A Systematic Review of LET-Guided Treatment Plan Optimisation in Proton Therapy: Identifying the Current State and Future Needs.

The well-known clinical benefits of proton therapy are achieved through higher target-conformality and normal tissue sparing than conventional radiotherapy. However, there is an increased sensitivity to uncertainties in patient motion/setup, proton range and radiobiological effect. Although recent efforts have mitigated some uncertainties, radiobiological effect remains unresolved due to a lack of clinical data for relevant endpoints. Therefore, RBE optimisations may be currently unsuitable for clinical treatment planning. LET optimisation is a novel method that substitutes RBE with LET, shifting LET hotspots outside critical structures. This review outlines the current status of LET optimisation in proton therapy, highlighting knowledge gaps and possible future research. Following the PRISMA 2020 guidelines, a search of the MEDLINE® and Scopus databases was performed in July 2023, identifying 70 relevant articles. Generally, LET optimisation methods achieved their treatment objectives; however, clinical benefit is patient-dependent. Inconsistencies in the reported data suggest further testing is required to identify therapeutically favourable methods. We discuss the methods which are suitable for near-future clinical deployment, with fast computation times and compatibility with existing treatment protocols. Although there is some clinical evidence of a correlation between high LET and adverse effects, further developments are needed to inform future patient selection protocols for widespread application of LET optimisation in proton therapy.

Daily Quantity and Kinematic Characteristics of Leg Movement in a Child With SMA (2 Copies SMN2).

PURPOSE: This case report describes daily leg movement quantity and kinematic characteristics of a child with spinal muscular atrophy (SMA) with 2 copies of SMN2, who was symptomatic at the time of treatment with disease-modifying therapies. KEY POINTS: Compared with infants with typical development, this child had differing values for leg movement quantity, duration, average acceleration, and peak acceleration measured across full days in the natural environment by wearable sensors. In addition, movement quantity and clinician-rated outcomes increased with age. CONCLUSIONS: Wearable sensors recorded movement quantity and kinematic characteristics in a treated infant with SMA (2 copies SMN2). These movement parameters were consistently different compared anecdotally with published data from infants with typical development, demonstrating their potential to add unique and complementary information to the assessment of motor function in SMA. RECOMMENDATIONS: Larger longitudinal studies are needed to determine the utility of wearable sensors as an assessment tool and an early predictor of motor outcomes in children with SMA.

Functional outcome measures in young, steroid-naïve boys with Duchenne muscular dystrophy.

The purpose of this study was to quantitate motor performance in 196 genetically confirmed steroid-naïve boys with Duchenne muscular dystrophy (DMD), to evaluate the test-retest reliability of measures of motor performance in young DMD boys, and to assess correlations among the different functional outcomes including timed tests. Boys aged 4-7 years were recruited in the FOR-DMD study, a comparative effectiveness study of different steroid regimens in DMD. Eligible boys had to be able to rise from the floor independently and to perform pulmonary function testing consistently. The boys were evaluated with standardized assessments at the screening and baseline visits at 32 sites in 5 countries (US, UK, Canada, Italy, Germany). Assessments included timed rise from floor, timed 10 m walk/run, six-minute walk distance, North Star Ambulatory Assessment (NSAA) and forced vital capacity (FVC). Mean age at baseline was 5.9 years (range 4.1-8.1 years). Test-retest reliability was high for functional assessments, regardless of time lag between assessments (up to 90 days) and for the majority of age groups. Correlations were strong among the functional measures and timed tests, less so with FVC. Physiotherapy measures are reliable in a young, steroid-naïve population and rise from floor velocity appears to be a sensitive measure of strength in this population.

Development of Duchenne Video Assessment scorecards to evaluate ease of movement among those with Duchenne muscular dystrophy.

BACKGROUND: Patients with Duchenne muscular dystrophy (DMD) adopt compensatory movement patterns as muscles weaken. The Duchenne Video Assessment (DVA) measures patient ease of movement through identification of compensatory movement patterns. The DVA directs caregivers to video record patients performing specific movement tasks at home using a secure mobile application, and DVA-certified physical therapists (PTs) score the videos using scorecards with prespecified compensatory movement criteria. The goal of this study was to develop and refine the DVA scorecards. METHODS: To develop the initial scorecards, 4 PTs collaboratively created compensatory movement lists for each task, and researchers structured the lists into scorecards. A 2-round modified Delphi process was used to gather expert opinion on the understandability, comprehensiveness, and clinical meaningfulness of the compensatory movements on the scorecards. Eight PTs who had evaluated ≥50 patients with DMD and participated in ≥10 DMD clinical trials were recruited for the panel. In Round 1, panelists evaluated compensatory movement criteria understandability via questionnaire and tested the scorecards. In Round 2, panelists participated in an in-person meeting to discuss areas of disagreement from Round 1 and reach consensus (≥75% agreement) on all revisions to the scorecards. RESULTS: During the Round 1 revisions to the scorecards, there were 67 changes (44%) to the wording of 153 original compensatory movement criteria and 3 criteria were removed. During the Round 2 revisions to the scorecards, there were 47 changes (31%) to the wording of 150 compensatory movement criteria, 20 criteria were added, and 30 criteria were removed. The panel reached 100% agreement on all changes made to scorecards during Round 2. CONCLUSION: PTs with extensive experience evaluating patients with DMD confirmed that the compensatory movement criteria included in the DVA scorecards were understandable, comprehensive, and clinically meaningful.

12-Month progression of motor and functional outcomes in congenital myotonic dystrophy.

BACKGROUND: We aim to describe 12-mo functional and motor outcome performance in a cohort of participants with congenital myotonic dystrophy (CDM). METHODS: CDM participants performed the 6 Minute Walk Test (6MWT), 10 Meter Run, 4 Stair Climb, Grip Strength, and Lip Force at baseline and 12-mo visits. Parents completed the Vineland Adaptive Behavior Scale. RESULTS: Forty-seven participants, aged 0 to 13 y old, with CDM were enrolled. 6MWT, 10 Meter Run, and 4 Stair Climb were completed in >85% of eligible participants. The only significant difference between mean baseline and 12-mo performance was an improvement in 6MWT in children 3-6 y old (P = .008). This age group also had the largest mean % improvement in performance in all other timed functional testing. In children >7 y, the slope of change on timed functional tests decreased or plateaued, with further reductions in performance in children ≥10 y. Participants with CTG repeat lengths <500 did not perform differently than those with repeat lengths >1000. CONCLUSIONS: The 6MWT, 10 Meter Run, and 4 Stair Climb were the most feasible measures. Our findings are consistent with the clinical profile and prior cross-sectional data, helping to establish reasonable expectations of functional trajectories in this population as well as identifying points in which therapeutic interventions may be best studied. Further study of outcomes in children >10 y old and <3 y is warranted, but this new information will assist planning of clinical trials in the CDM population.

Modified dynamic gait index and limits of stability in myotonic dystrophy type 1.

INTRODUCTION: The purpose of this study was to describe and compare the performance of balance and walking tests in relation to self-reported fall history in adults with myotonic dystrophy type 1 (DM1). METHODS: Twenty-two (13 male) participants with DM1 completed, a 6-month fall history questionnaire, the modified Dynamic Gait Index (mDGI), limits of stability (LoS) testing, and 10-m walking tests. RESULTS: Mean (SD) falls in 6 months was 3.7 (3.1), and 19 (86%) participants reported at least 1 fall. Significant differences in mDGI scores (P = 0.006) and 10-m fast walking gait velocity (P = 0.02) were found between those who had been classified as "fallers" and those who had been classified as "nonfallers." Significant correlations were found between mDGI scores and 10-m walking time. DISCUSSION: Falls are common in DM1, and the mDGI may have potential to distinguish fallers from nonfallers, whereas the LoS failed to detect such impairment. Future studies should further explore use of the mDGI in DM1. Muscle Nerve 58: 694-699, 2018.

Cloning, synthesis, and characterization of αO-conotoxin GeXIVA, a potent α9α10 nicotinic acetylcholine receptor antagonist.

We identified a previously unidentified conotoxin gene from Conus generalis whose precursor signal sequence has high similarity to the O1-gene conotoxin superfamily. The predicted mature peptide, αO-conotoxin GeXIVA (GeXIVA), has four Cys residues, and its three disulfide isomers were synthesized. Previously pharmacologically characterized O1-superfamily peptides, exemplified by the US Food and Drug Administration-approved pain medication, ziconotide, contain six Cys residues and are calcium, sodium, or potassium channel antagonists. However, GeXIVA did not inhibit calcium channels but antagonized nicotinic AChRs (nAChRs), most potently on the α9α10 nAChR subtype (IC50 = 4.6 nM). Toxin blockade was voltage-dependent, and kinetic analysis of toxin dissociation indicated that the binding site of GeXIVA does not overlap with the binding site of the competitive antagonist α-conotoxin RgIA. Surprisingly, the most active disulfide isomer of GeXIVA is the bead isomer, comprising, according to NMR analysis, two well-resolved but uncoupled disulfide-restrained loops. The ribbon isomer is almost as potent but has a more rigid structure built around a short 310-helix. In contrast to most α-conotoxins, the globular isomer is the least potent and has a flexible, multiconformational nature. GeXIVA reduced mechanical hyperalgesia in the rat chronic constriction injury model of neuropathic pain but had no effect on motor performance, warranting its further investigation as a possible therapeutic agent.

Characterization of a novel α-conotoxin from conus textile that selectively targets α6/α3ß2ß3 nicotinic acetylcholine receptors.

α6ß2 Nicotinic acetylcholine receptors (nAChRs) expressed by dopaminergic neurons in the CNS are potential therapeutic targets for the treatment of several neuropsychiatric diseases, including nicotine addiction and Parkinson disease. However, recent studies indicate that the α6 subunit can also associate with the ß4 subunit to form α6ß4 nAChRs that are difficult to pharmacologically distinguish from α6ß2, α3ß4, and α3ß2 subtypes. The current study characterized a novel 16-amino acid α-conotoxin (α-CTx) TxIB from Conus textile whose sequence is GCCSDPPCRNKHPDLC-amide as deduced from gene cloning. The peptide and an analog with an additional C-terminal glycine were chemically synthesized and tested on rat nAChRs heterologously expressed in Xenopus laevis oocytes. α-CTx TxIB blocked α6/α3ß2ß3 nAChR with an IC(50) of 28 nm. In contrast, the peptide showed little or no block of other tested subtypes at concentrations up to 10 µm. The three-dimensional solution structure of α-CTx TxIB was determined using NMR spectroscopy. α-CTx TxIB represents a uniquely selective ligand for probing the structure and function of α6ß2 nAChRs.

High-temperature "spectrochronopotentiometry": correlating electrochemical performance with in situ Raman spectroscopy in solid oxide fuel cells.

Carbon formation or "coking" on solid oxide fuel cell (SOFC) anodes adversely affects performance by blocking catalytic sites and reducing electrochemical activity. Quantifying these effects, however, often requires correlating changes in SOFC electrochemical efficiency measured during operation with results from ex situ measurements performed after the SOFC has been cooled and disassembled. Experiments presented in this work couple vibrational Raman spectroscopy with chronopotentiometry to observe directly the relationship between graphite deposited on nickel cermet anodes and the electrochemical performance of SOFCs operating at 725 °C. Raman spectra from Ni cermet anodes at open circuit voltage exposed to methane show a strong vibrational band at 1556 cm(-1) assigned to the "G" mode of highly ordered graphite. When polarized in the absence of a gas-phase fuel, these carbon-loaded anodes operate stably, oxidizing graphite to form CO and CO(2). Disappearance of graphite intensity measured in the Raman spectra is accompanied by a steep ∼0.8 V rise in the cell potential needed to keep the SOFC operating under constant current conditions. Continued operation leads to spectroscopically observable Ni oxidation and another steep rise in cell potential. Time-dependent spectroscopic and electrochemical measurements pass through correlated equivalence points providing unequivocal, in situ evidence that identifies how SOFC performance depends on the chemical condition of its anode. Chronopotentiometric data are used to quantify the oxide flux necessary to eliminate the carbon initially present on the SOFC anode, and data show that the oxidation mechanisms responsible for graphite removal correlate directly with the electrochemical condition of the anode as evidenced by voltammetry and impedance measurements. Electrochemically oxidizing the Ni anode damages the SOFC significantly and irreversibly. Anodes that have been reconstituted following electrochemical oxidation of carbon and Ni show qualitatively different kinetics of carbon removal, and the electrochemical performance of these systems is characterized by low maximum currents and large polarization resistances.

Nicotinic acetylcholine receptors in dorsal root ganglion neurons include the α6ß4* subtype.

The α6-containing nicotinic acetylcholine receptors (nAChRs) have recently been implicated in diseases of the central nervous system (CNS), including Parkinson's disease and substance abuse. In contrast, little is known about the role of α6* nAChRs in the peripheral nervous system (where the asterisk denotes the possible presence of additional subunits). Dorsal root ganglia (DRG) neurons are known to express nAChRs with a pharmacology consistent with an α7, α3ß4*, and α4ß2* composition. Here we present evidence that DRG neurons also express α6* nAChRs. We used RT-PCR to show the presence of α6 subunit transcripts and patch-clamp electrophysiology together with subtype-selective α-conotoxins to pharmacologically characterize the nAChRs in rat DRG neurons. α-Conotoxin BuIA (500 nM) blocked acetylcholine-gated currents (I(ACh)) by 90.3 ± 3.0%; the recovery from blockade was very slow, indicating a predominance of α(x)ß4* nAChRs. Perfusion with either 300 nM BuIA[T5A;P6O] or 200 nM MII[E11A], α-conotoxins that target the α6ß4* subtype, blocked I(ACh) by 49.3 ± 5 and 46.7 ± 8%, respectively. In these neurons, I(ACh) was relatively insensitive to 200 nM ArIB[V11L;V16D] (9.4±2.0% blockade) or 500 nM PnIA (23.0±4% blockade), α-conotoxins that target α7 and α3ß2*/α6ß2* nAChRs, respectively. We conclude that α6ß4* nAChRs are among the subtypes expressed by DRG, and to our knowledge, this is the first demonstration of α6ß4* in neurons outside the CNS.