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Background and Purpose: Select neuroactive steroids tune neural activity by modulating excitatory and inhibitory neurotransmission, including the endogenous cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-HC), which is an N-methyl-d-aspartate (NMDA) receptor positive allosteric modulator (PAM). NMDA receptor PAMs are potentially an effective pharmacotherapeutic strategy to treat conditions associated with NMDA receptor hypofunction., Experimental Approach: Using in vitro and in vivo electrophysiological recording experiments and behavioural approaches, we evaluated the effect of SAGE-718, a novel neuroactive steroid NMDA receptor PAM currently in clinical development for the treatment of cognitive impairment, on NMDA receptor function and endpoints that are altered by NMDA receptor hypoactivity and assessed its safety profile., Key Results: SAGE-718 potentiated GluN1/GluN2A-D NMDA receptors with equipotency and increased NMDA receptor excitatory postsynaptic potential (EPSP) amplitude without affecting decay kinetics in striatal medium spiny neurons. SAGE-718 increased the rate of unblock of the NMDA receptor open channel blocker ketamine on GluN1/GluN2A in vitro and accelerated the rate of return on the ketamine-evoked increase in gamma frequency band power, as measured with electroencephalogram (EEG), suggesting that PAM activity is driven by increased channel open probability. SAGE-718 ameliorated deficits due to NMDA receptor hypofunction, including social deficits induced by subchronic administration of phencyclidine, and behavioural and electrophysiological deficits from cholesterol and 24(S)-HC depletion caused by 7-dehydrocholesterol reductase inhibition. Finally, SAGE-718 did not produce epileptiform activity in a seizure model or neurodegeneration following chronic dosing., Conclusions and Implications: These findings provide strong evidence that SAGE-718 is a neuroactive steroid NMDA receptor PAM with a mechanism that is well suited as a treatment for conditions associated with NMDA receptor hypofunction., (© 2023 Sage Therapeutics. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objectives Developmental dysplasia of the hip (DDH) encompasses a spectrum of abnormalities in the immature hip. Surgical intervention is indicated if conservative management fails. Despite the increased supply of pediatric orthopedic surgeons (POSs) over the last few decades, there continues to be a maldistribution of surgeons. The purpose of this study is to determine outcomes following surgical management of hip dysplasia by POSs compared to non-pediatric orthopedic surgeons. Methods Pediatric patients who underwent surgical treatment for hip dysplasia from 2012 to 2019 were identified using a large national database. Patient demographics, comorbidities, and postoperative complications were compared by pediatric versus nonpediatric-trained orthopedic surgeons. Bivariate and multivariable regression analyses were performed. Results Of the 10,780 pediatric patients who underwent hip dysplasia surgery, 10,206 patients (94.7%) were operated on by a POS, whereas 574 (5.3%) were operated on by a non-pediatric orthopedic surgeon. POSs were more likely to operate on patients with a higher American Society of Anesthesiologists class (p<0.001) and those with a greater number of medical comorbidities, including cardiac (p=0.001), gastrointestinal (p=0.017), and neurological (p<0.001). Following analysis using multivariable regression models to control for patient baseline characteristics, there were no differences in any postoperative complications between patients treated by pediatric-trained and nonpediatric-trained orthopedic surgeons. Conclusions Compared to non-pediatric orthopedic surgeons, POSs were more likely to operate on younger patients with increased medical comorbidities. However, there were no differences in postoperative complications following surgical management for DDH in patients treated by nonpediatric and pediatric orthopedic surgeons., Competing Interests: Dr. Sean Tabaie is a current board member of the American Academy of Orthopaedic Surgeons (AAOS)., (Copyright © 2024, Dance et al.)

Introduction: This study presents stratified meta-analysis and projected cost per case analysis of direct anterior approach (DAA) versus posterior approach (PA) in total hip arthroplasty (THA) to determine the best surgical approach and guarantee hip joint longevity., Methods: Several online databases were searched for clinical trials comparing DAA and PA in primary THA. The stratified analysis was conducted to test for confounding and biases across the different types of included trials. The average cost and probability were used to determine projected added costs of medical and surgical management for complications., Results: 30 clinical trials included 11,562 patients who underwent THA. Almost 50% of these patients performed DAA. As compared to PA, both non-stratified and stratified analyses demonstrated that DAA has a significant higher incidence of the overall intra- and postoperative complications (non-stratified, OR 1.64; p  = 0.003) (stratified, OR 4.12; p  = 0.005), nerve injury (non-stratified, OR 22.0; p   <  0.00001) (stratified, OR 0.28; p  < 0.00001), higher rate of revision surgery (non-stratified; OR 1.54; p  = 0.01) (stratified, OR 7.37; p  = 0.006), and higher incidence of surgical wound complications (non-stratified; OR 1.67; p  = 0.002) as compared to PA following primary THA. In addition, DAA demonstrated higher trends of incidence (non-statistically significant) of femur fracture (Non-stratified, OR 1.32, p  = 0.10) and thrombo-embolic complications (Retrospective studies, OR 1.39, p  = 0.69). However, PA demonstrated higher trends of incidence (non-statistically significant) of hip joint dislocation, as compared to DAA. (Stratified RCTs, OR 0.63, p  = 0.65]. Collectively, this amounts a $421,068.68 surplus in DAA complication costs., Conclusions: PA may provide a more lucrative, safer approach to those undergoing THA given its comparable postoperative outcomes, reduced complication rates, and lower overall cost relative to DAA.

Pharmacogenomic testing, together with the early detection of drug-drug-gene interactions (DDGI) before initiating opioids, can improve the selection of dosage and reduce the risk of adverse drug interactions and therapeutic failures following Total Joint Arthroplasty. The variants of CYP genes can mediate DDGI. Orthopedic surgeons should become familiar with the genetic aspect of opioid use and abuse, as well as the influence of the patient genetic makeup in opioid selection and response, and polymorphic variants in pain modulation., Competing Interests: Disclosure The authors have no source of funding and no conflict of interest to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To quantify the financial impact of an anterior cruciate ligament (ACL) injury on the remaining career earnings of National Basketball Association (NBA) players., Methods: We performed a retrospective review of all NBA players who had an ACL rupture between 2000 and 2019. Players were matched to healthy controls by age, position, body mass index, and player efficiency rating at the time of injury (index year). Player information collected included demographic information, position, team role, draft pick, date of injury, contract length, and earnings during the 3 years before and 7 years after the index year, as well as new contract length and earnings after injury., Results: A total of 12 players (22%) did not return to play (RTP). No statistically significant difference in annual earnings was present at any time point between cohorts. When we examined the mean difference in earnings between the first 3 post-index seasons and the 3 pre-index seasons, both the ACL and control cohorts showed increased salaries as players' careers progressed, without a significant difference in earnings. When comparing cohorts, we found no significant difference in the length and earnings of contracts during the index year. Furthermore, there was no significant difference in the length or earnings of the first new contract signed after the index year between cohorts. Additionally, NBA players who were able to RTP after ACL reconstruction were more likely to experience increased earnings if they had greater experience and performance prior to their injury ( P < .01)., Conclusions: Our study found that NBA players did not experience diminished earnings after RTP from an ACL reconstruction when compared with matched controls. Furthermore, no differences were seen in lengths of new contracts or in contract earnings between cohorts. Players with greater experience and performance prior to injury were more likely to have increased earnings after ACL reconstruction., Level of Evidence: Level III, retrospective case-control study., (© 2021 by the Arthroscopy Association of North America. Published by Elsevier Inc.)

Aims: It has been suggested that the direct anterior approach (DAA) should be used for total hip arthroplasty (THA) instead of the posterior approach (PA) for better early functional outcomes. We conducted a value-based analysis of the functional outcome and associated perioperative costs, to determine which surgical approach gives the better short-term outcomes and lower costs., Methods: This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol and the Cochrane Handbook. Several online databases were searched. Non-stratified and stratified meta-analyses were conducted to test the confounding biases in the studies which were included. The mean cost and probability were used to determine the added costs of perioperative services., Results: The DAA group had significantly longer operating times (p < 0.001), reduced length of hospital stay by a mean of 13.4 hours (95% confidence interval (CI) 9.12 to 18; p < 0.001), and greater blood loss (p = 0.030). The DAA group had significantly better functional outcome at three (p < 0.001) and six weeks (p = 0.006) postoperatively according to the Harris Hip Score (HHS). However, there was no significant difference between the groups for the HHS at six to eight weeks (p = 0.230), 12 weeks (p = 0.470), six months (p = 0.740), and one year (p = 0.610), the 12-Item Short Form Survey (SF-12) physical score at six weeks (p = 0.580) and one year (p = 0.360), SF-12 mental score at six weeks (p = 0.170) and one year (p = 0.960), and University of California and Los Angeles (UCLA) activity scale at 12 weeks (p = 0.250). The mean non-stratified and stratified difference in costs for the operating theatre time and blood transfusion were $587.57 (95% CI 263.83 to 1,010.29) to $887.04 (95% CI 574.20 to 1,298.88) and $248.38 (95% CI 1,003.40 to 1,539.90) to $1,162.41 (95% CI 645.78 to 7,441.30), respectively, more for the DAA group. However, the mean differences in costs for the time in hospital were $218.23 and $192.05, respectively, less for the DAA group., Conclusion: The use of the DAA, rather than the PA, in THA has earlier benefits for function and pain. However, these are short-lasting, with no significant differences seen at later intervals. In addition the limited benefits were obtained with higher cumulative costs for DAA. Cite this article: Bone Joint J  2021;103-B(6):1078-1087.

Introduction: Hip fractures remain one of the most prevalent and deadly conditions afflicting those 65 years and older. For other health conditions (e.g. myocardial infarction), hospital location is associated with poorer health outcomes. To our knowledge, no study has investigated the relationship between hip fracture morality rate in the United States between urban and rural hospital settings., Methods: A retrospective cohort study was conducted to examine differences in in-hospital mortality between groups treated in rural, urban-teaching, and urban-non-teaching hospitals, as well as public and private hospitals. Mortality rates were also compared for variances between surgical treatment, sex, insurance, patient location, race, and income. Discharge data was collected for 256,240 inpatient stays from the 2012 National Inpatient Sample (NIS), Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality., Results: Odds of mortality were 14.6% greater in rural hospital hip fracture patients compared to Urban/Non-Teaching centers (p < 0.05)., Conclusions: Results from this study lend support to necessitate further research investigating prospective barriers to care of those in rural settings. This may point to limitations in resources and trained medical and surgical specialists in rural hospitals and need for continued research to mitigate such findings., Competing Interests: The authors report no conflicts of interest and no funding, (© 2020 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights reserved.)

Enhancing remyelination is a key therapeutic strategy for demyelinating diseases such as multiple sclerosis. To achieve this goal, a central challenge is being able to quantitatively and longitudinally track functional remyelination, especially with translatable biomarkers that can be performed in both preclinical models and in the clinic. We developed the methodology to stably measure multi-modal sensory evoked potentials from the skull surface over the course of months in individual mice and applied it to a genetic mouse model of oligodendrocyte ablation and demyelination. We found that auditory and somatosensory evoked potential latencies reliably increased over time during the early phase of the model and recovered spontaneously and almost completely during a later phase. Histological examination supported the interpretation that the evoked potential latency changes dynamically reflect changes in CNS myelination. Specifically, we found reduction of myelination in corresponding brain regions at the time that sensory evoked potentials were maximally impacted. Importantly, we also found that myelination levels recovered when evoked potential latencies recovered. Other changes known to associate with demyelination were also observed at the time of delayed evoked potentials, including the emergence of white matter vacuoles and increased markers for activated microglia and macrophages; these changes also fully reversed by the time that evoked potentials recovered. Our results support the hypothesis that skull-surface recorded evoked potential latencies can dynamically track CNS myelination changes. The methods developed here allow for longitudinally tracking functional myelination changes in vivo in preclinical rodent models with a quantitative biomarker that can also be applied clinically and will facilitate translational development of CNS remyelinating therapies., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Mutations in superoxide dismutase 1 (SOD1) are responsible for 20% of familial ALS. Given the gain of toxic function in this dominantly inherited disease, lowering SOD1 mRNA and protein is predicted to provide therapeutic benefit. An early generation antisense oligonucleotide (ASO) targeting SOD1 was identified and tested in a phase I human clinical trial, based on modest protection in animal models of SOD1 ALS. Although the clinical trial provided encouraging safety data, the drug was not advanced because there was progress in designing other, more potent ASOs for CNS application. We have developed next-generation SOD1 ASOs that more potently reduce SOD1 mRNA and protein and extend survival by more than 50 days in SOD1G93A rats and by almost 40 days in SOD1G93A mice. We demonstrated that the initial loss of compound muscle action potential in SOD1G93A mice is reversed after a single dose of SOD1 ASO. Furthermore, increases in serum phospho-neurofilament heavy chain levels, a promising biomarker for ALS, are stopped by SOD1 ASO therapy. These results define a highly potent, new SOD1 ASO ready for human clinical trial and suggest that at least some components of muscle response can be reversed by therapy.

How a mixture of acoustic sources is perceptually organized into discrete auditory objects remains unclear. One current hypothesis postulates that perceptual segregation of different sources is related to the spatiotemporal separation of cortical responses induced by each acoustic source or stream. In the present study, the dynamics of subthreshold membrane potential activity were measured across the entire tonotopic axis of the rodent primary auditory cortex during the auditory streaming paradigm using voltage-sensitive dye imaging. Consistent with the proposed hypothesis, we observed enhanced spatiotemporal segregation of cortical responses to alternating tone sequences as their frequency separation or presentation rate was increased, both manipulations known to promote stream segregation. However, across most streaming paradigm conditions tested, a substantial cortical region maintaining a response to both tones coexisted with more peripheral cortical regions responding more selectively to one of them. We propose that these coexisting subthreshold representation types could provide neural substrates to support the flexible switching between the integrated and segregated streaming percepts., (Copyright © 2015 the American Physiological Society.)

Natural acoustic stimuli contain slow temporal fluctuations, and the modulation of ongoing slow-wave activity by bottom-up and top-down factors plays essential roles in auditory cortical processing. However, the spatiotemporal pattern of intrinsic slow-wave activity across the auditory cortical modality is unknown. Using in vivo voltage-sensitive dye imaging in anesthetized guinea pigs, we measured spectral tuning to acoustic stimuli across several core and belt auditory cortical areas, and then recorded spontaneous activity across this defined network. We found that phase coherence in spontaneous slow-wave (delta-theta band) activity was highest between regions of core and belt areas that had similar frequency tuning, even if they were distant. Further, core and belt regions with high phase coherence were phase shifted. Interestingly, phase shifts observed during spontaneous activity paralleled latency differences for evoked activity. Our findings suggest that the circuits underlying this intrinsic source of slow-wave activity support coordinated changes in excitability between functionally matched but distributed regions of the auditory cortical network.

The neuroscience of tinnitus represents an ideal model to explore central issues in brain functioning such as the formation of auditory percepts, in addition to opening up new treatment avenues for the condition in the long-term. The present review discusses the origin and nature of tinnitus-related neural activity. First, we review evidence for the hypothesis that tinnitus is caused by the central nervous system changes induced by sensory deprivation, even when hearing loss is not visible in the audiogram. Second, we suggest that changes in neural activity in individual central structures may not be sufficient to underlie the tinnitus percept. Instead, we propose that tinnitus may arise from functional alterations at multiple levels which promote abnormal propagation of neural activity throughout the network involved in auditory perception. In this context, functional coupling within and between central auditory structures may be especially important to consider. Investigating how sensory deprivation affects functional coupling between areas, which might be reflected in changes in temporal coherence of intrinsic ongoing activity patterns, may give critical insights into the mechanisms of tinnitus., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The significance of the mismatch negativity (MMN), an event-related potential measured in humans which indexes novelty in the auditory environment, has motivated a search for a cellular correlate of this process. A leading candidate is stimulus-specific adaptation (SSA) in auditory cortex units, which shares several characteristics with the MMN. Whether auditory cortex responses encode sensory novelty, a defining property of the MMN, however, has not been resolved. To evaluate this key issue, we used several variations of the auditory oddball paradigm from the human literature and examined psychophysical and pharmacological properties of multiunit activity in the auditory cortex of awake rodents. We found converging evidence dissociating SSA from sensory novelty and the MMN. First, during an oddball paradigm with frequency deviants, neuronal responses showed clear SSA but failed to encode novelty in a manner analogous to the human MMN. Second, oddball paradigms using intensity or duration deviants revealed a pattern of unit responses that showed sensory adaptation, but again without any measurable novelty correlates aligning to the human MMN. Finally NMDA antagonists, which are known to disrupt the MMN, suppressed the magnitude of multiunit responses in a nonspecific manner, leaving the process of SSA intact. Together, our results suggest that auditory novelty detection as indexed by the MMN is dissociable from SSA at the level of activity encoded by auditory cortex neurons. Further, the NMDA sensitivity reported for the MMN, which models the disruption of MMN observed in schizophrenia, may occur at a mechanistic locus outside of SSA.

In the adult visual cortex, multiple feature maps exist and have characteristic spatial relationships with one another. The relationships can be reproduced by "dimension-reduction" computational models, suggesting that the principles of continuity and coverage may underlie cortical map organization. However, the mechanisms responsible for establishing these relationships are unknown. We explored whether removing one feature map during development causes a coordinated reorganization of the remaining maps or whether the remaining maps are unaffected. We removed the ocular dominance map by monocular enucleation in newborn ferrets, so that single eye stimulation drove the cortex in a more spatially uniform manner in adult monocular animals compared with normal animals. Maps of orientation, spatial frequency, and retinotopy formed in monocular ferrets, but their structures and spatial relationships differed from those in normal ferrets. The wavelength of the orientation map increased, so that the average orientation gradient across the cortex decreased. The decrease in the orientation gradient in monocular animals was most prominent in the high gradient regions of the spatial frequency map, indicating a coordinated reorganization between these two maps. In monocular animals, the orthogonal relationship between the orientation and spatial frequency maps was preserved, and the orthogonal relationship between the orientation and retinotopic maps became more pronounced. These results were consistent with detailed predictions of a dimension-reduction model of cortical organization. Thus, the number of feature maps in a cortical area influences the relationships between them, and inputs to the cortex have a significant role in generating these relationships.

Whether general principles can explain the layouts of cortical maps remains unresolved. In primary visual cortex of ferret, the relationships between the maps of visual space and response features are predicted by a "dimension-reduction" model. The representation of visual space is anisotropic, with the elevation and azimuth axes having different magnification. This anisotropy is reflected in the orientation, ocular dominance, and spatial frequency domains, which are elongated such that their directions of rapid change, or high-gradient axes, are orthogonal to the high-gradient axis of the visual map. The feature maps are also strongly interdependent-their high-gradient regions avoid one another and intersect orthogonally where essential, so that overlap is minimized. Our results demonstrate a clear influence of the visual map on each feature map. In turn, the local representation of visual space is smooth, as predicted when many features are mapped within a cortical area.