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Once known solely from dental material and thought to represent an early ornithischian dinosaur, the early-diverging pseudosuchian Revueltosaurus callenderi is described from a minimum of 12 skeletons from a monodominant bonebed in the upper part of the Chinle Formation of Arizona. This material includes nearly the entire skeleton and possesses a combination of plesiomorphic and derived character states that help clarify ingroup relationships within Pseudosuchia. A phylogenetic analysis recovers R. callenderi in a clade with Aetosauria and Acaenasuchus geoffreyi that is named Aetosauriformes. Key autapomorphies of R. callenderi include a skull that is longer than the femur, a complete carapace of dermal armor including paramedian and lateral rows, as well as ventral osteoderms, and a tail end sheathed in bone. Histology of the femur and associated osteoderms demonstrate that R. callenderi was slow growing and that the individuals from the bonebed were not young juveniles but had not ceased growing. A review of other material assigned to Revueltosaurus concludes that the genus cannot be adequately diagnosed based on the type materials of the three assigned species and that only R. callenderi can be confidently referred to Revueltosaurus. Published version

Cortical interneurons (GABAergic cells) arise during embryogenesis primarily from the medial and caudal ganglionic eminences (MGE and CGE, respectively) with a small population generated from the preoptic area (POA). Progenitors from the lateral ganglionic eminence (LGE) are thought to only generate GABAergic medium spiny neurons that populate the striatum and project to the globus pallidus. Here, we report evidence that neuronal precursors that express the LGE-specific transcription factor Islet1 (Isl1) can give rise to a small population of cortical interneurons. Lineage tracing and homozygous deletion of Nkx2.1 in Isl1 fate-mapped mice showed that neighboring MGE/POA-specific Nkx2.1 cells and LGE-specific Isl1 cells make both common and distinct lineal contributions towards cortical interneuron fate. Although the majority of cells had overlapping transcriptional domains between Nkx2.1 and Isl1, a population of Isl1-only derived cells also contributed to the adult cerebral cortex. The data indicate that Isl1-derived cells may originate from both the LGE and the adjacent LGE/MGE boundary regions to generate diverse neuronal progeny. Thus, a small population of neocortical interneurons appear to originate from Isl-1-positive precursors.

T-type calcium channels (Cav3.1 to Cav3.3) regulate low-threshold calcium spikes, burst firing and rhythmic oscillations of neurons and are involved in sensory processing, sleep, and hormone and neurotransmitter release. Here, we examined four heterozygous missense variants in CACNA1I, encoding the Cav3.3 channel, in patients with variable neurodevelopmental phenotypes. The p.(Ile860Met) variant, affecting a residue in the putative channel gate at the cytoplasmic end of the IIS6 segment, was identified in three family members with variable cognitive impairment. The de novo p.(Ile860Asn) variant, changing the same amino acid residue, was detected in a patient with severe developmental delay and seizures. In two additional individuals with global developmental delay, hypotonia, and epilepsy, the variants p.(Ile1306Thr) and p.(Met1425Ile), substituting residues at the cytoplasmic ends of IIIS5 and IIIS6, respectively, were found. Because structure modelling indicated that the amino acid substitutions differentially affect the mobility of the channel gate, we analysed possible effects on Cav3.3 channel function using patch-clamp analysis in HEK293T cells. The mutations resulted in slowed kinetics of current activation, inactivation, and deactivation, and in hyperpolarizing shifts of the voltage-dependence of activation and inactivation, with Cav3.3-I860N showing the strongest and Cav3.3-I860M the weakest effect. Structure modelling suggests that by introducing stabilizing hydrogen bonds the mutations slow the kinetics of the channel gate and cause the gain-of-function effect in Cav3.3 channels. The gating defects left-shifted and increased the window currents, resulting in increased calcium influx during repetitive action potentials and even at resting membrane potentials. Thus, calcium toxicity in neurons expressing the Cav3.3 variants is one likely cause of the neurodevelopmental phenotype. Computer modelling of thalamic reticular nuclei neurons indicated that the altered gating properties of the Cav3.3 disease variants lower the threshold and increase the duration and frequency of action potential firing. Expressing the Cav3.3-I860N/M mutants in mouse chromaffin cells shifted the mode of firing from low-threshold spikes and rebound burst firing with wild-type Cav3.3 to slow oscillations with Cav3.3-I860N and an intermediate firing mode with Cav3.3-I860M, respectively. Such neuronal hyper-excitability could explain seizures in the patient with the p.(Ile860Asn) mutation. Thus, our study implicates CACNA1I gain-of-function mutations in neurodevelopmental disorders, with a phenotypic spectrum ranging from borderline intellectual functioning to a severe neurodevelopmental disorder with epilepsy., T-type calcium channels regulate neuronal firing, are implicated in brain disease and are targets for anti-epileptic drugs. El Ghaleb et al. identify heterozygous missense variants of CACNA1I associated with variable neurodevelopmental disorders and epilepsy, and show how gain-of-function mutations cause hyper-excitability.

Precision treatments for epilepsy targeting the underlying genetic diagnoses are becoming a reality. Historically, the goal of epilepsy treatments was to reduce seizure frequency. In the era of precision medicine, however, outcomes such as prevention of epilepsy progression or even improvements in cognitive functions are both aspirational targets for any intervention. Developing methods, both in clinical trial design and in novel endpoints, will be necessary for measuring, not only seizures, but also the other neurodevelopmental outcomes that are predicted to be targeted by precision treatments. Biomarkers that quantitatively measure disease progression or network level changes are needed to allow for unbiased measurements of the effects of any gene-level treatments. Here, we discuss some of the promising electrophysiological biomarkers that may be of use in clinical trials of precision therapies, as well as the difficulties in implementing them. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01132-4.

Objective To estimate time to onset of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]), we conducted post hoc analyses of data from two randomized, placebo-controlled, Phase 3 trials, GWPCARE3 (NCT02224560) and GWPCARE4 (NCT02224690), of patients with Lennox-Gastaut syndrome. Methods Patients received plant-derived pharmaceutical formulation of highly purified CBD (Epidiolex, 100 mg/ml oral solution) at 10 mg/kg/day (CBD10; GWPCARE3) or 20 mg/kg/day (CBD20; both trials) or placebo for 14 weeks. Treatment started at 2.5 mg/kg/day for all groups and reached 10 mg/kg/day on Day 7 and 20 mg/kg/day (CBD20 and matching placebo only) on Day 11. Percentage change from baseline in drop seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated. Results Overall, 235 patients received CBD (CBD10 [GWPCARE3 only], n = 67; CBD20 [pooled GWPCARE3&4], n = 168) and 161 received placebo. Mean (range) age was 15.3 years (2.6-48.0). Patients had previously discontinued a median (range) of six (0-28) antiepileptic drugs (AEDs) and were currently taking a median of three (0-5) AEDs. Differences in drop seizure reduction between placebo and CBD emerged during the titration period and became nominally significant by Day 6 (p = .008) for pooled CBD treatment groups. Separation between placebo and CBD in >= 50% responder rate emerged by Day 6. Onset of the first reported AE occurred during the titration period in 45% of patients (CBD10, 46%; CBD20, 52%; placebo, 38%). In patients with AEs, resolution occurred within 4 weeks of onset in 53% of placebo and 39% of CBD patients and by end of study in 63% of placebo and 61% of CBD patients. Significance Treatment effect (efficacy and AEs) of CBD may occur within 1 week of starting treatment. Although AEs lasted longer for CBD than placebo, most resolved within the 14-week period.

Hip arthroscopy utilization continues to increase worldwide. Post-operative pain management is essential to allow appropriate rehabilitation. While multimodal analgesic protocols have been described, consensus agreement is lacking and opioid analgesia remains a mainstay of treatment. Unfortunately, the risk of persistent opioid use among opioid-naive and non-naive patients following hip arthroscopy remains unclear. Therefore, the purpose of this study was to identify rates of persistent post-operative opioid use, as well as to identify factors associated with persistent use. A retrospective cohort study was conducted using linked administrative data from Ontario, Canada. Participants were adults who underwent hip arthroscopy between 2013 and 2018. Patients 60 years of age as well as those who had undergone prior hip arthroscopy were excluded. The primary exposure was whether patients had filled ≥ 2 opioid prescriptions within 1 year prior to their hip arthroscopy to define the opioid naive and non-naive populations. The primary outcome was persistent opioid use, defined as 2 + prescriptions filled between 9 and 15 months post-op. A regression analysis was performed to identify factors associated with persistent opioid usage. Of the 1909 patients, 1525 (79.9%) were opioid-naive, while 384 (20.1%) had a prior history of opioid use within 1 year of surgery. 224 patients (11.7%) demonstrated persistent opioid use, with ≥ 2 prescriptions filled between 9 and 15 months post-op. Of those, 42 (18.8%) cases were among opioid-naive patients, while the remaining 182 (81.2%) were among non-naive patients. The risk of persistent post-operative use was significantly higher in those with prior opioid use (OR 31.95, 95% CI 22.15–46.09; p

The escalating socioeconomic burden of knee osteoarthritis (OA) underscores the need for innovative strategies to reduce wait times for total knee arthroplasty (TKA). The purpose of this study was to evaluate resource use, costs and health-related quality of life (HRQoL) across the continuum of care for patients with knee OA.This was a prospective study of 383 patients recruited from a high-volume teaching hospital at different stages of care (referral, consultation and presurgery). Outcomes included health care resource use; costs captured from the health care payer, private sector and societal perspectives; HRQoL measured using the Western Ontario and McMaster Universities Osteoarthritis Index, the 12-Item Short Form Health Survey, and EuroQoL 5-Dimension 5-Level tool; wait times; and the proportion of referrals deemed suitable candidates for surgery.The most commonly used conservative treatments were pharmacotherapy, exercise and lifestyle modification. Forty percent of patients referred for TKA were deemed not to be suitable candidates for surgery. The greatest proportion of costs was borne by the patient or private insurer; a small proportion was borne by the public payer. Across all stages of care, more than 60% of the total costs was attributed to productivity losses. HRQoL remained relatively stable throughout the waiting period (mean wait time from referral to TKA 13.2 mo) but improved postoperatively.The suboptimal primary care management of knee OA calls for the development of innovative models of care. This study may provide valuable guidance on the design and implementation of a new online educational platform to improve referral efficiency and expedite wait times for TKA.Le fardeau socioéconomique croissant de l’arthrose du genou rappelle que nous avons besoin de stratégies novatrices afin de réduire les temps d’attente pour l’arthroplastie totale du genou (ATG). Le but de cette étude est d’évaluer l’utilisation des ressources, les coûts et la qualité de vie liée à la santé (QVLS) dans tout le continuum des soins pour les patients souffrant d’arthrose du genou.Cette étude prospective a porté sur 383 patients recrutés dans un établissement d’enseignement fort achalandé, qui en étaient à différentes étapes du continuum de soins (demande de consultation, consultation et préchirurgie). Les paramètres incluaient l’utilisation des ressources en santé, les coûts du point de vue sociétal et des régimes d’assurance maladie publics et privés, la QVLS mesurée au moyen de l’indice WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index), du questionnaire Short Form Health Survey en 12 points et de l’outil EuroQoL appliqué à 5 dimensions et à 5 niveaux, les temps d’attente, et la proportion de demandes de consultation concernant des patients considérés comme de bons candidats à la chirurgie.Les traitements conservateurs les plus utilisés étaient la pharmacothérapie, l’exercice et les modifications à l’hygiène de vie. Quarante pour cent des patients adressés en consultation pour ATG ont été considérés comme de bons candidats à la chirurgie. La plus grande part des coûts a été assumée par le patient ou un assureur privé; une faible part des coûts a été assumée par le régime public. À toutes les étapes du continuum, plus de 60 % des coûts totaux ont été attribués à des pertes de productivité. La QVLS est demeurée relativement stable tout au long de la période d’attente (temps d’attente moyen entre la consultation et l’ATG, 13,2 mois) mais s’est améliorée après la chirurgie.La prise en charge sous-optimale de l’arthrose du genou en soins primaires rappelle qu’il est nécessaire d’établir des modèles de soins novateurs. Cette étude pourrait faciliter la mise au point et l’application d’une nouvelle plateforme éducative en ligne pour améliorer l’efficience des demandes de consultation et abréger les temps d’attente pour l’ATG.

Although neurologic symptoms occur in two-thirds of lysosomal storage disorders (LSDs), for most we do not understand the mechanisms underlying brain dysfunction. A major unanswered question is if the pathogenic hallmark of LSDs, storage accumulation, induces functional defects directly or is a disease bystander. Also, for most LSDs we do not know the impact of loss-of-function in individual cell types. Understanding these critical questions are essential to therapy development. Here, we determined the impact of genetic rescue in distinct cell types on neural circuit dysfunction in CLN3 disease, the most common pediatric dementia and a representative LSD. We restored Cln3 expression via AAV-mediated gene delivery and conditional genetic rescue in a CLN3 mouse model. Surprisingly, we found that low-level rescue of Cln3 expression in neurons alone normalized clinically-relevant electrophysiologic markers of network dysfunction, despite the presence of substantial residual histopathology, in contrast to restoring expression in astrocytes. Thus, loss of Cln3 function in neurons, not storage accumulation, underlies neurologic dysfunction in CLN3 disease, implying that storage clearance may be an inappropriate target for therapy development and an ineffectual biomarker.

Abstract Background The fetal brain is adapted to the hypoxic conditions present during normal in utero development. Relatively more hypoxic states, either chronic or acute, are pathologic and can lead to significant long-term neurodevelopmental sequelae. In utero hypoxic injury is associated with neonatal mortality and millions of lives lived with varying degrees of disability. Main body Genetic studies of children with neurodevelopmental disease indicate that epigenetic modifiers regulating DNA methylation and histone remodeling are critical for normal brain development. Epigenetic modifiers are also regulated by environmental stimuli, such as hypoxia. Indeed, epigenetic modifiers that are mutated in children with genetic neurodevelopmental diseases are regulated by hypoxia in a number of preclinical models and may be part of the mechanism for the long-term neurodevelopmental sequelae seem in children with hypoxic brain injury. Thus, a comprehensive understanding the role of DNA methylation and histone modifications in hypoxic injury is critical for developing novel strategies to treat children with hypoxic injury. Conclusions This review focuses on our current understanding of the intersection between epigenetics, brain development, and hypoxia. Opportunities for the use of epigenetics as biomarkers of neurodevelopmental disease after hypoxic injury and potential clinical epigenetics targets to improve outcomes after injury are also discussed. While there have been many published studies on the epigenetics of hypoxia, more are needed in the developing brain in order to determine which epigenetic pathways may be most important for mitigating the long-term consequences of hypoxic brain injury.

Background MECP2 Duplication syndrome (MDS) is a rare X-linked genomic disorder that is caused by interstitial chromosomal duplications at Xq28 encompassing the MECP2 gene. Although phenotypic features in MDS have been described, there is a limited understanding of the range of severity of these features, and how they evolve with age. Methods The cross-sectional results of N = 69 participants (ages 6 months-33 years) enrolled in a natural history study of MDS are presented. Clinical severity was assessed using a clinician-report measure as well as a parent-report measure. Data was also gathered related to the top 3 concerns of parents as selected from the most salient symptoms related to MDS. The Child Health Questionnaire was also utilized to obtain parental reports of each child's quality of life to establish disease burden. Results The results of linear regression from the clinician-reported measure show that overall clinical severity scores, motor dysfunction, and functional skills are significantly worse with increasing age. Top concerns rated by parents included lack of effective communication, abnormal walking/balance issues, constipation, and seizures. Higher levels of clinical severity were also related to lower physical health quality of life scores as reported by parents. Conclusions The data suggest that increasing levels of clinical severity are noted with older age, and this is primarily attributable to motor dysfunction, and functional skills. The results provide an important foundation for creating an MDS-specific severity scale highlighting the most important domains to target for treatment trials and will help clinicians and researchers define clinically meaningful changes.

Musculoskeletal disorders are a leading contributor to healthcare resource use and reduced quality of life, particularly in osteoarthritis of the hip/knee. Consequently, the volume of arthroplasty procedures continues to rise and there is a critical need to identify interventions that provide value-based care. Economic evaluations that assess both cost and health outcomes simultaneously allow clinicians and policymakers to make informed decisions regarding cost-effective interventions. The purpose of this review was to summarize and evaluate the methodological quality of economic evaluations of hip/knee interventions in arthroplasty. We identified 384 studies. Two-thirds did not meet the criteria for full economic evaluations (compared costs independently). Several studies (28%) inappropriately concluded interventions were cost-effective. Using a validated quality assessment tool, we determined the quality of full economic evaluations in hip/knee arthroplasty is generally good; however, important areas for quality improvement are related to reporting perspective, costing methodology, and funding. Value-based care in arthroplasty relies on the quality of the literature. Although the quality is generally good, few full economic evaluations are published in arthroplasty. Yet, these are necessary to appropriately infer intervention cost-effectiveness. Unfortunately, clinical decisions continue to be made using highly cited low-quality or partial economic evaluations.

Total joint arthroplasties (TJA) are successful procedures for the treatment of end-stage hip and knee arthritis. Length of stay in hospitals after these procedures has been steadily decreasing over time, with outpatient procedures (discharge on the same day as surgery) introduced in the US within the last 20 years. Reducing length of stay after TJA can provide cost savings. Centres in Canada have started to utilize outpatient TJA procedures, but we have identified some barriers that may have limited their implementation. We have summarized the current literature for outpatient TJA and discussed potential solutions for the current barriers.

Background CDKL5 deficiency disorder (CDD) is associated with refractory infantile onset epilepsy, global developmental delay, and variable features that include sleep, behavioral disturbances, and movement disorders. Current treatment is primarily symptom-based and informed by experience in caring for this population. Methods We describe medication and non-medication approaches to treatment of epilepsy and additional key neurologic symptoms (sleep disturbances, behavioral issues, movement disorders, and swallowing dysfunction) in a cohort of 177 individuals meeting criteria for CDD, 154 evaluated at 4 CDKL5 Centers of Excellence in the USA and 40 identified through the NIH Natural History Study of Rett and Related Disorders. Results The four most frequently prescribed anti-seizure medications were broad spectrum, prescribed in over 50% of individuals. While the goal was not to ascertain efficacy, we obtained data from 86 individuals regarding response to treatment, with 2-week response achieved in 14–48% and sustained 3-month response in 5–36%, of those with known response. Additional treatments for seizures included cannabis derivatives, tried in over one-third of individuals, and clinical trial medications. In combination with pharmacological treatment, 50% of individuals were treated with ketogenic diet for attempted seizure control. Surgical approaches included vagus nerve stimulators, functional hemispherectomy, and corpus callosotomy, but numbers were too limited to assess response. Nearly one-third of individuals received pharmacologic treatment for sleep disturbances, 13% for behavioral dysregulation and movement disorders, and 43% had gastrostomy tubes. Conclusions Treatment for neurologic features of CDD is currently symptom-based and empiric rather than CDD-specific, though clinical trials for CDD are emerging. Epilepsy in this population is highly refractory, and no specific anti-seizure medication was associated with improved seizure control. Ketogenic diet is commonly used in patients with CDD. While behavioral interventions are commonly instituted, information on the use of medications for sleep, behavioral management, and movement disorders is sparse and would benefit from further characterization and optimization of treatment approaches. The heterogeneity in treatment approaches highlights the need for systematic review and guidelines for CDD. Additional disease-specific and disease-modifying treatments are in development.

BACKGROUND Approximately 20% of total knee arthroplasty (TKA) patients are found to be dissatisfied or unsure of their satisfaction at 1-year post-surgery. This study attempted to predict 1-year post-surgery dissatisfied/unsure TKA patients with pre-surgery and surgical variables using logistic regression and machine learning methods. METHODS A retrospective analysis of patients who underwent primary TKA for osteoarthritis between 2012 and 2016 at a single institution was completed. Patients were split into satisfied and dissatisfied/unsure groups. Potential predictor variables included the following: demographic information, patella re-surfaced, posterior collateral ligament sacrificed, and subscales from the Knee Society Knee Scoring System, the Knee Society Clinical Rating System, the Western Ontario and McMaster Universities Osteoarthritis Index, and the 12-Item Short Form Health Survey version 2. Logistic regression and 6 different machine learning methods were used to create prediction models. Model performance was evaluated using discrimination (AUC [area under the receiver operating characteristic curve]) and calibration (Brier score, Cox intercept, and Cox slope) metrics. RESULTS There were 1432 eligible patients included in the analysis, 313 were considered to be dissatisfied/unsure. When evaluating discrimination, the logistic regression (AUC = 0.736) and extreme gradient boosted tree (AUC = 0.713) models performed best. When evaluating calibration, the logistic regression (Brier score = 0.141, Cox intercept = 0.241, and Cox slope = 1.31) and gradient boosted tree (Brier score = 0.149, Cox intercept = 0.054, and Cox slope = 1.158) models performed best. CONCLUSION The models developed in this study do not perform well enough as discriminatory tools to be used in a clinical setting. Further work needs to be done to improve the performance of pre-surgery TKA dissatisfaction prediction models.

Intrauterine hypoxia is a common cause of brain injury in children resulting in a broad spectrum of long-term neurodevelopmental sequela, including life-long disabilities that can occur even in the absence of severe neuroanatomic damage. Postnatal hypoxia-ischemia rodent models are commonly used to understand the effects of ischemia and transient hypoxia on the developing brain. Postnatal models, however, have some limitations. First, they do not test the impact of placental pathologies on outcomes from hypoxia. Second, they primarily recapitulate severe injury because they provoke substantial cell death, which is not seen in children with mild hypoxic injury. Lastly, they do not model preterm hypoxic injury. Prenatal models of hypoxia in mice may allow us to address some of these limitations to expand our understanding of developmental brain injury. The published rodent models of prenatal hypoxia employ multiple days of hypoxic exposure or complicated surgical procedures, making these models challenging to perform consistently in mice. Furthermore, large animal models suggest that transient prenatal hypoxia without ischemia is sufficient to lead to significant functional impairment to the developing brain. However, these large animal studies are resource-intensive and not readily amenable to mechanistic molecular studies. Therefore, here we characterized the effect of late gestation (embryonic day 17.5) transient prenatal hypoxia (5% inspired oxygen) on long-term anatomical and neurodevelopmental outcomes in mice. Late gestation transient prenatal hypoxia increased hypoxia-inducible factor 1 alpha protein levels (a marker of hypoxic exposure) in the fetal brain. Hypoxia exposure predisposed animals to decreased weight at postnatal day 2, which normalized by day 8. However, hypoxia did not affect gestational age at birth, litter size at birth, or pup survival. No differences in fetal brain cell death or long-term gray or white matter changes resulted from hypoxia. Animals exposed to prenatal hypoxia did have several long-term functional consequences, including sex-dichotomous changes. Hypoxia exposure was associated with a decreased seizure threshold and abnormalities in hindlimb strength and repetitive behaviors in males and females. Males exposed to hypoxia had increased anxiety-related deficits, whereas females had deficits in social interaction. Neither sex developed any motor or visual learning deficits. This study demonstrates that late gestation transient prenatal hypoxia in mice is a simple, clinically relevant paradigm for studying putative environmental and genetic modulators of the long-term effects of hypoxia on the developing brain.

We report a case of accommodative spasm in an 8-year-old girl discovered by handheld photoscreener. The patient was found to have a Chiari I malformation, and managed with atropine drops and reading glasses, ultimately with improvement in her symptoms. We believe this to be the first case of accommodative spasm diagnosis aided by the use of a handheld photoscreener.

The location of interictal spikes is used to aid surgical planning in patients with medically refractory epilepsy; however, their spatial and temporal dynamics are poorly understood. In this study, we analysed the spatial distribution of interictal spikes over time in 20 adult and paediatric patients (12 females, mean age = 34.5 years, range = 5–58) who underwent intracranial EEG evaluation for epilepsy surgery. Interictal spikes were detected in the 24 h surrounding each seizure and spikes were clustered based on spatial location. The temporal dynamics of spike spatial distribution were calculated for each patient and the effects of sleep and seizures on these dynamics were evaluated. Finally, spike location was assessed in relation to seizure onset location. We found that spike spatial distribution fluctuated significantly over time in 14/20 patients (with a significant aggregate effect across patients, Fisher’s method: P < 0.001). A median of 12 sequential hours were required to capture 80% of the variability in spike spatial distribution. Sleep and postictal state affected the spike spatial distribution in 8/20 and 4/20 patients, respectively, with a significant aggregate effect (Fisher’s method: P < 0.001 for each). There was no evidence of pre-ictal change in the spike spatial distribution for any patient or in aggregate (Fisher’s method: P = 0.99). The electrode with the highest spike frequency and the electrode with the largest area of downstream spike propagation both localized the seizure onset zone better than predicted by chance (Wilcoxon signed-rank test: P = 0.005 and P = 0.002, respectively). In conclusion, spikes localize seizure onset. However, temporal fluctuations in spike spatial distribution, particularly in relation to sleep and post-ictal state, can confound localization. An adequate duration of intracranial recording—ideally at least 12 sequential hours—capturing both sleep and wakefulness should be obtained to sufficiently sample the interictal network.

Temporal lobe epilepsy represents a major cause of drug-resistant epilepsy. Cognitive impairment is a frequent comorbidity, but the mechanisms are not fully elucidated. We hypothesized that the cognitive impairment in drug-resistant temporal lobe epilepsy could be due to perturbations of amyloid and tau signalling pathways related to activation of stress kinases, similar to those observed in Alzheimer’s disease. We examined these pathways, as well as amyloid-β and tau pathologies in the hippocampus and temporal lobe cortex of drug-resistant temporal lobe epilepsy patients who underwent temporal lobe resection (n = 19), in comparison with age- and region-matched samples from neurologically normal autopsy cases (n = 22). Post-mortem temporal cortex samples from Alzheimer’s disease patients (n = 9) were used as positive controls to validate many of the neurodegeneration-related antibodies. Western blot and immunohistochemical analysis of tissue from temporal lobe epilepsy cases revealed increased phosphorylation of full-length amyloid precursor protein and its associated neurotoxic cleavage product amyloid-β*56. Pathological phosphorylation of two distinct tau species was also increased in both regions, but increases in amyloid-β1-42 peptide, the main component of amyloid plaques, were restricted to the hippocampus. Furthermore, several major stress kinases involved in the development of Alzheimer’s disease pathology were significantly activated in temporal lobe epilepsy brain samples, including the c-Jun N-terminal kinase and the protein kinase R-like endoplasmic reticulum kinase. In temporal lobe epilepsy cases, hippocampal levels of phosphorylated amyloid precursor protein, its pro-amyloidogenic processing enzyme beta-site amyloid precursor protein cleaving enzyme 1, and both total and hyperphosphorylated tau expression, correlated with impaired preoperative executive function. Our study suggests that neurodegenerative and stress-related processes common to those observed in Alzheimer’s disease may contribute to cognitive impairment in drug-resistant temporal lobe epilepsy. In particular, we identified several stress pathways that may represent potential novel therapeutic targets.

The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of individuals. To explore whether statistical support for genetic etiologies can be generated on the basis of phenotypic features, we analyzed whole-exome sequencing data and phenotypic similarities by using Human Phenotype Ontology (HPO) in 314 individuals with DEEs. We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1 in two individuals with a phenotypic similarity that was higher than expected by chance (p = 0.003) and a phenotype related to epilepsy with myoclonic-atonic seizures. We subsequently found the same de novo variant in two individuals with neurodevelopmental disorders and generalized epilepsy in a cohort of 2,310 individuals who underwent diagnostic whole-exome sequencing. AP2M1 encodes the mu-subunit of the adaptor protein complex 2 (AP-2), which is involved in clathrin-mediated endocytosis (CME) and synaptic vesicle recycling. Modeling of protein dynamics indicated that the p.Arg170Trp variant impairs the conformational activation and thermodynamic entropy of the AP-2 complex. Functional complementation of both the mu-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2 mu conditional knockout mice revealed a significant impairment of CME of transferrin. In contrast, stability, expression levels, membrane recruitment, and localization were not impaired, suggesting a functional alteration of the AP-2 complex as the underlying disease mechanism. We establish a recurrent pathogenic variant in AP2M1 as a cause of DEEs with distinct phenotypic features, and we implicate dysfunction of the early steps of endocytosis as a disease mechanism in epilepsy.

© American Academy of Orthopaedic Surgeons. Background:Extensor mechanism disruption after total knee arthroplasty is a serious complication leading to notable patient morbidity. The purpose of this study is to compare the outcomes of extensor mechanism allograft with synthetic graft reconstruction.Methods:We retrospectively identified all patients who underwent extensor mechanism reconstruction using either allograft or synthetic graft from two high-volume academic arthroplasty institutions between 2006 and 2017. We collected extensor lag, need for ambulatory aids, and patient-reported outcome measures, as well as the incidence of postoperative complications and revision surgeries. We evaluated cost differences, considering both material cost and the need for revision surgery.Results:We identified 27 cases. A significantly greater postoperative extensor lag was found in the allograft group (P = 0.05). Graft failure after synthetic reconstruction was zero, with an overall revision surgery rate of 15%. Graft failure was 21%, and the revision surgery rate was 43% after allograft reconstruction. The allograft cost was significantly higher compared with the synthetic graft cost (P = 0.001). The mean total cost was 4,733.08 CAD for the synthetic group and 24,050.40 CAD for the allograft group (P = 0.17).Discussion:Synthetic reconstruction for extensor mechanism disruption shows benefit in postoperative extensor lag, graft failure, revision surgery, and cost when compared with allograft.Level of Evidence:Level III.

CDKL5 deficiency disorder (CDD) is characterized by epilepsy, intellectual disability, and autistic features, and CDKL5-deficient mice exhibit a constellation of behavioral phenotypes reminiscent of the human disorder. We previously found that CDKL5 dysfunction in forebrain glutamatergic neurons results in deficits in learning and memory. However, the pathogenic origin of the autistic features of CDD remains unknown. Here, we find that selective loss of CDKL5 in GABAergic neurons leads to autistic-like phenotypes in mice accompanied by excessive glutamatergic transmission, hyperexcitability, and increased levels of postsynaptic NMDA receptors. Acute, low-dose inhibition of NMDAR signaling ameliorates autistic-like behaviors in GABAergic knockout mice, as well as a novel mouse model bearing a CDD-associated nonsense mutation, CDKL5 R59X, implicating the translational potential of this mechanism. Together, our findings suggest that enhanced NMDAR signaling and circuit hyperexcitability underlie autistic-like features in mouse models of CDD and provide a new therapeutic avenue to treat CDD-related symptoms., Mouse models of CDKL5 deficiency disorder (CDD) recapitulate multiple clinical symptoms of CDD, such as intellectual disability and autism. Here, the authors show that selective loss of CDKL5 from GABAergic neurons leads to social deficits and stereotypic behaviors, which can be ameliorated through inhibition of NMDAR signaling.

To review the history, pharmacology, and clinical science of cannabidiol (CBD) in the treatment of epilepsy.Phase III randomized controlled trials and prospective open label trials have provided efficacy and safety data for the use of CBD in pediatric onset severe epilepsies. The product that was studied in the vast majority of these published trials, Epidiolex (99% of CBD and0.10% Δ9-tetrahydrocannabinol (THC); GW pharmaceuticals, Cambridge, UK), has now been FDA approved based on this published data.Identification of CBD, Δ9-THC, and the endocannabinoid system in the mid-20th century has led to advancement of cannabis-based therapies for epilepsy. Based on clinical trial data, Epidiolex is the first CBD medication approved by a national regulatory agency (US Food and Drug Administration for Dravet and Lennox Gastaut syndrome; European Medicines Agency for Lennox Gastaut syndrome). Approval of CBD as a treatment for these rare and severe pediatric-onset epilepsy syndromes is an important milestone, but the complete spectrum of use of cannabis-derived products, and the use of CBD for other epilepsy syndromes remains to be determined.

Background: At our institution, the standard treatment recommendation for esophageal cancer patients with stage IB–IIIB disease is for neoadjuvant chemoradiation per the CROSS regimen prior to surgery. This regimen can be difficult for patients to tolerate, and they may be unable to receive full dose therapy without treatment dose reductions and delays. Methods: We conducted a quality improvement (QI) project, STRENGTH (Seeking to Reactivate Esophageal and Gastric Treatment Health), to implement supportive care interventions in the prehabilitation phase of neoadjuvant treatment. Our QI program included a standardized chemotherapy order template with supportive care interventions implemented at specific time points. Following implementation of the STRENGTH pathway, a retrospective QI analysis assessed an equal number of patients in the pre-STRENGTH and STRENGTH group for chemotherapy and radiation therapy dose intensities, as well as treatment outcomes. Results: During the pre-STRENGTH period, patients received an average of 5 chemotherapy treatments (range, 2–6), with an average relative dose intensity of 91.8% for carboplatin and 86.7% for paclitaxel. During the STRENGTH period, patients received an average of 6 (range, 5–8) chemotherapy treatments, with an average relative dose intensity of 111.4% for carboplatin and 112.9% for paclitaxel. In the pre-STRENGTH group, one patient did not complete their planned radiation dose due to nausea, vomiting, and dehydration. All patients in the STRENGTH group received their planned radiation dose. In the STRENGTH group, there is a trend of improved pathologic response, longer progression-free survival, and shortened time to surgery. Conclusion: Implementation of the STRENGTH pathway improved chemotherapy dose intensity, with potentially improved oncologic outcomes in the STRENGTH group. We plan to further optimize the STRENGTH program with implementation of standardized dose reduction and delay protocols for both chemotherapy and radiation, and assess the effects of STRENGTH interventions on patient quality of life.

BACKGROUND The purpose of this study is to compare 90-day costs and outcomes for primary total hip arthroplasty patients between a nonobese (body mass index, 18.5-24.9) vs overweight (25-29.9), obese (30-34.9), severely obese (35-39.9), morbidly obese (40-44.9), and super obese (45+) cohorts. METHODS We conducted a retrospective review of an institutional database of primary total hip arthroplasty patients from 2006 to 2013. Thirty-three super-obese patients were identified, and the other 5 cohorts were randomly selected in a 2:1 ratio (n = 363). Demographics, 90-day outcomes (costs, reoperations, and readmissions), and outcomes after 3 years (revisions and change scores for Short-Form Health Survey, Harris Hip Score, and Western Ontario and McMaster Universities Arthritis Index) were collected. Costs were determined using unit costs from our institutional administrative data for all in-hospital resource utilization. Comparisons between the nonobese and other groups were made with Kruskal-Wallis tests for non-normal data and chi-square and Fisher exact test for categorical data. RESULTS The 90-day costs in the morbidly obese ($13,134 ± $7250 mean ± standard deviation, P < .01) and super-obese ($15,604 ± 6783, P < .01) cohorts were significantly greater than the nonobese cohorts ($10,315 ± 1848). Only the super-obese cohort had greater 90-day reoperation and readmission rates than the nonobese cohort (18.2% vs 0%, P < .01 and 21.2% vs 4.5%, P = .02, respectively). Reoperations and septic revisions after 3 years were greater in the super-obese cohort compared to the nonobese cohort 21.2% versus 3.0% (P = .01) and 18.2% versus 1.5% (P = .01), respectively. Improvements in Short-Form Health Survey, Harris Hip Score, and Western Ontario and McMaster Universities Arthritis Index were comparable in all cohorts. CONCLUSION Super-obese patients have greater risks and costs compared to nonobese patients, but also have comparable quality of life improvements.

Background Locally advanced esophageal cancer is often treated with neoadjuvant therapy followed by surgery. Many patients present with or experience clinical deconditioning during neoadjuvant therapy. Prehabilitation programs in other areas of surgery have demonstrated improved postoperative outcomes. The aims of this study were to evaluate the feasibility of a pilot prehabilitation program and determine preliminary effects on surgical and cancer-related outcomes. Methods A retrospective review of patients treated at a single institution with resectable esophageal cancer was performed (n = 22). Patients in the prehabilitation group received protocol-structured intervention in several clinical domains including nutrition, psychosocial support, and physical exercise. Results Clinical stage and comorbidities were well matched between groups. The structured prehabilitation program was feasible and well received by participants. Fewer patients required admission during neoadjuvant therapy in the prehabilitation group (27.3% versus 54.5%). Percentage weight loss during treatment was 3.0% in the prehabilitation group versus 4.3% in the control group. Compared with the control group, the prehabilitation group demonstrated 0.0% versus 18.2% 30-d postoperative readmission rate and 18.2% versus 27.3% 90-d postoperative readmission rate. There were no statistically significant differences between groups in regard to complications or mortality. Conclusions The pilot prehabilitation program demonstrated feasibility of implementing a structured program for patients receiving neoadjuvant therapy for esophageal cancer. Although the small population limits evaluation of statistical significance, trends in the data suggest a potential benefit of the prehabilitation program on neoadjuvant hospital admission rates, postsurgical readmission rates, and nutritional status.

Summary Objective Patients with Lennox‐Gastaut syndrome (LGS) who completed 1 of 2 randomized, double‐blind, placebo‐controlled trials of add‐on cannabidiol (CBD) (GWPCARE3, NCT02224560 or GWPCARE4, NCT02224690) were invited to enroll in an open‐label extension (OLE) study evaluating the long‐term safety and efficacy of CBD (GWPCARE5, NCT02224573). Herein we present an interim analysis of the safety, efficacy, and patient‐reported outcomes from this trial. Methods Patients received a pharmaceutical formulation of highly purified CBD oral solution (Epidiolex; 100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2‐week titration period, in addition to their existing medications. Doses could be reduced if not tolerated or increased up to 30 mg/kg/d if thought to be of benefit. Results This interim analysis was based on a November 2016 data cut. Of 368 patients who completed treatment in GWPCARE3 and GWPCARE4, 366 (99.5%) enrolled in the OLE study (GWPCARE5). Median treatment duration was 38 weeks at a mean modal dose of 23 mg/kg/d. Most patients (92.1%) experienced adverse events (AEs), primarily of mild (32.5%) or moderate (43.4%) severity. The most common AEs were diarrhea (26.8%), somnolence (23.5%), and convulsion (21.3%). Thirty‐five patients (9.6%) discontinued treatment due to AEs. Liver transaminase elevations were reported in 37 patients (10.1%), of whom 29 were receiving concomitant valproic acid; 34 cases resolved spontaneously or with dose modification of CBD or concomitant medication. Median reduction from baseline in drop seizure frequency (quantified monthly over 12‐week periods) ranged from 48% to 60% through week 48. Median reduction in monthly total seizure frequency ranged from 48% to 57% across all 12‐week periods through week 48. Eighty‐eight percent of patients/caregivers reported an improvement in the patient's overall condition per the Subject/Caregiver Global Impression of Change scale. Significance In this study, long‐term add‐on CBD treatment had an acceptable safety profile in patients with LGS and led to sustained reductions in seizures.

A substantial portion of the cost of total knee arthroplasty (TKA) results from the postoperative inpatient length of stay (LOS). Considering the annual increase in TKAs, reducing LOS represents a potential for cost savings. We sought to compare in-hospital costs and patient-reported outcomes for an early discharge protocol compared with the standard LOS following TKA.We conducted a retrospective matched cohort study, matching patients on age, sex, body mass index and preoperative Western OntarioMcMaster Universities Osteoarthritis Index (WOMAC) score. We compared costs associated with time in the operating room, intraoperative pain control and inpatient stay as well as 1-year postoperative patient-reported outcomes between early discharge and standard LOS groups.We included 50 patients in our study (25 per group). The average LOS in the early discharge group was 26.5 hours, compared with 48.9 hours in the standard care group. The early discharge group had higher intraoperative costs associated with pain control (mean difference 26.98, 95% confidence interval 14.41-37.90,In-hospital costs were significantly lower with a postoperative day 1 discharge protocol than with standard LOS following TKA, with no difference in patient-reported outcomes.Une portion substantielle du coût de l'arthroplastie pour prothèse totale du genou (PTG) est liée à la durée du séjour postopératoire. Compte tenu de l'augmentation annuelle des cas de PTG, abréger les séjours représente une source potentielle d'économies. Nous avons comparé les coûts hospitaliers et les résultats signalés par les patients avec un protocole de congé rapide et avec le séjour de durée standard après la PTG.Nous avons procédé à une étude de cohorte rétrospective appariée, où les patients étaient assortis selon le l'âge, le sexe, l'indice de masse corporelle et le score WOMAC (Western OntarioMcMaster Universities Osteoarthritis) préopératoire. Nous avons comparé les coûts associés au temps passé au bloc opératoire, au contrôle de la douleur peropératoire et au séjour hospitalier, de même que les résultats signalés par les patients 1 an après l'intervention entre les 2 groupes (congé rapide c. durée de séjour standard).Nous avons inclus 50 patients dans notre étude (25 par groupe). Le séjour moyen du groupe soumis au congé rapide a été de 26,5 heures, contre 48,9 heures pour le séjour standard. Le groupe soumis au congé rapide a présenté des coûts peropératoires plus élevés associés au contrôle de la douleur (différence moyenne 26,98, intervalle de confiance de 95 % 14,41-37,90,Les coûts perhospitaliers ont été significativement moindres avec le protocole de congé postopératoire rapide (après 1 jour), comparativement au séjour standard après la PTG, sans différence en ce qui concerne les résultats signalés par les patients.

Introduction: The impact of radiation prescription dose on postoperative complications during standard of care trimodality therapy for operable stage II-III esophageal and gastroesophageal junction cancers has not been established.Methods: We retrospectively reviewed 82 patients with esophageal or gastroesophageal junction cancers treated between 2004 and 2016 with neoadjuvant chemoradiation followed by resection at a single institution. Post-operative complications within 30 days were reviewed and scored using the Comprehensive Complication Index (CCI). Results were compared between patients treated with Results: Twenty-nine patients were treated with Conclusions: In selected esophageal and gastroesophageal junction cancer patients, radiation doses ≥ 50 Gy do not appear to increase 30 day post-operative complication rates. These findings suggest that the use of definitive doses of radiotherapy (50–50.4 Gy) in the neoadjuvant setting may not increase post-operative complications.

Over the past decade, pathogenic variants in all members of the ASXL family of genes, ASXL1, ASXL2, and ASXL3, have been found to lead to clinically distinct but overlapping syndromes. Bohring-Opitz syndrome (BOPS) was first described as a clinical syndrome and later found to be associated with pathogenic variants in ASXL1. This syndrome is characterized by developmental delay, microcephaly, characteristic facies, hypotonia, and feeding difficulties. Subsequently, pathogenic variants in ASXL2 were found to lead to Shashi-Pena syndrome (SHAPNS) and in ASXL3 to lead to Bainbridge-Ropers syndrome (BRPS). While SHAPNS and BRPS share many core features with BOPS, there also seem to be emerging clear differences. Here, we present five cases of BOPS, one case of SHAPNS, and four cases of BRPS. By adding our cohort to the limited number of previously published patients, we review the overlapping features of ASXL-related diseases that bind them together, while focusing on the characteristics that make each neurodevelopmental syndrome unique. This will assist in diagnosis of these overlapping conditions and allow clinicians to more comprehensively counsel affected families.

Background Patient-specific instrumentation (PSI) has been introduced in total knee arthroplasty (TKA) with the goal of increased accuracy of component positioning by custom fitting cutting guides to the patient’s bony anatomy. A criticism of this technology is the associated cost. The purpose of this randomized controlled trial was to determine the cost-utility of PSI compared with standard of care (SOC) instrumentation for TKA in an obese population. Methods Patients with body mass index greater than 30 with osteoarthritis and undergoing primary TKA were randomized to SOC or PSI. Patients completed a health care resource use diary and the EuroQol-5D at three, six, nine, and 12 months and the Western Ontario and McMaster Universities Osteoarthritis Index at three and 12 months postsurgery. We performed cost-utility and cost-effectiveness analyses from public health care payer and societal perspectives. Results One hundred seventy-three patients were included in the analysis with 86 patients randomized to PSI and 87 to SOC. PSI was dominated (more costly and less effective) by SOC from a health care payer perspective. From a societal perspective, an incremental cost-utility ratio was calculated at $11,230.00 per quality-adjusted life year gained, which is cost-effective at a willingness to pay threshold of $50,000. Net benefit analyses found PSI was not significantly cost-effective at any willingness to pay value from either perspective. Conclusion Our results suggest that widespread adoption of PSI may not be economically attractive or clinically indicated. Future considerations are to compare long-term clinical outcomes and radiographic alignment between the groups.

Significance Autism spectrum disorders (ASDs) have increasingly been associated with mitochondrial dysfunction, corroborated by mitochondrial DNA (mtDNA) germline and somatic variants being found in ASD patients. If mitochondrial defects can generate ASD, then specific mtDNA mutations should induce ASD endophenotypes in mice. We tested this prediction by introduction of an mtDNA ND6 gene missense mutation (ND6P25L) into the mouse germline and found ASD endophenotypes. The ND6P25L mice exhibit impaired social interaction, compulsive behavior, and increased anxiety. They have reduced electroencephalographic delta and theta wave power, increased predilection to seizures, but without diminution of hippocampal interneurons. These endophenotypes correlate with impaired cortical and hippocampal mitochondrial respiration and increased reactive oxygen species production. Thus, mitochondrial defects can be sufficient to produce ASD phenotypes., Autism spectrum disorders (ASDs) are characterized by a deficit in social communication, pathologic repetitive behaviors, restricted interests, and electroencephalogram (EEG) aberrations. While exhaustive analysis of nuclear DNA (nDNA) variation has revealed hundreds of copy number variants (CNVs) and loss-of-function (LOF) mutations, no unifying hypothesis as to the pathophysiology of ASD has yet emerged. Based on biochemical and physiological analyses, it has been hypothesized that ASD may be the result of a systemic mitochondrial deficiency with brain-specific manifestations. This proposal has been supported by recent mitochondrial DNA (mtDNA) analyses identifying both germline and somatic mtDNA variants in ASD. If mitochondrial defects do predispose to ASD, then mice with certain mtDNA mutations should present with autism endophenotypes. To test this prediction, we examined a mouse strain harboring an mtDNA ND6 gene missense mutation (P25L). This mouse manifests impaired social interactions, increased repetitive behaviors and anxiety, EEG alterations, and a decreased seizure threshold, in the absence of reduced hippocampal interneuron numbers. EEG aberrations were most pronounced in the cortex followed by the hippocampus. Aberrations in mitochondrial respiratory function and reactive oxygen species (ROS) levels were also most pronounced in the cortex followed by the hippocampus, but absent in the olfactory bulb. These data demonstrate that mild systemic mitochondrial defects can result in ASD without apparent neuroanatomical defects and that systemic mitochondrial mutations can cause tissue-specific brain defects accompanied by regional neurophysiological alterations.

© 2021 Joule Inc. or its licensors. BACKGROUND: An important aim of high tibial osteotomy (HTO) is to prevent or delay the need for total knee replacement (TKR). We sought to estimate the frequency and timing of conversion from HTO to TKR and the factors associated with it. METHODS: We prospectively evaluated patients with osteoarthritis (OA) of the knee who underwent medial opening wedge HTO from 2002 to 2014 and analyzed the cumulative incidence of TKR in July 2019. The presence or absence of TKR on the HTO limb was identified from the orthopedic surgery reports and knee radiographs contained in the electronic medical records for each patient at London Health Sciences Centre. We used cumulative incidence curves to evaluate the primary outcome of time to TKR. We used multivariable Cox proportional hazards analysis to assess potential preoperative predictors including radiographic disease severity, malalignment, correction size, pain, sex, age, body mass index (BMI) and year of surgery. RESULTS: Among 556 patients who underwent 643 HTO procedures, the cumulative incidence of TKR was 5% (95% confidence interval [CI] 3%–7%) at 5 years and 21% (95% CI 17%–26%) at 10 years. With the Cox proportional hazards multivariable model, the following preoperative factors were significantly associated with an increased rate of conversion: radiographic OA severity (adjusted hazard ratio [HR] 1.96, 95% CI 1.12–3.45), pain (adjusted HR 0.85, 95% CI 0.75–0.96)], female sex (adjusted HR 1.67, 95% CI 1.08–2.58), age (adjusted HR 1.50 per 10 yr, 95% CI 1.17–1.93) and BMI (adjusted HR 1.31 per 5 kng/m2, 95% CI 1.12–1.53). INTERPRETATION: We found that 79% of knees did not undergo TKR within 10 years after undergoing medial opening wedge HTO. The strongest predictor of conversion to TKR is greater radiographic disease at the time of HTO.

Objective The aim of the current study was to evaluate the utility of evoked potentials as a biomarker of cortical function in Rett syndrome (RTT). As a number of disease-modifying therapeutics are currently under development, there is a pressing need for biomarkers to objectively and precisely assess the effectiveness of these treatments. Method Yearly visual evoked potentials (VEPs) and auditory evoked potentials (AEPs) were acquired from individuals with RTT, aged 2 to 37 years, and control participants across 5 sites as part of the Rett Syndrome and Related Disorders Natural History Study. Baseline and year 1 data, when available, were analyzed and the repeatability of the results was tested. Two syndrome-specific measures from the Natural History Study were used for evaluating the clinical relevance of the VEP and AEP parameters. Results At the baseline study, group level comparisons revealed reduced VEP and AEP amplitude in RTT compared to control participants. Further analyses within the RTT group indicated that this reduction was associated with RTT-related symptoms, with greater severity associated with lower VEP and AEP amplitude. In participants with RTT, VEP and AEP amplitude was also negatively associated with age. Year 1 follow-up data analyses yielded similar findings and evidence of repeatability of EPs at the individual level. Interpretation The present findings indicate the promise of evoked potentials (EPs) as an objective measure of disease severity in individuals with RTT. Our multisite approach demonstrates potential research and clinical applications to provide unbiased assessment of disease staging, prognosis, and response to therapy. ANN NEUROL 2021;89:790-802.

Theropod dinosaurs are minor components of Late Triassic ecosystems in North America, comprising coelophysoids and various non-neotheropods from the Chinle Formation of Arizona, Utah, Colorado, and...

Background Adjustable bilateral Harada-Ito procedures have been described, sometimes with asymmetric adjustment used to correct vertical misalignment when coexisting with torsional strabismus. We investigated the causes of significant postoperative torsional incomitance noted in some patients undergoing these procedures. Methods The medical records of patients who underwent bilateral Harada-Ito procedures for bilateral trochlear nerve palsy between 1980 and 2018 were reviewed retrospectively. Cases with simultaneous operation on any other oblique or vertical rectus muscle were excluded. Surgical results, especially using Lancaster red-green (Lan R-G) plots, were correlated with the procedures performed. Results A total of 17 patients were included. At their last follow-up visit (mean, 12 months after surgery), 9 were diplopia free. Of the 8 with continuing diplopia, 2 had undercorrection and 1 had Brown syndrome. In 5 patients with continuing diplopia, there was relative intorsion of the eye movement paths in upgaze and relative extorsion of these paths in downgaze, a type of torsional incomitance. Asymmetric adjustment with tightening of one superior oblique tendon, and often loosening of the contralateral superior oblique tendon, had been performed in those 5 cases. Only 1 of the successful cases had the same type of asymmetric adjustment. There was a positive association between the severity of the preoperative Lan R-G pattern and postoperative diplopia. Conclusions Asymmetric adjustment of bilateral Harada-Ito procedures when attempting to correct the coexisting vertical misalignment can cause significant torsional incomitance with incomplete correction of extorsion in downgaze and intorsion in upgaze. This pattern may result in postoperative diplopia that is surgically challenging to correct.

Background The purpose of our study is to assess which patient-related and caregiver-related factors are predictive of caregiver strain and assistance when caring for total hip and knee arthroplasty (THA and TKA) patients within 2 weeks after surgery. Methods We conducted a prospective study of caregivers of participants enrolled in 2 randomized trials. Caregivers provided demographics and completed the Caregiver Strain Index and Caregiver Assistance Scale pre-surgery and post-surgery. We performed backwards stepwise regression with mixed-effects negative binomial models to investigate predictors of caregiver strain and assistance for THA and TKA caregivers. Results Three hundred six caregiver/patient pairs were included. Our models of caregiver strain found Caregiver Assistance Scale scores and patient age to be predictive for all caregivers. We also found caregiver gender and smoking status to be predictive for THA caregivers and caregiver age to be predictive for TKA caregivers. Our models of assistance provided by caregivers found time (post-surgery vs pre-surgery) was predictive for all caregivers. We also found patient body mass index, and patient and caregiver gender to be predictive for THA caregivers, and patient and caregiver employment status and caregiver education level to be predictive for TKA caregivers. Conclusion Our study identifies patient-related and caregiver-related factors which are associated with caregiver strain and assistance when caring for arthroplasty patients. As this is the first study to assess assistance provided by caregivers, it is important for future research to validate our results and to further explore whether patient-reported outcomes may also be related to assistance and strain.

Purpose To describe 10-week and 12-month outcomes following treatment for divergence insufficiency–type esotropia in adults. Methods In this prospective observational study, 110 adults with divergence insufficiency–type esotropia, with a distance esodeviation measuring 2Δ to 30Δ and at least 25% larger at distance than near, and binocular diplopia present at least “sometimes” at distance, were enrolled at 28 sites when initiating new treatment. Surgery, prism, or divergence exercises/therapy were chosen at the investigator’s discretion. Diplopia was assessed at enrollment and at 10-week and 12-month outcome examinations using a standardized diplopia questionnaire (DQ). Success was defined as DQ responses of “rarely” or “never” when looking straight ahead in the distance, with no alternative treatment initiated. Results Of the 110 participants, 32 (29%) were prescribed base-out prism; none had received prior treatment for esotropia. Success criteria were met by 22 of 30 at 10 weeks (73%; 95% CI, 54%-88%) and by 16 of 26 at 12 months (62%; 95% CI, 41%-80%). For the 76 (68%) who underwent strabismus surgery (82% of whom had been previously treated with prism), success criteria were met by 69 of 74 at 10 weeks (93%; 95% CI, 85%-98%) and by 57 of 72 at 12 months (79%; 95% CI, 68%-88%). Conclusions In this study cohort, both base-out prism as initial therapy and strabismus surgery (usually following prism) were successful in treating diplopia for most adults with divergence insufficiency–type esotropia when assessed during the first year of follow-up.

Background A significant proportion of the overall cost of total hip arthroplasty (THA) results from the inpatient hospital stay following the procedure. Considering the substantial and increasing number of these procedures performed annually, shifting to an outpatient model of care where the patient is discharged home the same day as their surgery represents a potential for significant cost savings. The potential significant impact of an outpatient care model on constrained healthcare budgets and lack of high-quality evidence regarding its effectiveness warrants a rigorous comparative trial. The purpose of this prospective, randomized controlled trial is to evaluate outpatient care pathways for THA. Specifically, our objectives are to compare the rate of serious adverse events and estimate the cost-effectiveness of outpatient compared to standard inpatient THA. Methods We will include patients undergoing primary THA whom have an American Society of Anaesthetists status equal to or less than three, live within a 60-min driving distance of the institution and have an adult to accompany them home postoperatively and stay with them overnight. Consenting patients will be randomized to be discharged on the same day as surgery, as outpatients, or as inpatients according to standard of care (minimum of one night in hospital) using a modified Zelen consent model. The primary outcome measure is the incidence of serious adverse events at 30 days postoperative. Participants and their caregivers will complete secondary outcomes measures at each follow-up visit including patient-reported outcome measures and self-reported cost questionnaires. Discussion This protocol is the first randomized trial to use blinding to evaluate outpatient THA compared to standard overnight stay and first to prospectively perform a full economic evaluation. It is also the first adequately powered trial to prospectively assess the safety of outpatient THA. Successful completion of this study could have the potential to provide clinical evidence for the role of outpatient THA in current practice. Trial registration This study was retrospectively registered on ClinicalTrials.gov (NCT03026764) on March 9th, 2016.

Background: We examined characteristics of early-onset colorectal cancer (CRC) patients to identified factors, which may lead to earlier diagnosis. Materials & methods: This is a retrospective study with inclusion criteria: CRC diagnosed between 2012 and 2018 and age at diagnosis

The CACNA1G gene encodes the low-voltage-activated Cav3.1 channel, which is expressed in various areas of the CNS, including the cerebellum. We studied two missense CACNA1G variants, p.L208P and p.L909F, and evaluated the relationships between the severity of Cav3.1 dysfunction and the clinical phenotype. The presentation was of a developmental and epileptic encephalopathy without evident cerebellar atrophy. Both patients exhibited axial hypotonia, developmental delay, and severe to profound cognitive impairment. The patient with the L909F mutation had initially refractory seizures and cerebellar ataxia, whereas the L208P patient had seizures only transiently but was overall more severely affected. In transfected mammalian cells, we determined the biophysical characteristics of L208P and L909F variants, relative to the wild-type channel and a previously reported gain-of-function Cav3.1 variant. The L208P mutation shifted the activation and inactivation curves to the hyperpolarized direction, slowed the kinetics of inactivation and deactivation, and reduced the availability of Ca2+ current during repetitive stimuli. The L909F mutation impacted channel function less severely, resulting in a hyperpolarizing shift of the activation curve and slower deactivation. These data suggest that L909F results in gain-of-function, whereas L208P exhibits mixed gain-of-function and loss-of-function effects due to opposing changes in the biophysical properties. Our study expands the clinical spectrum associated with CACNA1G mutations, corroborating further the causal association with distinct complex phenotypes.

Objectives The Multidimensional Symptom Index (MSI) is a 10-item parallel score frequency×interference patient-reported outcome for use in clinical pain research. This manuscript describes results related to measurement stability, discriminative accuracy when screening for major depressive disorder (MDD), and prognostic validity when predicting recovery trajectories after acute musculoskeletal (MSK) trauma. Methods Data were drawn from a longitudinal cohort study of adults with acute MSK trauma, supplemented by a secondary sample of adults with chronic pain. Results In a sample of n=23 stable participants over a 1-month period, reliability metrics indicated good stability for all 5 subscales (ICC3,1: 0.70 to 0.91). In a mixed acute/chronic sample (n=148), the Number of Symptoms and Nonsomatic Symptoms subscales showed clinically useful discriminative accuracy for MDD screening (area under the curve=0.86 and 0.88, respectively). In n=129 with acute MSK trauma, the Mean Interference and Nonsomatic Symptoms subscales showed significant prognostic validity for classifying participants into "recovery expected" or "recovery not expected" groups with 72.5% and 92.2% accuracy, respectively. Discussion The MSI holds promise as a tool for evaluating change, screening for MDD, and identifying those at high or low risk of poor recovery. The results favor sensitivity over specificity. The labile nature of the acute pain symptoms and a truncated distribution of Nonsomatic Symptoms scores in that group both require some caution in interpretation. The MSI appears to be a potentially useful tool for rapid pain phenotyping, evaluation, and quick screening purposes in clinical practice.

Background Arthrogryposis multiplex congenita (AMC) is characterized by joint contractures present in at least two body areas. In addition to these contractures, individuals with AMC can have decreased muscle mass, leading to limitations in activities of daily living. Exercise has the potential to maintain or improve the range of motion and muscle strength. However, this type of intervention necessitates frequent follow ups that are currently difficult to provide for youths with AMC because they often live far from a specialized hospital. To overcome this distance challenge, telecommunication technologies can be used to deliver rehabilitation remotely, which is called telerehabilitation. The study protocol for one such type of rehabilitation will be presented in this paper. Objective This pilot study aims to (1) evaluate the feasibility of using telerehabilitation to provide a home exercise program for youths with AMC, and (2) assess the effectiveness of a home exercise program. Methods A total of 10 youths aged 8-21 years with AMC will be recruited. The intervention consists of a 12-week individualized home-based exercise program delivered remotely using telerehabilitation. At baseline, youths will complete the Physical Activity Questionnaire for Adolescents and the Pediatrics Outcomes Data Collection Instrument to assess pain, function, and level of physical activity. During the first telerehabilitation meeting, the rehabilitation therapists will measure range of motion using a virtual goniometer and assess the youth’s functional level. The therapists will then use the Goal Attainment Scale to set objectives and develop the individualized intervention. Follow ups will occur every 3 weeks to make sure exercises are performed safely and to progress the exercises when needed. At the end of the 12-week intervention, rehabilitation therapists will re-evaluate the youth using the same outcome measures as the initial evaluation. The youths will be asked to complete the same questionnaires, with the addition of questions about their satisfaction regarding the intervention. Nonparametric and descriptive statistics will be used to evaluate the feasibility and effectiveness. Results Ethics approval was obtained in October 2018. Recruitment and data collection started in January 2019 and was completed in May 2020. Conclusions This pilot study will help us learn how a large-scale project may work in practice to improve outcomes in physical activity, pain, and function, and goal attainment among youths with AMC, thus informing a future clinical trial. International Registered Report Identifier (IRRID) DERR1-10.2196/18688

Rett syndrome is a debilitating neurodevelopmental disorder for which no disease-modifying treatment is available. Fortunately, advances in our understanding of the genetics and pathophysiology of Rett syndrome has led to the development of promising new therapeutics for the condition. Several of these therapeutics are currently being tested in clinical trials with others likely to progress to clinical trials in the coming years. The failure of recent clinical trials for Rett syndrome and other neurodevelopmental disorders has highlighted the need for electrophysiological or other objective biological markers of treatment response to support the success of clinical trials moving forward. The purpose of this review is to describe the existing studies of electroencephalography (EEG) and evoked potentials (EPs) in Rett syndrome and discuss the open questions that must be addressed before the field can adopt these measures as surrogate endpoints in clinical trials. In addition to summarizing the human work on Rett syndrome, we also describe relevant studies with animal models and the limited research that has been carried out on Rett-related disorders, particularly methyl-CpG binding protein 2 (MECP2) duplication syndrome, CDKL5 deficiency disorder, and FOXG1 disorder.

BackgroundRett syndrome (RTT) is a severe, progressive neurodevelopmental disorder with multisystem comorbidities that evolve across a patient’s lifespan requiring attentive coordination of subspecialty care by primary care providers. A comprehensive, up-to-date synthesis of medical comorbidities in RTT would aid care coordination and anticipatory guidance efforts by healthcare providers. Our objective was to review and summarise published evidence regarding prevalence of RTT medical comorbidities across all relevant organ systems.MethodsSearch of PubMed from January 2000 to July 2019 was performed using the search terms (Rett and MECP2 AND patient) OR (Rett and MECP2 AND cohort). Articles reporting the prevalence of clinical findings in RTT were assessed with respect to the size and nature of the cohorts interrogated and their relevance to clinical care.ResultsAfter review of over 800 records, the multisystem comorbidities of RTT were summarised quantitatively from 18 records comprising both retrospective and prospective cohorts (31–983 subjects). Neurological comorbidities had the highest prevalence, occurring in nearly all individuals with gastrointestinal and orthopaedic concerns almost as prevalent as neurological. With the exception of low bone mineral content which was relatively common, endocrine comorbidities were seen in only around one-third of patients. Although more prevalent compared with the general population, cardiac conduction abnormalities were the least common comorbidity in RTT.ConclusionsEffective care coordination for RTT requires knowledge of and attention to multiple comorbidities across multiple unrelated organ systems. Many issues common to RTT can potentially be managed by a primary care provider but the need for sub-specialist referral can be anticipated. Since the median life expectancy extends into the sixth decade with evolving subspecialty requirements throughout this time, paediatric providers may be tasked with continued coordination of these comorbidities or transitioning to adult medicine and specialists with experience managing individuals with complex medical needs.

BackgroundRett syndrome (RTT) is a severe neurodevelopmental disorder with complex medical comorbidities extending beyond the nervous system requiring the attention of health professionals. There is no peer-reviewed, consensus-based therapeutic guidance to care in RTT. The objective was to provide consensus on guidance of best practice for addressing these concerns.MethodsInformed by the literature and using a modified Delphi approach, a consensus process was used to develop guidance for care in RTT by health professionals.ResultsTypical RTT presents early in childhood in a clinically recognisable fashion. Multisystem comorbidities evolve throughout the lifespan requiring coordination of care between primary care and often multiple subspecialty providers. To assist health professionals and families in seeking best practice, a checklist and detailed references for guidance were developed by consensus.ConclusionsThe overall multisystem issues of RTT require primary care providers and other health professionals to manage complex medical comorbidities within the context of the whole individual and family. Given the median life expectancy well into the sixth decade, guidance is provided to health professionals to achieve current best possible outcomes for these special-needs individuals.