Search

The Little pocket mouse (Perognathus longimembris) encompasses 15 to 16 currently recognized subspecies, six of which are restricted to southern California and adjacent northern Baja California. Using cranial geomorphometric shape parameters and dorsal color variables we delineate six regional groups of populations from this area that we recognize as valid, but these differ in name combination and geographic range from the current taxonomy. We resurrect two names from their current placement in synonymies, synonymize two currently recognized subspecies, and we reassign a third. Importantly, we restrict the U. S. Federally endangered Pacific pocket mouse (P. l. pacificus Mearns) to the vicinity of its type locality at the mouth of the Tijuana River in the southwestern corner of San Diego County and resurrect P. l. cantwelli von Bloeker for the other two population segments along the coast, those that span the northwestern corner of San Diego County and adjacent Orange County and that in coastal Los Angeles County. The name cantwelli would now apply to the only extant populations of the Pacific pocket mouse, a reassignment with obvious management implications. Our taxonomic decisions also reconfigure the ranges of other subspecies of conservation concern, notably P. l. bangsi Mearns and P. l. brevinasus Osgood.

Aims The aims of this study were to assess mapping models to predict the three-level version of EuroQoL five-dimension utility index (EQ-5D-3L) from the Oxford Knee Score (OKS) and validate these before and after total knee arthroplasty (TKA). Methods A retrospective cohort of 5,857 patients was used to create the prediction models, and a second cohort of 721 patients from a different centre was used to validate the models, all of whom underwent TKA. Patient characteristics, BMI, OKS, and EQ-5D-3L were collected preoperatively and one year postoperatively. Generalized linear regression was used to formulate the prediction models. Results There were significant correlations between the OKS and EQ-5D-3L preoperatively ( r = 0.68; p < 0.001) and postoperatively ( r = 0.77; p < 0.001) and for the change in the scores ( r = 0.61; p < 0.001). Three different models (preoperative, postoperative, and change) were created. There were no significant differences between the actual and predicted mean EQ-5D-3L utilities at any timepoint or for change in the scores (p > 0.090) in the validation cohort. There was a significant correlation between the actual and predicted EQ-5D-3L utilities preoperatively ( r = 0.63; p < 0.001) and postoperatively ( r = 0.77; p < 0.001) and for the change in the scores ( r = 0.56; p < 0.001). Bland-Altman plots demonstrated that a lower utility was overestimated, and higher utility was underestimated. The individual predicted EQ-5D-3L that was within ± 0.05 and ± 0.010 (minimal clinically important difference (MCID)) of the actual EQ-5D-3L varied between 13% to 35% and 26% to 64%, respectively, according to timepoint assessed and change in the scores, but was not significantly different between the modelling and validation cohorts (p ≥ 0.148). Conclusion The OKS can be used to estimate EQ-5D-3L. Predicted individual patient utility error beyond the MCID varied from one-third to two-thirds depending on timepoint assessed, but the mean for a cohort did not differ and could be employed for this purpose. Cite this article: Bone Jt Open 2022;3(7):573–581.

Motivation: Extracellular vesicles (EVs) are produced and released by most cells and are now recognized to play a role in intercellular communication through the delivery of molecular cargo, including proteins, lipids, and RNA. Small RNA sequencing (small RNA-seq) has been widely used to characterize the small RNA content in EVs. However, there is a lack of a systematic assessment of the quality, technical biases, RNA composition, and RNA biotypes enrichment for small RNA profiling of EVs across cell types, biofluids, and conditions. Methods: We collected and reanalyzed small RNA-seq datasets for 2756 samples from 83 studies involving 55 with EVs only and 28 with both EVs and matched donor cells. We assessed their quality by the total number of reads after adapter trimming, the overall alignment rate to the host and non-host genomes, and the proportional abundance of total small RNA and specific biotypes, such as miRNA, tRNA, rRNA, and Y RNA. Results: We found that EV extraction methods varied in their reproducibility in isolating small RNAs, with effects on small RNA composition. Comparing proportional abundances of RNA biotypes between EVs and matched donor cells, we discovered that rRNA and tRNA fragments were relatively enriched, but miRNAs and snoRNA were depleted in EVs. Except for the export of eight miRNAs being context-independent, the selective release of most miRNAs into EVs was study-specific. Conclusion: This work guides quality control and the selection of EV isolation methods and enhances the interpretation of small RNA contents and preferential loading in EVs.

Background Robotic-assisted unicompartmental knee arthroplasty (UKA) improves implant accuracy, however whether this translates to patient function is less clear. Various outcomes have been reported but muscle recovery has not been previously investigated. Objective To explore sequential change in lower limb muscle strength following robotic-assisted UKA with isokinetic dynamometry. Results 12 participants undergoing rUKA for medial compartment osteoarthritis were assessed pre-operatively, and at 6- and 12-weeks post-operatively. Maximal muscle strength changed over time in both quadriceps (p = 0.006) and hamstrings (p = 0.018) muscle groups. Quadriceps strength reduced from 88.52(39.86)Nm to 74.47(27.58)Nm by 6-weeks (p = 0.026), and then recovered to 90.41(38.76)Nm by 12-weeks (p = 0.018). Hamstring strength reduced from 62.45(23.18)Nm to 54.12(20.49)Nm by 6-weeks (p = 0.016), and then recovered to 55.07(17.99)Nm by 12-weeks (p = 0.028). By 12-weeks quadriceps strength was 70% and hamstrings 83% of the values achieved in the un-operated limb. Substantial improvement was seen in all other measures over time, with sequential positive change in Timed-up-and-go test (p = 0.015), 10 m walk test (p = 0.021), range of knee flexion (p = 0.016) and PROMs (p

Aims This systematic review aims to compare the precision of component positioning, patient-reported outcome measures (PROMs), complications, survivorship, cost-effectiveness, and learning curves of MAKO robotic arm-assisted unicompartmental knee arthroplasty (RAUKA) with manual medial unicompartmental knee arthroplasty (mUKA). Methods Searches of PubMed, MEDLINE, and Google Scholar were performed in November 2021 according to the Preferred Reporting Items for Systematic Review and Meta-­Analysis statement. Search terms included “robotic”, “unicompartmental”, “knee”, and “arthroplasty”. Published clinical research articles reporting the learning curves and cost-effectiveness of MAKO RAUKA, and those comparing the component precision, functional outcomes, survivorship, or complications with mUKA, were included for analysis. Results A total of 179 articles were identified from initial screening, of which 14 articles satisfied the inclusion criteria and were included for analysis. The papers analyzed include one on learning curve, five on implant positioning, six on functional outcomes, five on complications, six on survivorship, and three on cost. The learning curve was six cases for operating time and zero for precision. There was consistent evidence of more precise implant positioning with MAKO RAUKA. Meta-analysis demonstrated lower overall complication rates associated with MAKO RAUKA (OR 2.18 (95% confidence interval (CI) 1.06 to 4.49); p = 0.040) but no difference in re-intervention, infection, Knee Society Score (KSS; mean difference 1.64 (95% CI -3.00 to 6.27); p = 0.490), or Western Ontario and McMaster Universities Arthritis Index (WOMAC) score (mean difference -0.58 (95% CI -3.55 to 2.38); p = 0.700). MAKO RAUKA was shown to be a cost-effective procedure, but this was directly related to volume. Conclusion MAKO RAUKA was associated with improved precision of component positioning but was not associated with improved PROMs using the KSS and WOMAC scores. Future longer-term studies should report functional outcomes, potentially using scores with minimal ceiling effects and survival to assess whether the improved precision of MAKO RAUKA results in better outcomes. Cite this article: Bone Joint J 2022;104-B(5):541–548.

Zebrafish spontaneously regenerate their retina in response to damage through the action of Müller glia. Even though Müller glia (MG) are conserved in higher vertebrates, the capacity to regenerate retinal damage is lost. Recent work has focused on the regulation of inflammation during tissue regeneration with precise temporal roles for macrophages and microglia. Senescent cells that have withdrawn from the cell cycle have mostly been implicated in aging, but are still metabolically active, releasing pro-inflammatory signaling molecules as part of the Senescence Associated Secretory Phenotype (SASP). Here, we discover that in response to retinal damage, a subset of cells expressing markers of microglia/macrophages also express markers of senescence. These cells display a temporal pattern of appearance and clearance during retina regeneration. Premature removal of senescent cells by senolytic treatment led to a decrease in proliferation and incomplete repair of the ganglion cell layer after NMDA damage. Our results demonstrate a role for modulation of senescent cell responses to balance inflammation, regeneration, plasticity, and repair as opposed to fibrosis and scarring.

Aims The aim of this study was to identify the minimal clinically important difference (MCID), minimal important change (MIC), minimal detectable change (MDC), and patient-acceptable symptom state (PASS) in the Forgotten Joint Score (FJS) according to patient satisfaction six months following total hip arthroplasty (THA) in a UK population. Methods During a one-year period, 461 patients underwent a primary THA and completed preoperative and six-month FJS, with a mean age of 67.2 years (22 to 93). At six months, patient satisfaction was recorded as very satisfied, satisfied, neutral, dissatisfied, or very dissatisfied. The difference between patients recording neutral (n = 31) and satisfied (n = 101) was used to define the MCID. MIC for a cohort was defined as the change in the FJS for those patients declaring their outcome as satisfied, whereas receiver operating characteristic curve analysis was used to determine the MIC for an individual and the PASS. Distribution-based methodology was used to calculate the MDC. Results Using satisfaction as the anchor, the MCID for the FJS was 8.1 (95% confidence interval (CI) 3.7 to 15.9; p = 0.040), which was affirmed when adjusting for confounding. The MIC for the FJS for a cohort of patients was 17.7 (95% CI 13.7 to 21.7) and for an individual patient was 18. The MDC90 for the FJS was eight, meaning that 90% of patients scoring more than this will have experienced a real change that is beyond measurement error. The PASS threshold for the FJS was defined as 29. Conclusion The MCID and MIC can be used respectively to assess whether there is a clinical difference between two groups, or whether a cohort or patient has had a meaningful change in their FJS. Both values were greater than measurement error (MDC90), suggesting a real change. The PASS threshold for the postoperative FJS can be used as a marker of achieving patient satisfaction following THA. Cite this article: Bone Joint J 2021;103-B(12):1759–1765.

Aims The primary aim of this study was to assess whether non-fatal postoperative venous thromboembolism (VTE) within six months of surgery influences the knee-specific functional outcome (Oxford Knee Score (OKS)) one year after total knee arthroplasty (TKA). Secondary aims were to assess whether non-fatal postoperative VTE influences generic health and patient satisfaction at this time. Methods A study of 2,393 TKAs was performed in 2,393 patients. Patient demographics, comorbidities, OKS, EuroQol five-dimension score (EQ-5D), and Forgotten Joint Score (FJS) were collected preoperatively and one year postoperatively. Overall patient satisfaction with their TKA was assessed at one year. Patients with VTE within six months of surgery were identified retrospectively and compared with those without. Results A total of 37 patients (1.5%) suffered a VTE and were significantly more likely to have associated comorbidities of stroke (p = 0.026), vascular disease (p = 0.026), and kidney disease (p = 0.026), but less likely to have diabetes (p = 0.046). In an unadjusted analysis, patients suffering a VTE had a significantly worse postoperative OKS (difference in mean (DIM) 4.8 (95% confidence interval (CI) 1.6 to 8.0); p = 0.004) and EQ-5D (DIM 0.146 (95% CI 0.059 to 0.233); p = 0.001) compared with patients without a VTE. After adjusting for confounding variables VTE remained a significant independent predictor associated with a worse postoperative OKS (DIM -5.4 (95% CI -8.4 to -2.4); p < 0.001), and EQ-5D score (DIM-0.169 (95% CI -0.251 to -0.087); p < 0.001). VTE was not independently associated with overall satisfaction after TKA (odds ratio 0.89 (95% CI 0.35 to 2.07); p = 0.717). Conclusion Patients who had a VTE within six months of their TKA had clinically significantly worse knee-specific outcome (OKS) and general health (EQ-5D) scores one year postoperatively, but the overall satisfaction with their TKA was similar to those patients who did not have a VTE. Cite this article: Bone Joint J 2021;103-B(7):1254–1260.

Electronic skin (E-skin) is an emerging wearable device typically used to mimic the function of the human skin, mainly by replicating the role of tactile sensory receptors in the skin. This study showed an interesting modification of the E-skin, called an electro-prosthetic E-skin, which adds the functionality of distance sensing and stimulation of the palmar digital nerve. The electro-prosthetic E-skin operates as a closed loop to deliver the finger aperture distance information to the nervous system. This E-skin was implemented as an additional layer mounted to the original human skin, to be worn on the fingertip with a thin silicone substrate. The E-skin was designed to be mounted onto the index fingertip, to deliver the distance information between the fingertips and to enhance the finger aperture distance control. In this study, we demonstrated that electro-prosthetic proprioception (EPP), implemented with the electro-prosthetic E-skin, successfully delivered the distance information between the fingertips and enhanced the finger aperture distance control accuracy. Clinical Relevance- Presented electro-prosthetic E-skin delivering finger aperture distance via electro-prosthetic proprioception (EPP) will enhance accuracy of the finger aperture distance control. This technology can be applied to the neurosurgery to minimize unforced errors caused by the limited human control accuracy over the fingertip.

Sleep in epilepsy is best studied in longitudinal preclinical animal models, where state changes can have significant effects on epileptic activities. Voluminous data makes it very difficult to mark sleep stages manually. This demands an automated way to detect sleep and wake states. We developed an approach to characterize sleep-wake states in continuous video-electroencephalography (EEG) recordings in animals. We compared brute force approach based on frequency band-power based thresholding with machine learning algorithms to detect sleep in 600 hours of EEG data from 4 epileptic and 2 control animals. We found that conventional delta and theta band-powers were prominent in sleep; however, this was not sufficient to detect sleep algorithmically. We therefore extracted a set of novel frequency bands to robustly differentiate individual sleep states by using brute-force algorithm and machine learning models, among which k-nearest neighbors (KNN) was the best predictor of sleep with 94% accuracy. We subsequently characterized sleep patterns in animals with chronically induced epileptic spiking in the neocortex from tetanus toxin injections using brute-force algorithm. We found that epileptic spiking animals (without seizures) sleep more frequently, with significantly longer sleep segments and overall daily sleep time, as compared to control animals. This automated algorithm could help expedite sleep studies and help us understand the relationship between sleep and patients with epilepsy.

Neurotraumas and neurological diseases often result in compromised proprioceptive feedback, which plays a critical role in motor control by delivering real-time position information. Electro-prosthetic proprioception (EPP) using frequency-modulated electrotactile feedback is a promising solution, as it can deliver proprioceptive information such as a joint angle via tactile channel. Prior works demonstrated that EPP successfully delivered distance information between the end effector and the target object. In this study, we implemented the electronic skin (E-skin) monitoring the elbow joint angle and delivering it to the nervous system via tactile channel. We also demonstrated that EPP improved both accuracy and precision of the elbow joint angle control. The gyroscope measuring the elbow joint angle and electrodes delivering electrotactile feedback were integrated together as a skin using thin silicon coating and polyurethane film. We call this novel E-skin, monitoring and delivering joint angle information, as an electro-prosthetic E-skin. Elbow joint angle matching test with two healthy human subjects showed that the EPP, via electro-prosthetic E-skin, enhanced 101.7% accuracy and 63.8% precision in elbow joint angle control. Clinical Relevance-Presented electro-prosthetic E-skin will address the compromised proprioceptive feedback by delivering joint angle information by electro-prosthetic proprioception (EPP) via tactile channel. This novel E-skin will open up a new path to assist and rehabilitative motor control problems after neurotraumas and neurological diseases.

Aims Debate continues regarding the optimum management of periprosthetic distal femoral fractures (PDFFs). This study aims to determine which operative treatment is associated with the lowest perioperative morbidity and mortality when treating low (Su type II and III) PDFFs comparing lateral locking plate fixation (LLP-ORIF) or distal femoral arthroplasty (DFA). Methods This was a retrospective cohort study of 60 consecutive unilateral (PDFFs) of Su types II (40/60) and III (20/60) in patients aged ≥ 60 years: 33 underwent LLP-ORIF (mean age 81.3 years (SD 10.5), BMI 26.7 (SD 5.5); 29/33 female); and 27 underwent DFA (mean age 78.8 years (SD 8.3); BMI 26.7 (SD 6.6); 19/27 female). The primary outcome measure was reoperation. Secondary outcomes included perioperative complications, calculated blood loss, transfusion requirements, functional mobility status, length of acute hospital stay, discharge destination and mortality. Kaplan-Meier survival analysis was performed. Cox multivariate regression analysis was performed to identify risk factors for reoperation after LLP-ORIF. Results Follow-up was at mean 3.8 years (1.0 to 10.4). One-year mortality was 13% (8/60). Reoperation was more common following LLP-ORIF: 7/33 versus 0/27 (p = 0.008). Five-year survival for reoperation was significantly better following DFA; 100% compared to 70.8% (95% confidence interval (CI) 51.8% to 89.8%, p = 0.006). There was no difference for the endpoint mechanical failure (including radiological loosening); ORIF 74.5% (56.3 to 92.7), and DFA 78.2% (52.3 to 100, p = 0.182). Reoperation following LLP-ORIF was independently associated with medial comminution; hazard ratio (HR) 10.7 (1.45 to 79.5, p = 0.020). Anatomical reduction was protective against reoperation; HR 0.11 (0.013 to 0.96, p = 0.046). When inadequately fixed fractures were excluded, there was no difference in five-year survival for either reoperation (p = 0.156) or mechanical failure (p = 0.453). Conclusion Absolute reoperation rates are higher following LLP fixation of low PDFFs compared to DFA. Where LLP-ORIF was well performed with augmentation of medial comminution, there was no difference in survival compared to DFA. Though necessary in very low fractures, DFA should be used with caution in patients with greater life expectancies due to the risk of longer term aseptic loosening. Cite this article: Bone Joint J 2021;103-B(4):635–643.

Individual education programs (IEPs) are the foundation for guiding speech-language pathologists (SLPs) to develop appropriate interventions for culturally and linguistically diverse (CLD) students who qualify for speech-language services under the Individuals with Disabilities Education Act. There is a growing number of CLD students with speech-language impairments who need special attention given to their culture and language. This article highlights key culturally and linguistically responsive features to aid SLPs in developing meaningful IEPs for this diverse group of students.

This systematic review and meta-analysis were conducted to compare the accuracy of component positioning, alignment and balancing techniques employed, patient-reported outcomes, and complications of robotic-arm assisted total knee arthroplasty (RATKA) with manual TKA (mTKA) and the associated learning curve. Searches of PubMed, Medline and Google Scholar were performed in October 2020 using PRISMA guidelines. Search terms included “robotic”, “knee” and “arthroplasty”. The criteria for inclusion were published clinical research articles reporting the learning curve for RATKA and those comparing the component position accuracy, alignment and balancing techniques, functional outcomes, or complications with mTKA. There were 198 articles identified, following full text screening, 16 studies satisfied the inclusion criteria and reported the learning curve of rTKA (n=5), component positioning accuracy (n=6), alignment and balancing techniques (n=7), functional outcomes (n=7), or complications (n=5). Two studies reported the learning curve using CUSUM analysis to establish an inflexion point for proficiency which ranged from 7 to 11 cases and there was no learning curve for component positioning accuracy. The meta-analysis showed a significantly lower difference between planned component position and implanted component position, and the spread was narrower for RATKA compared with the mTKA group (Femur coronal: mean 1.31, 95% confidence interval (CI) 1.08–1.55, ppp=0.004). There was no difference in arthrofibrosis, superficial and deep infection, wound dehiscence, or overall complication rates. RATKA demonstrated improved accuracy of component positioning and patient-reported outcomes. The learning curve of RATKA for operating time was between 7 and 11 cases. Future well-powered studies on RATKAs should report on the knee alignment and balancing techniques utilised to enable better comparisons on which techniques maximise patient outcomes.Level of evidence III.

Aims The aim of this study was to determine whether fixation, as opposed to revision arthroplasty, can be safely used to treat reducible Vancouver B type fractures in association with a cemented collarless polished tapered femoral stem (the Exeter). Methods This retrospective cohort study assessed 152 operatively managed consecutive unilateral Vancouver B fractures involving Exeter stems; 130 were managed with open reduction and internal fixation (ORIF) and 22 with revision arthroplasty. Mean follow-up was 6.5 years (SD 2.6; 3.2 to 12.1). The primary outcome measure was revision of at least one component. Kaplan–Meier survival analysis was performed. Regression analysis was used to identify risk factors for revision following ORIF. Secondary outcomes included any reoperation, complications, blood transfusion, length of hospital stay, and mortality. Results Fractures (B1 n = 74 (49%); B2 n = 50 (33%); and B3 n = 28 (18%)) occurred at median of 4.2 years (interquartile range (IQR) 1.2 to 9.2) after primary total hip arthroplasty (THA) (n = 138) or hemiarthroplasty (n = 14). Rates of revision and reoperation were significantly higher following revision arthroplasty compared to ORIF for B2 (p = 0.001) and B3 fractures (p = 0.050). Five-year survival was significantly better following ORIF: 92% (95% confidence interval (CI) 86.4% to 97.4%) versus 63% (95% CI 41.7% to 83.3%), p < 0.001. ORIF was associated with reduced blood transfusion requirement and reoperations, but there were no differences in medical complications, hospital stay, or mortality between surgical groups. No independent predictors of revision following ORIF were identified: where the bone-cement interface was intact, fixation of B2 or B3 fractures was not associated with an increased risk of revision. Conclusion When the bone-cement interface was intact and the fracture was anatomically reducible, all Vancouver B fractures around Exeter stems could be managed with fixation as opposed to revision arthroplasty. Fixation was associated with reduced need for blood transfusion and lower risk of revision surgery compared with revision arthroplasty. Cite this article: Bone Joint J 2021;103-B(2):309–320.

Aims The primary aim of this study was to compare the hip-specific functional outcome of robotic assisted total hip arthroplasty (rTHA) with manual total hip arthroplasty (mTHA) in patients with osteoarthritis (OA). Secondary aims were to compare general health improvement, patient satisfaction, and radiological component position and restoration of leg length between rTHA and mTHA. Methods A total of 40 patients undergoing rTHA were propensity score matched to 80 patients undergoing mTHA for OA. Patients were matched for age, sex, and preoperative function. The Oxford Hip Score (OHS), Forgotten Joint Score (FJS), and EuroQol five-dimension questionnaire (EQ-5D) were collected pre- and postoperatively (mean 10 months (SD 2.2) in rTHA group and 12 months (SD 0.3) in mTHA group). In addition, patient satisfaction was collected postoperatively. Component accuracy was assessed using Lewinnek and Callanan safe zones, and restoration of leg length were assessed radiologically. Results There were no significant differences in the preoperative demographics (p ≥ 0.781) or function (p ≥ 0.383) between the groups. The postoperative OHS (difference 2.5, 95% confidence interval (CI) 0.1 to 4.8; p = 0.038) and FJS (difference 21.1, 95% CI 10.7 to 31.5; p < 0.001) were significantly greater in the rTHA group when compared with the mTHA group. However, only the FJS was clinically significantly greater. There was no difference in the postoperative EQ-5D (difference 0.017, 95% CI -0.042 to 0.077; p = 0.562) between the two groups. No patients were dissatisfied in the rTHA group whereas six were dissatisfied in the mTHA group, but this was not significant (p = 0.176). rTHA was associated with an overall greater rate of component positioning in a safe zone (p ≤ 0.003) and restoration of leg length (p < 0.001). Conclusion Patients undergoing rTHA had a greater hip-specific functional outcome when compared to mTHA, which may be related to improved component positioning and restoration of leg length. However, there was no difference in their postoperative generic health or rate of satisfaction. Cite this article: Bone Joint Res 2021;10(1):22–30.

Background Gorham-Stout disease is a rare condition characterized by vascular proliferation and the massive destruction of bone tissue. With less than 400 cases in the literature of Gorham-Stout syndrome, we performed a unique study combining whole-genome sequencing and RNA-Seq to probe the genomic features and differentially expressed pathways of a presented case, revealing new possible drivers and biomarkers of the disease. Case presentation We present a case report of a white 45-year-old female patient with marked bone loss of the left humerus associated with vascular proliferation, diagnosed with Gorham-Stout disease. The analysis of whole-genome sequencing showed a dominance of large structural DNA rearrangements. Particularly, rearrangements in chromosomes seven, twelve, and twenty could contribute to the development of the disease, especially a gene fusion involving ATG101 that could affect macroautophagy. The study of RNA-sequencing data from the patient uncovered the PI3K/AKT/mTOR pathway as the most affected signaling cascade in the Gorham-Stout lesional tissue. Furthermore, M2 macrophage infiltration was detected using immunohistochemical staining and confirmed by deconvolution of the RNA-seq expression data. Conclusions The way that DNA and RNA aberrations lead to Gorham-Stout disease is poorly understood due to the limited number of studies focusing on this rare disease. Our study provides the first glimpse into this facet of the disease, exposing new possible therapeutic targets and facilitating the clinicopathological diagnosis of Gorham-Stout disease.

Small extracellular vesicles (sEVs), 50–150 nm in diameter, have been proposed to mediate cell–cell communication with important implications in tumor microenvironment interactions, tumor growth, and metastasis. We previously showed that mutant KRAS colorectal cancer (CRC) cells release sEVs containing Rab13 protein and mRNA. Previous work had shown that disruption of intracellular Rab13 trafficking inhibits epithelial cell proliferation and invasiveness. Here, we show that Rab13 additionally regulates the secretion of sEVs corresponding to both traditional exosomes and a novel subset of vesicles containing both β1-integrin and Rab13. We find that exposure of recipient cells to sEVs from KRAS mutant donor cells increases proliferation and tumorigenesis and that knockdown of Rab13 blocks these effects. Thus, Rab13 serves as both a cargo protein and as a regulator of sEV secretion. Our data support a model whereby Rab13 can mediate its effects on cell proliferation and invasiveness via autocrine and paracrine signaling.

Aims The primary aim of the study was to compare the knee-specific functional outcome of robotic unicompartmental knee arthroplasty (rUKA) with manual total knee arthroplasty (mTKA) for the management of isolated medial compartment osteoarthritis. Secondary aims were to compare length of hospital stay, general health improvement, and satisfaction between rUKA and mTKA. Methods A powered (1:3 ratio) cohort study was performed. A total of 30 patients undergoing rUKA were propensity score matched to 90 patients undergoing mTKA for isolated medial compartment arthritis. Patients were matched for age, sex, body mass index (BMI), and preoperative function. The Oxford Knee Score (OKS) and EuroQol five-dimension questionnaire (EQ-5D) were collected preoperatively and six months postoperatively. The Forgotten Joint Score (FJS) and patient satisfaction were collected six months postoperatively. Length of hospital stay was also recorded. Results There were no significant differences in the preoperative demographics (p ⩾ 0.150) or function (p ⩾ 0.230) between the groups. The six-month OKS was significantly greater in the rUKA group when compared with the mTKA group (difference 7.7, p < 0.001). There was also a greater six-month postoperative EQ-5D (difference 0.148, p = 0.002) and FJS (difference 24.2, p < 0.001) for the rUKA when compared to the mTKA. No patient was dissatisfied in the rUKA group and five (6%) were dissatisfied in the mTKA, but this was not significant (p = 0.210). Length of stay was significantly (p < 0.001) shorter in the rUKA group (median two days, interquartile range (IQR) 1 to 3) compared to the mTKA (median four days, IQR 3 to 5). Conclusion Patients with isolated medial compartment arthritis had a greater knee-specific functional outcome and generic health with a shorter length of hospital stay after rUKA when compared to mTKA. Cite this article: Bone Joint Res 2019;9(1):15–22.

Aims There are comparatively few randomized studies evaluating knee arthroplasty prostheses, and fewer still that report longer-term functional outcomes. The aim of this study was to evaluate mid-term outcomes of an existing implant trial cohort to document changing patient function over time following total knee arthroplasty using longitudinal analytical techniques and to determine whether implant design chosen at time of surgery influenced these outcomes. Methods A mid-term follow-up of the remaining 125 patients from a randomized cohort of total knee arthroplasty patients (initially comprising 212 recruited patients), comparing modern (Triathlon) and traditional (Kinemax) prostheses was undertaken. Functional outcomes were assessed with the Oxford Knee Score (OKS), knee range of movement, pain numerical rating scales, lower limb power output, timed functional assessment battery, and satisfaction survey. Data were linked to earlier assessment timepoints, and analyzed by repeated measures analysis of variance (ANOVA) mixed models, incorporating longitudinal change over all assessment timepoints. Results The mean follow-up of the 125 patients was 8.12 years (7.3 to 9.4). There was a reduction in all assessment parameters relative to earlier assessments. Longitudinal models highlight changes over time in all parameters and demonstrate large effect sizes. Significant between-group differences were seen in measures of knee flexion (medium-effect size), lower limb power output (large-effect size), and report of worst daily pain experienced (large-effect size) favouring the Triathlon group. No longitudinal between-group differences were observed in mean OKS, average daily pain report, or timed performance test. Satisfaction with outcome in surviving patients at eight years was 90.5% (57/63) in the Triathlon group and 82.8% (48/58) in the Kinemax group, with no statistical difference between groups (p = 0.321). Conclusion At a mean 8.12 years, this mid-term follow-up of a randomized controlled trial cohort highlights a general reduction in measures of patient function with patient age and follow-up duration, and a comparative preservation of function based on implant received at time of surgery. Cite this article: Bone Joint J 2020;102-B(4):434–441.

Background Epithelial-to-mesenchymal transition (EMT) is a process linked to metastasis and drug resistance with non-coding RNAs (ncRNAs) playing pivotal roles. We previously showed that miR-100 and miR-125b, embedded within the third intron of the ncRNA host gene MIR100HG, confer resistance to cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in colorectal cancer (CRC). However, whether the MIR100HG transcript itself has a role in cetuximab resistance or EMT is unknown. Methods The correlation between MIR100HG and EMT was analyzed by curating public CRC data repositories. The biological roles of MIR100HG in EMT, metastasis and cetuximab resistance in CRC were determined both in vitro and in vivo. The expression patterns of MIR100HG, hnRNPA2B1 and TCF7L2 in CRC specimens from patients who progressed on cetuximab and patients with metastatic disease were analyzed by RNAscope and immunohistochemical staining. Results The expression of MIR100HG was strongly correlated with EMT markers and acted as a positive regulator of EMT. MIR100HG sustained cetuximab resistance and facilitated invasion and metastasis in CRC cells both in vitro and in vivo. hnRNPA2B1 was identified as a binding partner of MIR100HG. Mechanistically, MIR100HG maintained mRNA stability of TCF7L2, a major transcriptional coactivator of the Wnt/β-catenin signaling, by interacting with hnRNPA2B1. hnRNPA2B1 recognized the N6-methyladenosine (m6A) site of TCF7L2 mRNA in the presence of MIR100HG. TCF7L2, in turn, activated MIR100HG transcription, forming a feed forward regulatory loop. The MIR100HG/hnRNPA2B1/TCF7L2 axis was augmented in specimens from CRC patients who either developed local or distant metastasis or had disease progression that was associated with cetuximab resistance. Conclusions MIR100HG and hnRNPA2B1 interact to control the transcriptional activity of Wnt signaling in CRC via regulation of TCF7L2 mRNA stability. Our findings identified MIR100HG as a potent EMT inducer in CRC that may contribute to cetuximab resistance and metastasis by activation of a MIR100HG/hnRNPA2B1/TCF7L2 feedback loop.

Control of movement uses error feedback during practice to predict actions for the next movement. We have shown that augmenting error can enhance motor learning, while such findings are encouraging, new methods are needed to accommodate a person's individual reactions to error. The current study demonstrates the design we call error fields (EF), where we temper the augmentation when errors are less likely. We tested the ability of healthy participants (n=21) to adapt to a visual transformation, and we enhanced the training with error fields. We found that training with error fields led to the fastest learning and greatest reduction in error. EF training reduced error more and faster than controls who practiced without error fields (50% more and 46% faster in the target direction; 21% more and 67% faster in the direction perpendicular to that). Moreover, EF was also significantly greater and faster than our previous error augmentation (EA) technique. Hence, clear advantages exist no mater how this is measured or compared to controls. These findings represent an effective teaching method for enhanced training that leverages the statistics of error.

Walking is an important activity that supports the health-related quality of life, and for those who need assistance, robotic devices are available to help. Recent progress in wearable robots has identified the importance of customizing the assistance provided by the robot to the individual, resulting in robot adaptation to the human. However, current implementations minimize the role of human adaptation to the robot, for example, by the users modifying their movements based on the provided robot assistance. This study investigated the effect of visual feedback to guide the users in adapting their movements in response to wearable robot assistance. The visual feedback helped the users reduce their metabolic cost of walking without any changes in robot assistance in a given time. In a case with the initially metabolic expensive (IMExp) exoskeleton condition, both training methods helped reduce the metabolic cost of walking. The results suggest that visual feedback training is helpful to use the exoskeleton for various conditions. Without feedback, the training is helpful only for the IMExp exoskeleton condition. This result suggests visual feedback training can be useful to facilitate the use of non-personalized, generic assistance, where the assistance is not tuned for each user, in a relatively short time.

Background Neurorehabilitation engineering faces numerous challenges to translating new technologies, but it is unclear which of these challenges are most limiting. Our aim is to improve understanding of rehabilitation therapists’ real-time decision-making processes on the use of rehabilitation technology (RT) in clinical treatment. Methods We used a phenomenological qualitative approach, in which three OTs and two PTs employed at a major, technology-encouraging rehabilitation hospital wrote vignettes from a written prompt describing their RT use decisions during treatment sessions with nine patients (4 with stroke, 2 traumatic brain injury, 1 spinal cord injury, 1 with multiple sclerosis). We then coded the vignettes using deductive qualitative analysis from 17 constructs derived from the RT literature and the Consolidated Framework for Implementation Research (CFIR). Data were synthesized using summative content analysis. Results Of the constructs recorded, the five most prominent are from CFIR determinants of: (i) relative advantage, (ii) personal attributes of the patients, (iii) clinician knowledge and beliefs of the device/intervention, (iv) complexity of the devices including time and setup, and (v) organizational readiness to implement. Therapists characterized candidate RT as having a relative disadvantage compared to conventional treatment due to lack of relevance to functional training. RT design also often failed to consider the multi-faceted personal attributes of the patients, including diagnoses, goals, and physical and cognitive limitations. Clinicians’ comfort with RT was increased by their previous training but was decreased by the perceived complexity of RT. Finally, therapists have limited time to gather, setup, and use RT. Conclusions Despite decades of design work aimed at creating clinically useful RT, many lack compatibility with clinical translation needs in inpatient neurologic rehabilitation. New RT continue to impede the immediacy, versatility, and functionality of hands-on therapy mediated treatment with simple everyday objects.

Little is known about how two people physically coupled together (a dyad) can accomplish tasks. In a pilot study we tested how healthy inexperienced and experienced dyads learn to repeatedly reach to a target and stop while challenged with a 30 degree visuomotor rotation. We employed the Pantograph investigational device that haptically couples partners movements while providing cursor feedback, and we measured the amount and speed of learning to test a prevailing hypothesis: dyads with no experience learn faster than an experienced person coupled with a novice. We found significant straightening of movements for dyads in terms of amount of learning (2.662±0.102 cm and 2.576±0.024 cm for the novice-novice and novice-experienced groups) at rapid rates (time constants of 17.83 ± 2.85 and 18.17.17±6.72 movements), which was nearly half the learning time as solo individuals' studies. However, we found no differences between the novice-novice and experienced-novice groups, though retrospectively our power was only 3 percent. This pilot study demonstrates new opportunities to investigate the advantages of partner-facilitated learning with solely haptic communication which and can lead to insights on control in human physical interactions and can guide the design of future human-robot-human interaction systems.

Extracellular vesicles (EVs) are capable of transferring cargo from donor to recipient cells, but precisely how cargo content is regulated for export is mostly unknown. For miRNA cargo, we previously showed that when compared to isogenic colorectal cancer (CRC) cells expressing wild-type KRAS, a distinct subset of miRNAs are differentially enriched in EVs from KRAS mutant active CRC cells, with miR-100 being one of the most enriched. The mechanisms that could explain how miR-100 and other miRNAs are differentially exported into EVs have not been fully elucidated. Here, we tested the effect of N6-methyladenosine (m6A) modification on miRNA export into EVs by depletion of METTL3 and ALKBH5, a writer and eraser of m6A modification, respectively. While the effects of ALKBH5 knockdown were quite modest, decreased levels of METTL3 led to reduced cellular and extracellular levels of a subset of miRNAs that contain consensus sequences for m6A modification. Functional testing of EVs prepared from cells expressing shRNAs against METTL3 showed that they were less capable of conferring colony growth in 3D to wild-type KRAS cells and were also largely incapable of conferring the spread of cetuximab resistance. Our data support a role for METTL3 modification on cellular miRNA levels and export of specific miRNAs., miRNA, Base modification, Extracellular vesicle, m6A, RNA, Tumor microenvironment

Epithelial-to-mesenchymal transition (EMT) is a process linked to metastasis and drug resistance with non-coding RNAs (ncRNAs) playing pivotal roles. We previously showed that miR-100 and miR-125b, embedded within the third intron of the ncRNA host gene MIR100HG, confer resistance to cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in colorectal cancer (CRC). However, whether the MIR100HG transcript itself has a role in cetuximab resistance or EMT is unknown.The correlation between MIR100HG and EMT was analyzed by curating public CRC data repositories. The biological roles of MIR100HG in EMT, metastasis and cetuximab resistance in CRC were determined both in vitro and in vivo. The expression patterns of MIR100HG, hnRNPA2B1 and TCF7L2 in CRC specimens from patients who progressed on cetuximab and patients with metastatic disease were analyzed by RNAscope and immunohistochemical staining.The expression of MIR100HG was strongly correlated with EMT markers and acted as a positive regulator of EMT. MIR100HG sustained cetuximab resistance and facilitated invasion and metastasis in CRC cells both in vitro and in vivo. hnRNPA2B1 was identified as a binding partner of MIR100HG. Mechanistically, MIR100HG maintained mRNA stability of TCF7L2, a major transcriptional coactivator of the Wnt/β-catenin signaling, by interacting with hnRNPA2B1. hnRNPA2B1 recognized the N6-methyladenosine (mMIR100HG and hnRNPA2B1 interact to control the transcriptional activity of Wnt signaling in CRC via regulation of TCF7L2 mRNA stability. Our findings identified MIR100HG as a potent EMT inducer in CRC that may contribute to cetuximab resistance and metastasis by activation of a MIR100HG/hnRNPA2B1/TCF7L2 feedback loop.

In metazoan, regulatory molecules tightly control gene expression. Among them, microRNAs (miRNAs) are key regulators of several important features, like cell proliferation, differentiation, and homeostasis. During miRNA biogenesis, the canonical strand that loads onto RISC can be switched, in a process called “arm switching.” Due to the miRNA-to-target pairing peculiarities, switching events can lead to changes on the gene-targeted repertoire, promoting the modulation of a distinct set of biological routes. To understand how these events affect cell regulation, we conducted an extensive and detailed in silico analysis of RNA-seq datasets from several tissues and key developmental stages of zebrafish. We identified interesting patterns of miRNA arm switching occurrence, mainly associated with the control of protein coding genes during embryonic development. Additionally, our data show that miRNA isoforms (isomiRs) play an important role in differential arm usage. Our findings provide new insights on how such events emerge and coordinate gene expression regulation, opening perspectives for novel investigations in the area.

During motor learning, people often practice reaching in variety of movement directions in a randomized sequence. Such training has been shown to enhance retention and transfer capability of the acquired skill compared to the blocked repetition of the same movement direction. The learning system must accommodate such randomized order either by having a memory for each movement direction, or by being able to generalize what was learned in one movement direction to the controls of nearby directions. While our preliminary study used a comprehensive dataset from visuomotor learning experiments and evaluated the first-order model candidates that considered the memory of error and generalization across movement directions, here we expanded our list of candidate models that considered the higher-order effects and error-dependent learning rates. We also employed cross-validation to select the leading models. We found that the first-order model with a constant learning rate was the best at predicting learning curves. This model revealed an interaction between the learning and forgetting processes using the direction-specific memory of error. As expected, learning effects were observed at the practiced movement direction on a given trial. Forgetting effects (error increasing) were observed at the unpracticed movement directions with learning effects from generalization from the practiced movement direction. Our study provides insights that guide optimal training using the machine-learning algorithms in areas such as sports coaching, neurorehabilitation, and human-machine interactions.

African Americans remain conspicuously absent from today’s cohort of gifted and talented students (Milner & Ford, 2007). Although they represent 17.2% of the public school population, they comprise a meager 3.5% of the total gifted population (National Center for Education Statistics, 2007). At times the rate of underrepresentation has hovered between 50% and 70% (Ford & Grantham, 2003). Several causal factors have been attributed to the lack of students in these programs. As an example, biased attitudes and assumptions about African American children; failure to recognize culturally mediated attributes that constitute giftedness; narrowly constructed assessment procedures; lack of multicultural competence among school personnel; and student and family concerns about the social isolation that may result from enrollment in gifted programs have been cited as salient factors that contribute to the limited participation of African American students in gifted program initiatives (Ford & Grantham, 2003; Ford, Harris, Tyson, & Trotman, 2002; Milner & Ford, 2007).

Phenotypic convergence across distantly related taxa can be driven by similar selective pressures from the environment or intrinsic constraints. The roles of these processes on physiological strategies, such as homeothermy, are poorly understood. We studied the evolution of thermal properties of mammalian pelage in a diverse community of rodents inhabiting the Mojave Desert, USA. We used a heat flux device to measure the thermal insulation of museum specimens and determined whether thermal properties were associated with habitat preferences while assessing phylogenetic dependence. Species that prefer arid habitats exhibited lower conductivity and thinner pelage relative to species with other habitat preferences. Despite being thinner, the pelage of arid species exhibited comparable insulation to the pelage of the other species due to its lower conductivity. Thus, arid species have insulative pelage while simultaneously benefitting from thin pelage that promotes convective cooling. We found no evidence of intrinsic constraints or phylogenetic dependence, indicating pelage readily evolves to environmental pressures. Thermoregulatory simulations demonstrated that arid specialists reduced energetic costs required for homeothermy by 14.5% by evolving lower conductivity, providing support for adaptive evolution of pelage. Our study indicates that selection for lower energetic requirements of homeothermy has shaped evolution of pelage thermal properties.

Objective A major challenge that limits understanding and treatment of epileptic events from mesial temporal structures comes from our inability to detect and map interictal networks reproducibly using scalp electrodes. Here, we developed a novel approach to map interictal spike networks and demonstrate their relationships to seizure onset and lesions in patients with foramen ovale electrode implantations. Methods We applied the direct Directed Transfer Function to reveal interictal spike propagation from bilateral foramen ovale electrodes on 10 consecutive patients and co-registered spatially with both seizure onset zones and temporal lobe lesions. Results Highly reproducible, yet unique interictal spike networks were seen for each patient (correlation: 0.93 ± 0.13). Interictal spikes spread in both anterior and posterior directions within each temporal lobe, often reverberating between sites. Spikes propagated to the opposite temporal lobe predominantly through posterior pathways. Patients with structural lesions (N = 4), including tumors and sclerosis, developed reproducible spike networks adjacent to their lesions that were highly lateralized compared to patients without lesions. Only 5% of mesial temporal lobe spikes were time-locked with scalp electrode spikes. Our preliminary observation on two lesional patients suggested that along with lesion location, Interictal spike networks also partially co-registered with seizure onset zones suggesting interrelationship between seizure onset and a subset of spike networks. Conclusions This is the first demonstration of patient-specific, reproducible interictal spike networks in mesial temporal structures that are closely linked to both temporal lobe lesions and seizure onset zones. Significance Interictal spike connectivity is a novel approach to map epileptic networks that could help advance invasive and non-invasive epilepsy treatments.

SUMMARY Unlike the adult mammalian retina, Müller glia (MG) in the adult zebrafish retina are able to dedifferentiate into a ‘‘stem cell’’-like state and give rise to multipotent progenitor cells upon retinal damage. We show that miR-216a is downregulated in MG after constant intense light lesioning and that miR-216a suppression is necessary and sufficient for MG dedifferentiation and proliferation during retina regeneration. miR-216a targets the H3K79 methyltransferase Dot1l, which is upregulated in proliferating MG after retinal damage. Loss-of-function experiments show that Dot1l is necessary for MG reprogramming and mediates MG proliferation downstream of miR-216a. We further demonstrate that miR-216a and Dot1l regulate MG-mediated retina regeneration through canonical Wnt signaling. This article reports a regulatory mechanism upstream of Wnt signaling during retina regeneration and provides potential targets for enhancing regeneration in the adult mammalian retina., Graphical Abstract, In Brief Unlike the adult mammalian retina, Müller glia in the adult zebrafish retina are able to reprogram into a stem cell-like state and give rise to multipotent progenitor cells upon retinal damage. Kara et al. show that miR-216a suppression stimulates Müller glia reprogramming through upregulation of the H3K79 methyltransferase Dot1l and activation of Wnt/β-catenin signaling.

In a screen for human kinases that regulate Xenopus laevis embryogenesis, we identified Nagk and other components of the UDP-GlcNAc glycosylation salvage pathway as regulators of anteroposterior patterning and Wnt signaling. We find that the salvage pathway does not affect other major embryonic signaling pathways (Fgf, TGFβ, Notch, or Shh), thereby demonstrating specificity for Wnt signaling. We show that the role of the salvage pathway in Wnt signaling is evolutionarily conserved in zebrafish and Drosophila. Finally, we show that GlcNAc is essential for the growth of intestinal enteroids, which are highly dependent on Wnt signaling for growth and maintenance. We propose that the Wnt pathway is sensitive to alterations in the glycosylation state of a cell and acts as a nutritional sensor in order to couple growth/proliferation with its metabolic status. We also propose that the clinical manifestations observed in congenital disorders of glycosylation (CDG) in humans may be due, in part, to their effects on Wnt signaling during development.

Aims The aims of this systematic review were to assess the learning curve of semi-active robotic arm-assisted total hip arthroplasty (rTHA), and to compare the accuracy, patient-reported functional outcomes, complications, and survivorship between rTHA and manual total hip arthroplasty (mTHA). Methods Searches of PubMed, Medline, and Google Scholar were performed in April 2020 in line with the Preferred Reporting Items for Systematic Review and Meta-Analysis statement. Search terms included “robotic”, “hip”, and “arthroplasty”. The criteria for inclusion were published clinical research articles reporting the learning curve for rTHA (robotic arm-assisted only) and those comparing the implantation accuracy, functional outcomes, survivorship, or complications with mTHA. Results There were 501 articles initially identified from databases and references. Following full text screening, 17 articles that satisfied the inclusion criteria were included. Four studies reported the learning curve of rTHA, 13 studies reported on implant positioning, five on functional outcomes, ten on complications, and four on survivorship. The meta-analysis showed a significantly greater number of cases of acetabular component placement in the safe zone compared with the mTHA group (95% confidence interval (CI) 4.10 to 7.94; p < 0.001) and that rTHA resulted in a significantly better Harris Hip Score compared to mTHA in the short- to mid-term follow-up (95% CI 0.46 to 5.64; p = 0.020). However, there was no difference in infection rates, dislocation rates, overall complication rates, and survival rates at short-term follow-up. Conclusion The learning curve of rTHA was between 12 and 35 cases, which was dependent on the assessment goal, such as operating time, accuracy, and team working. Robotic arm-assisted total hip arthroplasty was associated with improved accuracy of component positioning and functional outcome, however no difference in complication rates or survival were observed at short- to mid-term follow-up. Overall, there remains an absence of high-quality level I evidence and cost analysis comparing rTHA and mTHA. Cite this article: Bone Joint J 2021;103-B(6):1009–1020.

Background Neurorehabilitation engineering faces numerous challenges to translating new technologies, but it is unclear which of these challenges are most limiting. Here we focus on tracing the real-time behavior and rehabilitation technology (RT) use decisions of the primary gatekeepers of RT: rehabilitation therapists. Methods Three OTs and two PTs employed at a major, technology-encouraging rehabilitation hospital wrote vignettes from a written prompt describing their RT use decisions during treatment sessions with nine patients (4 with stroke, 2 traumatic brain injury, 1 spinal cord injury, 1 with multiple sclerosis). We then coded the vignettes using deductive qualitative analysis from 17 constructs derived from the RT literature and the Consolidated Framework for Implementation Research (CFIR) to analyze the vignettes. Data were synthesized using summative content analysis. Results Of the constructs recorded, the five most prominent are from CFIR determinants of: (i) relative advantage, (ii) personal attributes of the patients, (iii) clinician knowledge and beliefs of the device/intervention, (iv) complexity of the devices including time and setup, and (v) organizational readiness to implement. Therapists characterized candidate RT as having a relative disadvantage compared to conventional treatment due to lack of relevance to functional training. RT design also often failed to take into account the multi-faceted personal attributes of the patients, including diagnoses, goals, and physical and cognitive limitations. Clinicians’ comfort with RT was increased by their previous training but was decreased by the perceived complexity of RT. Finally, therapists have limited time to gather, setup, and use RT. Conclusions Despite decades of design work aimed at creating clinically useful RT, many lack compatibility with clinical translation needs in inpatient neurologic rehabilitation. New RT continue to impede the immediacy, versatility, and functionality of hands-on therapy mediated treatment with simple everyday objects.

Debate continues regarding the optimum management of periprosthetic distal femoral fractures (PDFFs). This study aims to determine which operative treatment is associated with the lowest perioperative morbidity and mortality when treating low (Su type II and III) PDFFs comparing lateral locking plate fixation (LLP-ORIF) or distal femoral arthroplasty (DFA).This was a retrospective cohort study of 60 consecutive unilateral (PDFFs) of Su types II (40/60) and III (20/60) in patients aged ≥ 60 years: 33 underwent LLP-ORIF (mean age 81.3 years (SD 10.5), BMI 26.7 (SD 5.5); 29/33 female); and 27 underwent DFA (mean age 78.8 years (SD 8.3); BMI 26.7 (SD 6.6); 19/27 female). The primary outcome measure was reoperation. Secondary outcomes included perioperative complications, calculated blood loss, transfusion requirements, functional mobility status, length of acute hospital stay, discharge destination and mortality. Kaplan-Meier survival analysis was performed. Cox multivariate regression analysis was performed to identify risk factors for reoperation after LLP-ORIF.Follow-up was at mean 3.8 years (1.0 to 10.4). One-year mortality was 13% (8/60). Reoperation was more common following LLP-ORIF: 7/33 versus 0/27 (p = 0.008). Five-year survival for reoperation was significantly better following DFA; 100% compared to 70.8% (95% confidence interval (CI) 51.8% to 89.8%, p = 0.006). There was no difference for the endpoint mechanical failure (including radiological loosening); ORIF 74.5% (56.3 to 92.7), and DFA 78.2% (52.3 to 100, p = 0.182). Reoperation following LLP-ORIF was independently associated with medial comminution; hazard ratio (HR) 10.7 (1.45 to 79.5, p = 0.020). Anatomical reduction was protective against reoperation; HR 0.11 (0.013 to 0.96, p = 0.046). When inadequately fixed fractures were excluded, there was no difference in five-year survival for either reoperation (p = 0.156) or mechanical failure (p = 0.453).Absolute reoperation rates are higher following LLP fixation of low PDFFs compared to DFA. Where LLP-ORIF was well performed with augmentation of medial comminution, there was no difference in survival compared to DFA. Though necessary in very low fractures, DFA should be used with caution in patients with greater life expectancies due to the risk of longer term aseptic loosening. Cite this article

Made available in DSpace on 2021-06-25T10:55:23Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-12-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Background: During vertebrate evolution, the heart has undergone remarkable changes that lead to morphophysiological differences in the fully formed heart of these species, such as chamber septation, heart rate frequency, blood pressure, and cardiac output volume. Despite these differences, the heart developmental process is guided by a core gene set conserved across vertebrates. Nonetheless, the regulatory mechanisms controlling the expression of genes involved in heart development and maintenance are largely uncharted. MicroRNAs (miRNAs) have been described as important regulatory elements in several biological processes, including heart biology. These small RNA molecules are broadly conserved in sequence and genomic context in metazoans. Mutations may occur in miRNAs and/or genes that contribute to the establishment of distinct repertoires of miRNA-target interactions, thereby favoring the differential control of gene expression and, consequently, the origin of novel phenotypes. In fact, several studies showed that miRNAs are integrated into genetic regulatory networks (GRNs) governing specific developmental programs and diseases. However, studies integrating miRNAs in vertebrate heart GRNs under an evolutionary perspective are still scarce. Results: We comprehensively examined and compared the heart miRNome of 20 species representatives of the five major vertebrate groups. We found 54 miRNA families with conserved expression and a variable number of miRNA families with group-specific expression in fishes, amphibians, reptiles, birds, and mammals. We also detected that conserved miRNAs present higher expression levels and a higher number of targets, whereas the group-specific miRNAs present lower expression levels and few targets. Conclusions: Both the conserved and group-specific miRNAs can be considered modulators orchestrating the core and peripheral genes of heart GRNs of vertebrates, which can be related to the morphophysiological differences and similarities existing in the heart of distinct vertebrate groups. We propose a hypothesis to explain evolutionary differences in the putative functional roles of miRNAs in the heart GRNs analyzed. Furthermore, we present new insights into the molecular mechanisms that could be helping modulate the diversity of morphophysiology in the heart organ of vertebrate species. Laboratório Especial de Toxinologia Aplicada (LETA) CeTICS Instituto Butantan Department of Chemical and Biological Sciences Institute of Biosciences of Botucatu São Paulo State University (UNESP) Department of Biophysics and Pharmacology Institute of Biosciences of Botucatu São Paulo State University (UNESP) Department of Biological Sciences Vanderbilt University Department of Molecular Biosciences The Wenner-Gren Institute (MBW) Stockholm University Department of Chemical and Biological Sciences Institute of Biosciences of Botucatu São Paulo State University (UNESP) Department of Biophysics and Pharmacology Institute of Biosciences of Botucatu São Paulo State University (UNESP) FAPESP: 2012/15589-7 FAPESP: 2013/06864-7

The aim of this study was to determine whether fixation, as opposed to revision arthroplasty, can be safely used to treat reducible Vancouver B type fractures in association with a cemented collarless polished tapered femoral stem (the Exeter).This retrospective cohort study assessed 152 operatively managed consecutive unilateral Vancouver B fractures involving Exeter stems; 130 were managed with open reduction and internal fixation (ORIF) and 22 with revision arthroplasty. Mean follow-up was 6.5 years (SD 2.6; 3.2 to 12.1). The primary outcome measure was revision of at least one component. Kaplan-Meier survival analysis was performed. Regression analysis was used to identify risk factors for revision following ORIF. Secondary outcomes included any reoperation, complications, blood transfusion, length of hospital stay, and mortality.Fractures (B1 n = 74 (49%); B2 n = 50 (33%); and B3 n = 28 (18%)) occurred at median of 4.2 years (interquartile range (IQR) 1.2 to 9.2) after primary total hip arthroplasty (THA) (n = 138) or hemiarthroplasty (n = 14). Rates of revision and reoperation were significantly higher following revision arthroplasty compared to ORIF for B2 (p = 0.001) and B3 fractures (p = 0.050). Five-year survival was significantly better following ORIF: 92% (95% confidence interval (CI) 86.4% to 97.4%) versus 63% (95% CI 41.7% to 83.3%), p0.001. ORIF was associated with reduced blood transfusion requirement and reoperations, but there were no differences in medical complications, hospital stay, or mortality between surgical groups. No independent predictors of revision following ORIF were identified: where the bone-cement interface was intact, fixation of B2 or B3 fractures was not associated with an increased risk of revision.When the bone-cement interface was intact and the fracture was anatomically reducible, all Vancouver B fractures around Exeter stems could be managed with fixation as opposed to revision arthroplasty. Fixation was associated with reduced need for blood transfusion and lower risk of revision surgery compared with revision arthroplasty. Cite this article

High-cost situations need to be avoided. However, occasionally, cost may only be learned by experience. Here, we tested whether an artificially induced unstable and invisible high-cost region, a "limit-push" force field, might reshape people's motion distributions. Healthy and neurologically impaired (chronic stroke) populations attempted 600 interceptions of a projectile while holding a robot handle that could render forces to the hand. The "limit-push," in the middle of the study, pushed the hand outward unless the hand stayed within a box-shaped region. Both healthy and some stroke survivors adapted through selection of safer actions, avoiding the high-cost regions (outside the box); they stayed more inside and even kept a greater distance from the box's boundaries. This was supported by other measures that showed subjects distributed their hand movements within the box more uniformly. These effects lasted a very short time after returning to the no-force condition. Although most robotic teaching approaches focus on shifting the mean, this limit-push treatment demonstrates how both mean and variance might be reshaped in motor training and neurorehabilitation.

In both movement training and neurorehabilitation, there have been numerous examples of how average performance can be manipulated through practice using enhanced visual feedback. Objective : Rather than just influencing the mean, our objective was to use a novel feedback technique called limit-push to influence the trial-to-trial variability of motion by distorting vision. Method : Limit-push was previously done using robotic forces; the present study employed only visual distortions that imitated the limit-push approach. Results : Like the robotic force treatment, our results showed how subjects significantly shifted the distributions of their motions. This effect was even greater than that of the original limit-push experiment that used robotic forces. Significance : Such visual distortion interventions do not require a robot for enhanced training. Conclusion : The visual limit-push technique appears to be able to selectively alter both the central tendency and variability in performance training applications.

Objective Interictal spikes are a biomarker of epilepsy, yet their precise roles are poorly understood. Using long-term neocortical recordings from epileptic patients, we investigated the spatial-temporal propagation patterns of interictal spiking. Methods Interictal spikes were detected in 10 epileptic patients. Short time direct directed transfer function was used to map the spatial-temporal patterns of interictal spike onset and propagation across different cortical topographies. Results Each patient had unique interictal spike propagation pattern that was highly consistent across times, regardless of the frequency band. High spiking brain regions were often not spike onset regions. We observed frequent spike propagations to shorter distances and that the central sulcus forms a strong barrier to spike propagation. Spike onset and seizure onset seemed to be distinct networks in most cases. Conclusions Patients in epilepsy have distinct and unique network of causal propagation pattern which are very consistent revealing the underlying epileptic network. Although spike are epileptic biomarkers, spike origin and seizure onset seems to be distinct in most cases. Significance Understanding patterns of interictal spike propagation could lead to the identification patient-specific epileptic networks amenable to surgical or other treatments.

RNA transfer via extracellular vesicles (EVs) influences cell phenotypes; however, lack of information regarding biogenesis of RNA-containing EVs has limited progress in the field. Here, we identify endoplasmic reticulum membrane contact sites (ER MCSs) as platforms for the generation of RNA-containing EVs. We identify a subpopulation of small EVs that is highly enriched in RNA and regulated by the ER MCS linker protein VAP-A. Functionally, VAP-A-regulated EVs are critical for miR-100 transfer between cells and in vivo tumor formation. Lipid analysis of VAP-A-knockdown EVs revealed reductions in the EV biogenesis lipid ceramide. Knockdown of the VAP-A-binding ceramide transfer protein CERT led to similar defects in EV RNA content. Imaging experiments revealed that VAP-A promotes luminal filling of multivesicular bodies (MVBs), CERT localizes to MVBs, and the ceramide-generating enzyme neutral sphingomyelinase 2 colocalizes with VAP-A-positive ER. We propose that ceramide transfer via VAP-A-CERT linkages drives the biogenesis of a select RNA-containing EV population.

The use of model systems that are capable of robust, spontaneous retina regeneration has allowed for the identification of genetic pathways and components that are required for retina regeneration. Complemented by mouse models in which retina regeneration can be induced after forced expression of key factors, altered chromatin accessibility, or inhibition of kinase/signaling cascades, a clearer picture of the key regulatory events that control retina regeneration is emerging. In all cases, Müller glia (MG) serve as an adult retinal stem cell that must be reprogrammed to allow for regeneration, with the end goal being to understand why regenerative pathways are blocked in mammals, but spontaneous in other vertebrates such as zebrafish. miRNAs have emerged as key gene regulatory molecules that control both development and regeneration in vertebrates. Here, we focus on a small subset of miRNAs that control MG reprogramming during retina regeneration and have the potential to serve as therapeutic targets for treatment of visual disorders and damage.

Diagonal spring elements can render torque to any orthotic joint, and here we describe the theoretical framework for an ExoNET device that utilizes stacked spring elements as torque generators. Stacked spring elements act mathematically as basis functions, which can be simultaneously tuned to deliver any torque-angle relation. Here we outline the theory, demonstrate our initial developments in several example applications, and then describe the design considerations necessary to develop a functional prototype. We show several exemplary solutions: replicating the torque-angle profile of a single muscle (brachioradialis), two-joint gravity compensation for arm weight, error augmentation and limit push fields capable of providing forces for rehabilitation, and attractor torque fields that collectively pull the arm towards a desired position. This ExoNET system has the potential to be quickly and inexpensively constructed and easily configured by the end user or clinician for specific needs. It shifts control intelligence from the software to physical hardware, which is an efficient solution for neurorehabilitation, military, manual labor, and performance enhancement.