Utility of Electrical Neuromodulation for Treating Chronic Pain Syndromes in the Pediatric Setting: A Systematic Review.

OBJECTIVES: Chronic pain syndromes in children can carry significant threats to psychological well-being, opioid overuse, functional impairments, and severe disability. While several high-level studies, almost exclusively in adults, have demonstrated the utility of implantable electrical neuromodulation systems for treating various chronic pain syndromes, there exists a paucity of pediatric-specific evidence. Unfortunately, evidence and practice patterns established from adults may not be fully translatable to children given differences in disease manifestations and anatomical variances. MATERIALS AND METHODS: We performed a systematic review using conventional PRISMA methodology to identify studies reporting use of implantable electrical neuromodulation systems in children. The primary outcome parameters collected were analgesic relief and functional benefits. Additionally, previous interventions attempted, neuromodulation parameters, and limitations were collected as reported. RESULTS: A total of 11 studies was identified, which described 19 patients who were refractory to multidisciplinary pain management strategies. The cohort was mostly adolescent (18/19), suffered from CRPS (14/19), and received SCS (17/19). Nearly all patients, both those with CRPS (13/14) and non-CRPS conditions (4/4), reported significant pain relief and functional recovery following neuromodulation. There were no severe complications reported; limitations included suboptimal benefit or loss of analgesia (3/19), lead or device revision (3/19), and subcutaneous infection (1/19), all of which were congruent with adult outcomes. CONCLUSION: There exist children with chronic pain refractory to standard of care approaches who could be considered for neuromodulation interventions. The existing data, which was limited and from a low tier of evidence, suggest that these interventions are relatively safe and provide meaningful pain reduction and functional improvements. While not previously reported, we recommend careful consideration of the pubertal growth spurt prior to device lead placement-if reasonable and appropriate-given the possibility of inferior lead migration with physiologic growth in patients with SCS devices or foraminal extrusion in patients with dorsal root ganglion stimulation devices.

Ultrafast excited state dynamics of silver ion-mediated cytosine-cytosine base pairs in metallo-DNA.

To better understand the nexus between structure and photophysics in metallo-DNA assemblies, the parallel-stranded duplex formed by the all-cytosine oligonucleotide, dC20, and silver nitrate was studied by circular dichroism (CD), femtosecond transient absorption spectroscopy, and time-dependent-density functional theory calculations. Silver(I) ions mediate Cytosine-Cytosine (CC) base pairs by coordinating to the N3 atoms of two cytosines. Although these silver(I) mediated CC base pairs resemble the proton-mediated CC base pairs found in i-motif DNA at first glance, a comparison of experimental and calculated CD spectra reveals that silver ion-mediated i-motif structures do not form. Instead, the parallel-stranded duplex formed between dC20 and silver ions is proposed to contain consecutive silver-mediated base pairs with high propeller twist-like ones seen in a recent crystal structure of an emissive, DNA-templated silver cluster. Femtosecond transient absorption measurements with broadband probing from the near UV to the near IR reveal an unusually long-lived (>10 ns) excited state in the dC20 silver ion complex that is not seen in dC20 in single-stranded or i-motif forms. This state is also absent in a concentrated solution of cytosine-silver ion complexes that are thought to assemble into planar ribbons or sheets that lack stacked silver(I) mediated CC base pairs. The large propeller twist angle present in metal-mediated base pairs may promote the formation of long-lived charged separated or triplet states in this metallo-DNA.

Pupillometry measures of autonomic nervous system regulation with advancing age in a healthy pediatric cohort.

PURPOSE: To determine if variables of the pupillary light response mature with age and sex in a healthy pediatric cohort and the utility of pupillometry in assessment among pediatric participants. METHODS: After 1 min in a dark room to establish baseline, pupillometry was performed on 323 healthy, pediatric participants (646 eyes; 2-21 years; 175 females). Variables included initial pupil diameter, pupil diameter after light stimulus, percent pupillary constriction, latency to onset of constriction, average constriction velocity, maximum constriction velocity, average dilation velocity, and time from light stimulus to 75% of the initial pupil diameter. Data analyses employed ANOVAs and non-linear regressions. RESULTS: Analyses of age group differences revealed that participants 12-21 years old had a larger initial pupil diameter and pupil diameter after light stimulus, with males aged 12-18 years demonstrating a larger pupil diameter than all younger participants (ps < 0.05). Participants 12-18 years old had a slower maximum constriction velocity than participants 6-11 years old, with no sex differences (ps < 0.05). Furthermore, males aged 12-18 years old had a smaller percent constriction than males 6-11 years old (ps < 0.05). Regressions revealed that percent constriction and dilation velocity seemed to mature linearly, initial pupil diameter and ending pupil diameter matured quadratically, and the constriction velocity terms matured cubically. CONCLUSIONS: Results revealed maturation of the pupillary light response by age and sex in healthy pediatric participants. Given the value of the pupillary light response as a biomarker, the results provide normative benchmarks for comparison in health and disease, including opiate-exposed and concussion patients.

Determining peripheral skin temperature: subjective versus objective measurements.

AIM: Diseases that affect peripheral vasculature or neurological function can manifest with peripheral skin temperature abnormalities. This pilot study investigates the accuracy of current physical examination techniques and determines whether a hand-held infrared device can be used to estimate peripheral skin temperature and detect temperature disparities. METHODS: Comparison between traditional physical examination of hands/feet by 30 healthcare professionals and a hand-held infrared device was made in 12 individuals (ages 4-25 years; 5 with disorders affecting peripheral skin temperature). Thermal camera measurements served as the reference temperature for comparison. RESULTS: A total of 231 extremity examinations by healthcare professionals were analysed. Healthcare professionals correctly identified subjects with colder or warmer than normal peripheral temperature. Hand-held device measurements were significantly different than reference measurements, with the size of the temperature difference diverging significantly between hands (1.20°C) and feet (0.78°C). When analysing temperature disparities, healthcare professionals identified fewer clinically significant disparities (≥3.0°C) than the hand-held device (76% vs. 99%). CONCLUSION: Although different from reference temperatures, the hand-held infrared device provided a more accurate and objective method than traditional physical exam in identifying peripheral skin temperature asymmetries that may be related to chronic paediatric illness.

Influence of Internal Bond Rotation on Ultrafast IR Anisotropy Measurements and the Internal Rotational Potential.

Measurement of molecular orientation relaxation using ultrafast infrared (IR) pump-probe experiments is widely used to understand the properties of liquids and other systems. In the simplest situation, the anisotropy decay is a single exponential reflecting diffusive orientational relaxation. However, the anisotropy decay is frequently biexponential. The faster component is caused by solvent caging restricting angular sampling until constraint release permits all angles to be sampled. Here, we describe another mechanism that limits the range of sampling, i.e., sampling of a restricted range of angles via internal bond reorientation on a rotational potential surface with barriers. If the internal angular sampling occurs faster than the entire molecule's diffusive orientational relaxation, it will produce a fast component of anisotropy decay with a cone angle determined by the shape of the internal rotation potential. We studied four molecules to illustrate the effects of internal bond rotations on anisotropy decay. The molecules are p-chlorobenzonitrile, phenylselenocyanate, phenylthiocyanate, and 2-nitrophenylselenocyante in the solvent N,N-dimethylformamide. The CN stretch is used as the IR chromophore. p-Chlorobenzonitrile does not have internal rotation; its anisotropy decays as a single exponential. The other three have bent geometries and internal rotation of the moieties containing the CN occurs; the anisotropies decay as biexponentials. The faster of the two decays can be understood in terms of motions on the rotational potential surface. A method is developed for extracting the intramolecular rotational potential surface by employing a modification of the harmonic cone model, and the results are compared to density functional theory calculations.

Pendant Group Functionalization of Cyclic Olefin for High Temperature and High-Density Energy Storage.

High-temperature flexible polymer dielectrics are critical for high density energy storage and conversion. The need to simultaneously possess a high bandgap, dielectric constant and glass transition temperature forms a substantial design challenge for novel dielectric polymers. Here, by varying halogen substituents of an aromatic pendant hanging off a bicyclic mainchain polymer, a class of high-temperature olefins with adjustable thermal stability are obtained, all with uncompromised large bandgaps. Halogens substitution of the pendant groups at para or ortho position of polyoxanorborneneimides (PONB) imparts it with tunable high glass transition from 220 to 245 °C, while with high breakdown strength of 625-800 MV/m. A high energy density of 7.1 J/cc at 200 °C is achieved with p-POClNB, representing the highest energy density reported among homo-polymers. Molecular dynamic simulations and ultrafast infrared spectroscopy are used to probe the free volume element distribution and chain relaxations pertinent to dielectric thermal properties. An increase in free volume element is observed with the change in the pendant group from fluorine to bromine at the para position; however, smaller free volume element is observed for the same pendant when at the ortho position due to steric hindrance. With the dielectric constant and bandgap remaining stable, properly designing the pendant groups of PONB boosts its thermal stability for high density electrification.

Rethinking Vibrational Stark Spectroscopy: Peak Shifts, Line Widths, and the Role of Non-Stark Solvent Coupling.

A vibration's transition frequency is partly determined by the first-order Stark effect, which accounts for the electric field experienced by the mode. Using ultrafast infrared pump-probe and FT-IR spectroscopies, we characterized both the 0 → 1 and 1 → 2 vibrational transitions' field-dependent peak positions and line widths of the CN stretching mode of benzonitrile (BZN) and phenyl selenocyanate (PhSeCN) in ten solvents. We present a theoretical model that decomposes the observed line width into a field-dependent Stark contribution and a field-independent non-Stark solvent coupling contribution (NSC). The model demonstrates that the field-dependent peak position is independent of the line width, even when the NSC dominates the latter. Experiments show that when the Stark tuning rate is large compared to the NSC (PhSeCN), the line width has a field dependence, albeit with major NSC-induced excursions from linearity. When the Stark tuning rate is small relative to the NSC (BZN), the line width is field-independent. BZN's line widths are substantially larger for the 1 → 2 transition, indicating a 1 → 2 transition enhancement of the NSC. Additionally, we examine, theoretically and experimentally, the difference in the 0 → 1 and 1 → 2 transitions' Stark tuning rates. Second-order perturbation theory combined with density functional theory explain the difference and show that the 1 → 2 transition's Stark tuning rate is ∼10% larger. The Stark tuning rate of PhSeCN is larger than BZN's for both transitions, consistent with the theoretical calculations. This study provides new insights into vibrational line shape components and a more general understanding of the vibrational response to external electric fields.

DNA-like Photophysics in Self-Assembled Silver(I)-Nucleobase Nanofibers.

Supramolecular assemblies form when silver nitrate is added to an aqueous solution of adenine (Ade) or 2-aminopurine (2AP) in a 2:1 mole ratio. Atomic force microscopy images reveal nanofibers that are ∼30 nm in diameter and micrometers in length in the dried film formed from a room-temperature solution. Femtosecond broadband transient absorption spectroscopy was used to investigate the dynamics of excited states formed by UV excitation of the nanofibers in room-temperature aqueous solutions in an effort to learn how nonradiative decay pathways of the uncomplexed nucleobases are altered in the silver-ion-mediated assemblies. The changes in the spectroscopy and dynamics of Ade and 2AP upon forming nanofibers with silver ions closely parallel the ones seen when these bases are organized into DNA strands. The similarities strongly suggest that these structures feature extensive π-π stacking interactions between nucleobases. The results show that time-resolved spectroscopy combined with growing understanding of the photophysics of DNA strands can deliver new insights into the properties of metal-nucleobase nanoassemblies.

Congenital Central Hypoventilation Syndrome: Neurocognition Already Reduced in Preschool-Aged Children.

BACKGROUND: Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by severe hypoventilation and autonomic dysregulation, with typical presentation in the neonatal period, and deficient cognitive skills in school-aged patients. We hypothesized that younger (preschool) children with CCHS would also show neurocognitive delay and that CCHS-related physiologic factors would impact neurocognitive test results. METHODS: We studied developmental (Bayley) test results collected during routine clinical care in 31 children (mean age 25.0 ± 8.5 months; range, 6-40 months) with PHOX2B mutation-confirmed CCHS by comparing them with the normative reference mean from the Bayley standardization sample; we also examined associations between Bayley scores and CCHS disease-related factors. RESULTS: Preschool patients with CCHS fell significantly below the normative mean of 100 on Bayley indices of mental (mean, 83.35 ± 24.75) and motor (mean, 73.33 ± 20.48) development (P < .001 for both). Significantly lower Bayley mental and motor scores were associated with severe breath-holding spells, prolonged sinus pauses, and need for 24 h/d artificial ventilation. Lower Bayley motor scores were also associated with seizures. Bayley scores differed among children with the three most common polyalanine repeat expansion mutation genotypes (mental, P = .001; motor, P = .006), being essentially normal in children with the 20/25 genotype but significantly lower in the other genotype groups (P < .05). CONCLUSIONS: These results confirm neurodevelopmental impairment of CCHS preschoolers, with severity related to physiologic compromise and PHOX2B genotype. These findings suggest that adverse effects begin early in the disease process, supporting the need for neurodevelopmental monitoring and intervention from early infancy.