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Closed treatment of paediatric diaphyseal forearm fractures carries the risk of re-displacement, which can lead to symptomatic malunions. This is because growth will not correct angulation deformity as it does in metaphyseal fractures. The purpose of this prospective cohort study was to evaluate the outcomes after 3-D-planned corrective osteotomy with patient-specific surgical guides for paediatric malunited forearm fractures causing impaired pro-supination. Our primary outcome measure was the gain in pro-supination at 12 months follow-up. Fifteen patients with a mean age at trauma of 9.6 years and time until osteotomy of 5.9 years were included. Preoperatively, patients displayed a mean pro-supination of 67° corresponding to 44% of the contralateral forearm. At final follow-up, this improved to 128°, achieving 85% of the contralateral side. Multivariate linear regression analysis revealed that predictors of greater functional gain after 3-D corrective osteotomy are severe preoperative impairment in pro-supination, shorter interval until 3-D corrective osteotomy and greater angulation of the radius.Level of evidence: III. ispartof: JOURNAL OF HAND SURGERY-EUROPEAN VOLUME vol:47 issue:2 pages:164-171 ispartof: location:England status: published

Diagnostic criteria for amyotrophic lateral sclerosis (ALS) are complex, incorporating multiple levels of certainty from possible through to definite, and are thereby prone to error. Specifically, interrater variability was previously established to be poor, thereby limiting utility as diagnostic enrollment criteria for clinical trials. In addition, the different levels of diagnostic certainty do not necessarily reflect disease progression, adding confusion to the diagnostic algorithm. Realizing these inherent limitations, the World Federation of Neurology, the International Federation of Clinical Neurophysiology, the International Alliance of ALS/MND Associations, the ALS Association (United States), and the Motor Neuron Disease Association convened a consensus meeting (Gold Coast, Australia, 2019) to consider the development of simpler criteria that better reflect clinical practice, and that could merge diagnostic categories into a single entity. The diagnostic accuracy of the novel Gold Coast criteria was subsequently interrogated through a large cross-sectional study, which established an increased sensitivity for ALS diagnosis when compared with previous criteria. Diagnostic accuracy was maintained irrespective of disease duration, functional status, or site of disease onset. Importantly, the Gold Coast criteria differentiated atypical phenotypes, such as primary lateral sclerosis, from the more typical ALS phenotype. It is proposed that the Gold Coast criteria should be incorporated into routine practice and clinical trial settings.

Patient stem cell-derived models enable imaging of complex disease phenotypes and the development of scalable drug discovery platforms. Current preclinical methods for assessing cellular activity do not, however, capture the full intricacies of disease-induced disturbances and instead typically focus on a single parameter, which impairs both the understanding of disease and the discovery of effective therapeutics. Here, we describe a cloud-based image processing and analysis platform that captures the intricate activity profile revealed by GCaMP fluorescence recordings of intracellular calcium changes and enables the discovery of molecules that correct 153 parameters that define the amyotrophic lateral sclerosis motor neuron disease phenotype. In a high-throughput screen, we identified compounds that revert the multiparametric disease profile to that found in healthy cells, a novel and robust measure of therapeutic potential quite distinct from unidimensional screening. This platform can guide the development of therapeutics that counteract the multifaceted pathological features of diseased cellular activity.

BACKGROUND: Short-term follow-up studies have shown that reduced metaphyseal both-bone forearm fractures in children should be treated with K-wires to prevent redisplacement and inferior functional results. Minimum 5-year follow-up studies are limited. Range of motion, patient-reported outcome measures, and radiographic parameters at minimum 5-year follow-up should be evaluated because they could change insights into how to treat pediatric metaphyseal forearm fractures. QUESTIONS/PURPOSES: (1) Does K-wire stabilization of reduced metaphyseal both-bone forearm fractures in children provide better forearm rotation at minimum 5-year follow-up? (2) Do malunions (untreated redisplaced fractures) of reduced metaphyseal both-bone forearm fractures in children induce worse functional results? (3) Which factors lead to limited forearm rotation at minimum 5-year follow-up? METHODS: We analyzed the extended minimum 5-year follow-up of a randomized controlled trial in which children with a reduced metaphyseal both-bone forearm fracture were randomized to either an above-elbow cast (casting group) or fixation with K-wires and an above-elbow cast (K-wire group). Between January 2006 and December 2010, 128 patients were included in the original randomized controlled trial: 67 in the casting group and 61 in the K-wire group. For the current study, based on an a priori calculation, it was determined that, with an anticipated mean limitation in prosupination (forearm rotation) of 7° ± 7° in the casting group and 3° ± 5° in the K-wire group, a power of 80% and a significance of 0.05, the two groups should consist of 50 patients each. Between January 2014 and May 2016, 82% (105 of 128) of patients were included, with a mean follow-up of 6.8 ± 1.4 years: 54 in the casting group and 51 in the K-wire group. At trauma, patients had a mean age of 9 ± 3 years and had mean angulations of the radius and ulna of 25° ± 14° and 23° ± 18°, respectively. The primary result was limitation in forearm rotation. Secondary outcome measures were radiologic assessment, patient-reported outcome measures (QuickDASH and ABILHAND-kids), handgrip strength, and VAS score for cosmetic appearance. Assessments were performed by the first author (unblinded). Multivariable logistic regression analysis was performed to analyze which factors led to a clinically relevant limitation in forearm rotation. RESULTS: There was a mean limitation in forearm rotation of 5° ± 11° in the casting group and 5° ± 8° in the K-wire group, with a mean difference of 0.3° (95% CI -3° to 4°; p = 0.86). Malunions occurred more often in the casting group than in the K-wire group: 19% (13 of 67) versus 7% (4 of 61) with an odds ratio of 0.22 for K-wiring (95% CI 0.06 to 0.80; p = 0.02). In patients in whom a malunion occurred (malunion group), there was a mean limitation in forearm rotation of 6° ± 16° versus 5° ± 9° in patients who did not have a malunion (acceptable alignment group), with a mean difference 0.8° (95% CI -5° to 7°; p = 0.87). Factors associated with a limited forearm rotation ≥ 20° were a malunion after above-elbow casting (OR 5.2 [95% CI 1.0 to 27]; p = 0.045) and a refracture (OR 7.1 [95% CI 1.4 to 37]; p = 0.02). CONCLUSION: At a minimum of 5 years after injury, in children with a reduced metaphyseal both-bone forearm fracture, there were no differences in forearm rotation, patient-reported outcome measures, or radiographic parameters between patients treated with only an above-elbow cast compared with those treated with additional K-wire fixation. Redisplacements occurred more often if treated by an above-elbow cast alone. If fracture redisplacement is not treated promptly, this leads to a malunion, which is a risk factor for a clinically relevant (≥ 20°) limitation in forearm rotation at minimum 5-year follow-up. Children with metaphyseal both-bone forearm fractures can be treated with closed reduction and casting without additional K-wire fixation. Nevertheless, a clinician should inform parents and patient about the high risk of fracture redisplacement (and therefore malunion), with risk for limited forearm rotation if left untreated. Weekly radiographic monitoring is essential. If redisplacement occurs, remanipulation and fixation with K-wires should be considered based on gender, age, and direction of angulation. Future research is required to establish the influence of (skeletal) age, gender, and the direction of malunion angulation on clinical outcome. LEVEL OF EVIDENCE: Level I, therapeutic study.

SUMMARY Dysregulated axonal trafficking of mitochondria is linked to neurodegenerative disorders. We report a high-content screen for small-molecule regulators of the axonal transport of mitochondria. Six compounds enhanced mitochondrial transport in the sub-micromolar range, acting via three cellular targets: F-actin, Tripeptidyl peptidase 1 (TPP1), or Aurora Kinase B (AurKB). Pharmacological inhibition or small hairpin RNA (shRNA) knockdown of each target promotes mitochondrial axonal transport in rat hippocampal neurons and induced pluripotent stem cell (iPSC)-derived human cortical neurons and enhances mitochondrial transport in iPSC-derived motor neurons from an amyotrophic lateral sclerosis (ALS) patient bearing one copy of SOD1A4V mutation. Our work identifies druggable regulators of axonal transport of mitochondria, provides broadly applicable methods for similar image-based screens, and suggests that restoration of proper axonal trafficking of mitochondria can be achieved in human ALS neurons., Graphical Abstract, In Brief Shlevkov et al. establish a high-content screen for enhancers of axonal mitochondrial trafficking. Identified compounds act through three cellular targets: F-Actin, Tripeptidyl peptidase 1, and Aurora Kinase B. Motor neurons derived from a SOD1+/A4VALS patient have decreased mitochondrial motility, which can be reversed by inhibitors of these targets.

Patient stem cell-derived models enable imaging of complex disease phenotypes and the development of scalable drug discovery platforms. Current preclinical methods for assessing cellular activity do not, however, capture the full intricacies of disease-induced disturbances, and instead typically focus on a single parameter, which impairs both the understanding of disease and the discovery of effective therapeutics. Here, we describe a cloud-based image processing and analysis platform that captures the intricate activity profile revealed by GCaMP fluorescent recordings of intracellular calcium changes and enables discovery of molecules that correct 153 parameters that define the amyotrophic lateral sclerosis motor neuron disease phenotype. In a high-throughput screen we identified compounds that revert the multiparametric disease profile to that found in healthy cells, a novel and robust measure of therapeutic potential quite distinct from unidimensional screening. This platform can guide the development of therapeutics that counteract the multifaceted pathological features of diseased cellular activity.