Clinical activity indices, clinical response, steroid-free remission, biochemical response, and adverse events (AEs) were evaluated over 52 weeks. RESULTS: Twenty-one subjects, 18 with ulcerative colitis or indeterminate IBD, received tofacitinib. At the end of the 12-week induction period, 9 out of 21 (42.9%) subjects showed clinical response and 7 out of 21 (33.3%) were in steroid-free remission. Of evaluable subjects at 52 weeks, 7 out of 17 (41.2%) showed clinical response and were in steroid-free remission. Of those remaining on tofacitinib at 1 year, none required concomitant systemic corticosteroids. Tofacitinib was discontinued in 8 subjects because of refractory disease, including 8 who ultimately underwent colectomy, and in 1 subject who developed a sterile intra-abdominal abscess. There were no instances of thrombi, zoster reactivation, or clinically significant hyperlipidemia, all of which were AEs of interest. CONCLUSIONS: There is limited experience with tofacitinib in pediatric IBD. In this cohort, tofacitinib induced rapid clinical response with sustained efficacy in nearly half of subjects. This study provides encouraging evidence for the efficacy and safety of tofacitinib as part of the treatment paradigm for young individuals with moderate-to-severe IBD. Larger, well-powered, prospective studies are warranted.

Nonalcoholic fatty liver disease.

On the basis of strong research and consensus, nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in children and is soon to be the most common indication for liver transplantation in adults. Although the disease begins as simple steatosis, some patients may progress to nonalcoholic steatohepatitis (NASH) and cirrhosis, making early identification and treatment critical.• The diagnosis of NAFLD can be challenging because patients are typically asymptomatic, with no major clinical symptoms of liver disease. Overweight and obese children are at the highest risk for disease. (1)(2)• On the basis of moderate research and consensus, serum ALT is usually mildly elevated but is an imperfect test with a low sensitivity for detecting NAFLD at commonly used thresholds.(10) Liver biopsy is still considered the gold standard for diagnosis but is too invasive for population-level screening and is often used selectively. Novel, noninvasive diagnostic modalities and serum biomarkers are currently being studied but warrant further validation, especially in children.• On the basis of moderate research and consensus, assessing serum liver tests in any overweight or obese child is reasonable.Liver disease should be suspected if the serum ALT is ‡22 U/L(0.37 mkat/L) in girls and ‡25 U/L (0.42 mkat/L) in boys. (10)Subspecialist referral should be considered for those with a normal BMI, persistent ALT elevation longer than 6 months,specific symptoms of advanced liver disease such as splenomegaly, or concerning laboratory findings on selected screening tests.• On the basis of strong research evidence, weight loss is the most efficacious treatment for NAFLD.• On the basis of some research and consensus, initiation of vitamin E therapy (400 IU BID) may be started, although its use probably should be restricted to those children with biopsy-proven disease. (12)• On the basis of some research and consensus, novel elastography-based imaging modalities are being studied in children and several drugs show promise in treating NAFLD.

Motor patterns associated with crawling in a soft-bodied arthropod.

Soft-bodied animals lack distinct joints and levers, and so their locomotion is expected to be controlled differently from that of animals with stiff skeletons. Some invertebrates, such as the annelids, use functionally antagonistic muscles (circumferential and longitudinal) acting on constant-volume hydrostatics to produce extension and contraction. These processes form the basis for most theoretical considerations of hydrostatic locomotion in organisms including larval insects. However, caterpillars do not move in this way, and their powerful appendages provide grip independent of their dimensional changes. Here, we show that the anterograde wave of movement seen in the crawling tobacco hornworm, Manduca sexta, is mediated by co-activation of dorsal and ventral muscles within a body segment, rather than by antiphasic activation, as previously believed. Furthermore, two or three abdominal segments are in swing phase simultaneously, and the activities of motor neurons controlling major longitudinal muscles overlap in more than four segments. Recordings of muscle activity during natural crawling show that some are activated during both their shortening and elongation. These results do not support the typical peristaltic model of crawling, but they do support a tension-based model of crawling, in which the substrate is utilized as an anchor to generate propulsion.

Plasma methylphenidate concentrations in youths treated with high-dose osmotic release oral system formulation.

BACKGROUND: Children and adolescents are being treated increasingly for attention-deficit/hyperactivity disorder (ADHD) with a variety of stimulants in higher than Food and Drug Administration (FDA)-approved doses and in combination with other medications. OBJECTIVE: We sought to determine methylphenidate (MPH) concentrations in children and adolescents treated with high-dose, extended-release osmotic release oral system (OROS) MPH plus concomitant medications, and to examine MPH concentrations with respect to the safety and tolerability of treatment. METHODS: Plasma MPH concentrations were measured by liquid chromatography-mass spectrometry 4-5 hours after administration of medication in a sample of youths diagnosed with ADHD. These youths were treated naturalistically with higher than FDA-approved doses of OROS MPH in addition to their concomitant medications. Markers of safety and tolerability (e.g., measures of blood pressure and heart rate) were also examined. RESULTS: Among the 17 patients (with a mean age of 16.2 +/- 2 years and a mean number of concurrent medications of 2.23 +/- 0.94), the mean plasma MPH concentration was 28 +/- 9.1 ng/mL, despite a mean daily dose of OROS MPH of 169 +/- 5 mg (3.0 +/- 0.8 mg/kg per day). No patient had a plasma MPH level >or=50 ng/mL or clinical signs of stimulant toxicity. No correlation was found between plasma MPH concentrations and OROS MPH dose or changes in vital signs. CONCLUSIONS: High-dose OROS MPH, used in combination with other medications, was not associated with either unusually elevated plasma MPH concentrations or with clinically meaningful changes in vital signs. Study limitations include a single time-point sampling of MPH concentrations, a small sample size, and a lack of outcome measures to address treatment effectiveness.

Multivariate genomewide linkage scan of neurocognitive traits and ADHD symptoms: suggestive linkage to 3q13.

Family and twin studies suggest that a range of neurocognitive traits index the inherited liability to ADHD; however, the utility of such measures as endophenotypes in molecular genetic studies remains largely untested. The current article examined whether the inclusion of neurocognitive measures in a genomewide linkage analysis of ADHD could aid in identifying QTL linked to the behavioral symptoms of the condition. Data were from an affected sibling pair linkage study of DSM-IV ADHD conducted at Massachusetts General Hospital. The sample included 1,212 individuals from 271 families. ADHD symptoms were assessed with the K-SADS-E. The neurocognitive battery included Wechsler Intelligence Scales subtests, the Stroop, the Wisconsin Card Sorting Test (WCST), the Rey-Osterreith Complex Figure, a working memory CPT, the CVLT and WRAT-III subscales. Evidence for linkage was assessed using a simulation-based method that combines information from univariate analyses into the equivalent of a multivariate test. After correction for multiple trait testing, a region on chromosome 3q13 showed suggestive linkage to all neurocognitive traits examined and inattention symptoms of ADHD. The second highest peak occurred on 22q12 but showed linkage to a single subscale of the WCST. In univariate analysis, this region retained criteria for suggestive linkage to this measure after correction for multiple trait testing. Our primary findings raise the possibility that one or more genes on 3q13 influence neurocognitive functions and behavioral symptoms of inattention. Overall, these data support the utility of neurocognitive traits as ADHD endophenotypes, but also highlight their limited genetic overlap with the disorder.

Dynamic properties of a locomotory muscle of the tobacco hornworm Manduca sexta during strain cycling and simulated natural crawling.

Caterpillars are soft-bodied terrestrial climbers that perform a wide variety of complex movements with several hundred muscles and a relatively small number of neurons. Control of movements is therefore expected to place unusual demands on the mechanical properties of the muscles. The muscles develop force slowly (1-6 s to peak) yet over a strain range extending from under 60% to more than 160% of resting length, with a length-tension relationship resembling that of supercontracting or cross-striated muscle. In passive and active sinusoidal strain cycling, muscles displayed viscoelastic qualities, with very low and stretch-velocity dependent resilience; there was a positive linear relationship between stretch velocity and the fraction of work dissipation attributable to passive muscle properties (20-80%). In linear stretches of unstimulated muscles at velocities bracketing those encountered in natural crawling, the rise in tension showed a distinct transition to a lower rate of increase, with transition tension dependent upon stretch velocity; peak force was exponentially related to stretch velocity. When stretching ceased, force decayed exponentially, with slower decay associated with lower stretch velocities; the decay time constant was exponentially related to stretch velocity. From the kinematics of caterpillars crawling horizontally we determined that the ventral interior lateral muscle (VIL) of the third abdominal segment (A3) is at or near resting length for most of the crawl cycle, with a fairly linear shortening by 25-30% and re-lengthening occupying about 45% of cycle duration. Synchronized kinematic and EMG recordings showed that during horizontal crawling A3 VIL is stimulated as the muscle shortens from about 95% to 75% of its resting length. We subjected in vitro VIL preparations to strain cycling and stimulus phase and duration similar to that of natural crawling. The resulting work loops were figure-eight shaped, with the muscle performing work during the shortest 45-65% of the strain cycle but dissipating work during the rest of the cycle. The muscle remained in the ascending limb of its length-tension relationship throughout the crawl cycle. Peak force occurred at the end of re-lengthening, nearly a full second after stimulation ceased, underscoring the importance of understanding passive muscle properties to explain caterpillar locomotion. Whether A3 VIL functions as an actuator at all during simulated natural strain cycling is highly sensitive to stimulus timing but far less so to stimulus duration. The muscle's elastomer-like properties appear to play a major role in its function.

Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature.

OBJECTIVE: Recent studies have provided variable information on the frequency and context of diversion and the use of nonprescribed and prescribed stimulant medications in adolescent and young adult populations. The purpose of this systematic review of the literature is to evaluate the extent and characteristics of stimulant misuse and diversion in attention-deficit/hyperactivity disorder (ADHD) and non-ADHD individuals. METHOD: We conducted a systematic review of the literature of available studies looking at misuse and diversion of prescription ADHD medications using misuse, diversion, stimulants, illicit use, and ADHD medications as key words for the search. RESULTS: We identified 21 studies representing 113,104 subjects. The studies reported rates of past year nonprescribed stimulant use to range from 5% to 9% in grade school- and high school-age children and 5% to 35% in college-age individuals. Lifetime rates of diversion ranged from 16% to 29% of students with stimulant prescriptions asked to give, sell, or trade their medications. Recent work suggests that whites, members of fraternities and sororities, individuals with lower grade point averages, use of immediate-release compared to extended-release preparations, and individuals who report ADHD symptoms are at highest risk for misusing and diverting stimulants. Reported reasons for use, misuse, and diversion of stimulants include to concentrate, improve alertness, "get high," or to experiment. CONCLUSIONS: The literature suggests that individuals both with and without ADHD misuse stimulant medications. Recent work has begun to document the context, motivation, and demographic profile of those most at risk for using, misusing, and diverting stimulants. The literature highlights the need to carefully monitor high-risk individuals for the use of nonprescribed stimulants and educate individuals with ADHD as to the pitfalls of the misuse and diversion of the stimulants.

When ADHD and substance use disorders intersect: relationship and treatment implications.

There has been increasing interest in the overlap between attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs). In this report, we describe the developmental relationship between ADHD and SUDs. ADHD alone and in combination with co-occurring psychopathology is a risk factor for the development of SUDs in adulthood. Conversely, approximately one fifth of adults with SUDs have ADHD. Pharmacotherapeutic treatment of ADHD in children reduces the risk for later cigarette smoking and SUDs in adulthood. In contrast, medication treatment alone of adults with ADHD and current SUD is inadequate for both ADHD and SUD. Stimulant diversion continues to be of concern, particularly in older adolescents and young adults.