Optical coherence tomography-guided Brillouin microscopy highlights regional tissue stiffness differences during anterior neural tube closure in the Mthfd1l murine mutant.

Neurulation is a highly synchronized biomechanical process leading to the formation of the brain and spinal cord, and its failure leads to neural tube defects (NTDs). Although we are rapidly learning the genetic mechanisms underlying NTDs, the biomechanical aspects are largely unknown. To understand the correlation between NTDs and tissue stiffness during neural tube closure (NTC), we imaged an NTD murine model using optical coherence tomography (OCT), Brillouin microscopy and confocal fluorescence microscopy. Here, we associate structural information from OCT with local stiffness from the Brillouin signal of embryos undergoing neurulation. The stiffness of neuroepithelial tissues in Mthfd1l null embryos was significantly lower than that of wild-type embryos. Additionally, exogenous formate supplementation improved tissue stiffness and gross embryonic morphology in nullizygous and heterozygous embryos. Our results demonstrate the significance of proper tissue stiffness in normal NTC and pave the way for future studies on the mechanobiology of normal and abnormal embryonic development.

Mechanisms of neurodevelopmental toxicity of topiramate.

Prescriptions for antiseizure medications (ASMs) have been rapidly growing over the last several decades due, in part, to an expanding list of clinical indications for which they are now prescribed. This trend has raised concern for potential adverse neurodevelopmental outcomes in ASM-exposed pregnancies. Recent large scale population studies have suggested that the use of topiramate (TOPAMAX, Janssen-Cilag), when prescribed for seizure control, migraines, and/or weight management, is associated with an increased risk for autism spectrum disorder (ASD), intellectual disability, and attention-deficit/hyperactivity disorder (ADHD) in exposed offspring. Here, we critically review epidemiologic evidence demonstrating the neurobehavioral teratogenicity of topiramate and speculate on the neuromolecular mechanisms by which prenatal exposure may perturb neurocognitive development. Specifically, we explore the potential role of topiramate's pharmacological interactions with ligand- and voltage-gated ion channels, especially GABAergic signaling, its effects on DNA methylation and histone acetylation, whether topiramate induces oxidative stress, and its association with fetal growth restriction as possible mechanisms contributing to neurodevelopmental toxicity. Resolving this biology will be necessary to reduce the risk of adverse pregnancy outcomes caused by topiramate or other ASMs.

Light-dependent N-end rule-mediated disruption of protein function in Saccharomyces cerevisiae and Drosophila melanogaster.

Here we describe the development and characterization of the photo-N-degron, a peptide tag that can be used in optogenetic studies of protein function in vivo. The photo-N-degron can be expressed as a genetic fusion to the amino termini of other proteins, where it undergoes a blue light-dependent conformational change that exposes a signal for the class of ubiquitin ligases, the N-recognins, which mediate the N-end rule mechanism of proteasomal degradation. We demonstrate that the photo-N-degron can be used to direct light-mediated degradation of proteins in Saccharomyces cerevisiae and Drosophila melanogaster with fine temporal control. In addition, we compare the effectiveness of the photo-N-degron with that of two other light-dependent degrons that have been developed in their abilities to mediate the loss of function of Cactus, a component of the dorsal-ventral patterning system in the Drosophila embryo. We find that like the photo-N-degron, the blue light-inducible degradation (B-LID) domain, a light-activated degron that must be placed at the carboxy terminus of targeted proteins, is also effective in eliciting light-dependent loss of Cactus function, as determined by embryonic dorsal-ventral patterning phenotypes. In contrast, another previously described photosensitive degron (psd), which also must be located at the carboxy terminus of associated proteins, has little effect on Cactus-dependent phenotypes in response to illumination of developing embryos. These and other observations indicate that care must be taken in the selection and application of light-dependent and other inducible degrons for use in studies of protein function in vivo, but importantly demonstrate that N- and C-terminal fusions to the photo-N-degron and the B-LID domain, respectively, support light-dependent degradation in vivo.

Performance evaluation and model of spacesuit cooling by hydrophobic hollow fiber-membrane based water evaporation through pores.

A comprehensive mathematical model is presented that accurately estimates and predicts failure modes through the computations of heat rejection, temperature drop and lumen side pressure drop of the hollow fiber (HF) membrane-based NASA Spacesuit Water Membrane Evaporator (SWME). The model is based on mass and energy balances in terms of the physical properties of water and membrane transport properties. The mass flux of water vapor through the pores is calculated based on Knudsen diffusion with a membrane structure parameter that accounts for effective mean pore diameter, porosity, thickness, and tortuosity. Lumen-side convective heat transfer coefficients are calculated from laminar flow boundary layer theory using the Nusselt correlation. Lumen side pressure drop is estimated using the Hagen-Poiseuille equation. The coupled ordinary differential equations for mass flow rate, water temperature and lumen side pressure are solved simultaneously with the equations for mass flux and convective heat transfer to determine overall heat rejection, water temperature and lumen side pressure drop. A sensitivity analysis is performed to quantify the effect of input variability on SWME response and identify critical failure modes. The analysis includes the potential effect of organic and/or inorganic contaminants and foulants, partial pore entry due to hydrophilization, and other unexpected operational failures such as bursting or fiber damage. The model can be applied to other hollow fiber membrane-based applications such as low temperature separation and concentration of valuable biomolecules from solution.

Evaluation of Mechanically-Assisted Crevice Corrosion of Different Modular Dual Mobility Constructs.

BACKGROUND: Modular dual mobility (MDM) acetabular component use is rising in total hip arthroplasty. However, concern of mechanically assisted crevice corrosion (MACC) at the shell-liner interface remains. We investigated shell-liner corrosion using retrieval analyses and corrosion chamber testing. METHODS: We analyzed fretting and corrosion on 10 matched pairs of 2 commercial MDM constructs (MDM1 and MDM2). Also, pristine pairs of Ti6Al4V shells and CoCrMo liners from 3 commercial dual mobility systems (MDM1, MDM2, and MDM3) were tested in vitro to model MACC performance. Three pairs of each were placed into an electrochemical chamber with stepwise increasing cyclic compression loads while measuring currents generated at the shell-liner taper. Onset fretting loads and fretting currents were calculated. RESULTS: Corrosion damage scores on retrieved components were low but higher in the MDM2 to MDM1 liners (P = .006), specifically outside the taper region (P = .00003). Fretting currents were higher in the MDM2 than in MDM1 or MDM3 (P = .011). Onset loads were also higher in the MDM2 (P = .001). CONCLUSION: Among retrieved liners, MDM2 tapers seem prone to non-mechanical corrosion modes. Higher onset loads and fretting currents in MDM2 tapers indicate greater MACC resistance but higher severity once corrosion begins. Differences among the devices were likely due to taper design and surface finish. Currents in all 3 were <5 µA, much lower than those observed with head-neck tapers. Our findings suggest that, among the types of corrosion observed in these MDM designs, mechanically driven corrosion may not be the most significant.

Deep Learning Phenotype Automation and Cohort Analyses of 1,946 Knees Using the Coronal Plane Alignment of the Knee Classification.

BACKGROUND: The Coronal Plane Alignment of the Knee (CPAK) classification allows for knee phenotyping which can be used in preoperative planning prior to total knee arthroplasty. We used deep learning (DL) to automate knee phenotyping and analyzed CPAK distributions in a large patient cohort. METHODS: Patients who had full-limb radiographs from a large arthritis database were retrospectively included. A DL algorithm was developed to automate CPAK knee alignment parameters including the lateral distal femoral, medial proximal tibia, hip-knee-ankle, and joint line obliquity angles. The algorithm was validated against a fellowship-trained arthroplasty surgeon. After applying the algorithm in a large patient cohort (n = 1,946 knees), the distribution of CPAK was compared across patient sex and baseline Kellgren-Lawrence (KL) scores. RESULTS: There was no significant difference in the CPAK angles (n = 140, P = .66-.98, inter-class correlation coefficient = 0.89-0.91) or phenotype classifications made by the algorithm and surgeon (P = .96). The deep learning algorithm measured the entire cohort (n = 1,946 knees, mean age 61 years [range, 46 to 80 years], 51% women) in < 5 hours. Women had more valgus CPAK phenotypes than men (P < .05). Patients who had higher KL grades at baseline (2 to 4) were more varus using the CPAK classification compared to lower KL grades (0 to 1) (P < .05). CONCLUSION: We applied an accurate, automated DL algorithm on a large patient cohort to determine knee phenotypes, helping to validate and strengthen the CPAK classification system. Analyses revealed that sex-specific and major bone loss adjustments may need to be accounted for when using this system.

Re-initiation of elective total knee arthroplasty with an adapted pathway during the 2020 COVID-19 pandemic was safe and effective.

INTRODUCTION: In June 2020 when elective total knee arthroplasty (TKA) resumed after the initial COVID-19 surge, we adapted our TKA pathway focusing on a shorter hospitalization, increased home discharge, and use of post-discharge telemedicine and telerehabilitation. The purpose of this study was to evaluate if changes in postoperative care affected early TKA outcomes. MATERIALS AND METHODS: Five hundred and fifty-four patients who underwent elective primary unilateral TKA for primary osteoarthritis between June and August 2020 (study group) were matched 1:1 for age, sex, body mass index, and Charlson comorbidity index with control patients who underwent surgery between August and November 2019. Study patients were discharged 25 h earlier on average compared to controls, more frequently on the same-day or postoperative day-1 (24.9% vs. 16.1%; p = 0.001), and more frequently home (97.3% vs. 83.8%; p < 0.001). Study patients used telemedicine (11.7% vs. 0%; p < 0.001) and telerehabilitation (19.7% vs. 2.5%; p < 0.001) at higher rates than controls. Generalized estimating equations, Mann-Whitney U, and Chi-Square tests were used to compare outcomes between groups including unscheduled office visits, ER visits, readmissions, Center for Medicare and Medicaid Services (CMS) complications, manipulation under anesthesia (MUA), and patient-reported outcomes measures (PROMs). RESULTS: Rates of emergency room visits, readmissions, CMS complications, MUA, and improvements in PROMs were similar between cohorts. Study patients experienced higher rates of unscheduled outpatient visits (9.2% vs. 4.9%; p = 0.004), predominantly due to wound complications. CONCLUSIONS: A protocol implemented during the COVID-19 pandemic that leveraged a shortened hospitalization, higher rates of home discharge, and increased use of telemedicine and telerehabilitation was safe and effective.

FKBP8 variants are risk factors for spina bifida.

Neural tube defects (NTDs) are a group of severe congenital malformations caused by a failure of neural tube closure during early embryonic development. Although extensively investigated, the genetic etiology of NTDs remains poorly understood. FKBP8 is critical for proper mammalian neural tube closure. Fkbp8-/- mouse embryos showed posterior NTDs consistent with a diagnosis of spina bifida (SB). To date, no publication has reported any association between FKBP8 and human NTDs. Using Sanger sequencing on genomic DNA samples from 472 SB and 565 control samples, we identified five rare (MAF ≤ 0.001) deleterious variants in SB patients, while no rare deleterious variant was identified in the controls (P = 0.0191). p.Glu140* affected FKBP8 localization to the mitochondria and created a truncated form of the FKBP8 protein, thus impairing its interaction with BCL2 and ultimately leading to an increase in cellular apoptosis. p.Ser3Leu, p.Lys315Asn and p.Ala292Ser variants decreased FKBP8 protein level. p.Lys315Asn further increased the cellular apoptosis. RNA sequencing on anterior and posterior tissues isolated from Fkbp8-/- and wildtype mice at E9.5 and E10.5 showed that Fkbp8-/- embryos have an abnormal expression profile within tissues harvested at posterior sites, thus leading to a posterior NTD. Moreover, we found that Fkbp8 knockout mouse embryos have abnormal expression of Wnt3a and Nkx2.9 during the early stage of neural tube development, perhaps also contributing to caudal specific NTDs. These findings provide evidence that functional variants of FKBP8 are risk factors for SB, which may involve a novel mechanism by which Fkbp8 mutations specifically cause SB in mice.

CIC de novo loss of function variants contribute to cerebral folate deficiency by downregulating FOLR1 expression.

Background Cerebral folate deficiency (CFD) syndrome is characterised by a low concentration of 5-methyltetrahydrofolate in cerebrospinal fluid, while folate levels in plasma and red blood cells are in the low normal range. Mutations in several folate pathway genes, including FOLR1 (folate receptor alpha, FRα), DHFR (dihydrofolate reductase) and PCFT (proton coupled folate transporter) have been previously identified in patients with CFD. Methods In an effort to identify causal mutations for CFD, we performed whole exome sequencing analysis on eight CFD trios and identified eight de novo mutations in seven trios. Results Notably, we found a de novo stop gain mutation in the capicua (CIC) gene. Using 48 sporadic CFD samples as a validation cohort, we identified three additional rare variants in CIC that are putatively deleterious mutations. Functional analysis indicates that CIC binds to an octameric sequence in the promoter regions of folate transport genes: FOLR1, PCFT and reduced folate carrier (Slc19A1; RFC1). The CIC nonsense variant (p.R353X) downregulated FOLR1 expression in HeLa cells as well as in the induced pluripotent stem cell (iPSCs) derived from the original CFD proband. Folate binding assay demonstrated that the p.R353X variant decreased cellular binding of folic acid in cells. Conclusion This study indicates that CIC loss of function variants can contribute to the genetic aetiology of CFD through regulating FOLR1 expression. Our study described the first mutations in a non-folate pathway gene that can contribute to the aetiology of CFD.

Front-End Design for SiPM-Based Monolithic Neutron Double Scatter Imagers.

Neutron double scatter imaging exploits the kinematics of neutron elastic scattering to enable emission imaging of neutron sources. Due to the relatively low coincidence detection efficiency of fast neutrons in organic scintillator arrays, imaging efficiency for double scatter cameras can also be low. One method to realize significant gains in neutron coincidence detection efficiency is to develop neutron double scatter detectors which employ monolithic blocks of organic scintillator, instrumented with photosensor arrays on multiple faces to enable 3D position and multi-interaction time pickoff. Silicon photomultipliers (SiPMs) have several advantageous characteristics for this approach, including high photon detection efficiency (PDE), good single photon time resolution (SPTR), high gain that translates to single photon counting capabilities, and ability to be tiled into large arrays with high packing fraction and photosensitive area fill factor. However, they also have a tradeoff in high uncorrelated and correlated noise rates (dark counts from thermionic emissions and optical photon crosstalk generated during avalanche) which may complicate event positioning algorithms. We have evaluated the noise characteristics and SPTR of Hamamatsu S13360-6075 SiPMs with low noise, fast electronic readout for integration into a monolithic neutron scatter camera prototype. The sensors and electronic readout were implemented in a small-scale prototype detector in order to estimate expected noise performance for a monolithic neutron scatter camera and perform proof-of-concept measurements for scintillation photon counting and three-dimensional event positioning.

Unraveling the complex genetics of neural tube defects: From biological models to human genomics and back.

Neural tube defects (NTDs) are a classic example of preventable birth defects for which there is a proven-effective intervention, folic acid (FA); however, further methods of prevention remain unrealized. In the decades following implementation of FA nutritional fortification programs throughout at least 87 nations, it has become apparent that not all NTDs can be prevented by FA. In the United States, FA fortification only reduced NTD rates by 28-35% (Williams et al., 2015). As such, it is imperative that further work is performed to understand the risk factors associated with NTDs and their underlying mechanisms so that alternative prevention strategies can be developed. However, this is complicated by the sheer number of genes associated with neural tube development, the heterogeneity of observable phenotypes in human cases, the rareness of the disease, and the myriad of environmental factors associated with NTD risk. Given the complex genetic architecture underlying NTD pathology and the way in which that architecture interacts dynamically with environmental factors, further prevention initiatives will undoubtedly require precision medicine strategies that utilize the power of human genomics and modern tools for assessing genetic risk factors. Herein, we review recent advances in genomic strategies for discovering genetic variants associated with these defects, and new ways in which biological models, such as mice and cell culture-derived organoids, are leveraged to assess mechanistic functionality, the way these variants interact with other genetic or environmental factors, and their ultimate contribution to human NTD risk.

Cost of Aseptic Revision Total Knee Arthroplasty at a Tertiary Medical Center.

BACKGROUND: Revision total knee arthroplasty (TKA) involves varying levels of case complexity and costs depending on the following: (1) number of components revised, (2) duration of operating room time, and (3) length of hospital stay. However, the cost associated with different types of aseptic TKA revisions, based on number and type of components revised, is not well described. We sought to determine differences in cost associated with different revision types, and to correlate this with average national hospital and surgeon reimbursement based on current Centers for Medicare and Medicaid Services data. METHODS: This is a retrospective review of aseptic revision TKAs performed at a single tertiary referral center from 2015 to 2018. Patient demographic data, operating room time, and direct surgery and total hospital costs obtained from an internal accounting database (Enterprise Performance Systems, Inc) were collected. Patients were stratified by the components revised (polyethylene liner only, tibia only, femur only, or both femur and tibia). We hypothesized that direct surgery and total hospital costs would increase as case complexity increased from poly exchange to single-component revisions and both-component revisions. RESULTS: In total, 106 patients were included (19 poly exchanges, 10 tibia-only revisions, 13 femur-only revisions, and 64 both-component revisions). Operating room time was significantly lower for poly exchange than all other groups (P < .001). Direct surgery and total hospital costs were significantly lower for poly exchange than all other groups (P < .001), and were significantly lower for tibia-only and femur-only revisions compared to both-component revisions (P < .001). Average national surgeon reimbursement by Medicare decreased as a percentage of direct surgery cost as case complexity increased from poly exchange to tibia-only, femur-only, and both-component revisions. Total hospital cost per average Diagnosis Related Group weight was lowest for single-component revisions and highest for both-component revision. CONCLUSION: There are significant differences in cost associated with aseptic TKA revisions based on number and type of components revised. These differences may not be accurately reflected in reimbursement, and often represent a burden to those who treat complex revisions.

Fresh Osteochondral Allograft Transplantation for Osteochondral Lesions of the Talus: A Systematic Review.

Osteochondral lesions of the talus (OLTs) are difficult to treat. Despite a multitude of interventions, there are no generally-agreed-upon guidelines regarding treatment. The objective of this study was to conduct a systematic review of clinical outcomes after fresh osteochondral allografts transplantation of the talus. PubMed, the Cochrane Central Register of Controlled Trials, EMBASE, and Medline were searched using PRISMA guidelines. Studies that evaluated outcomes after fresh osteochondral allograft transplantation for OLTs were included. Clinical outcomes, according to standardized scoring systems, such as the American Orthopaedics Foot & Ankle Society (AOFAS) Ankle/Hindfoot Scale and the Visual Analog Scale (VAS) were compared across studies. The literature search yielded 12 eligible studies with a mean Coleman Methodology Score of 68.1 (57-79). A total of 191 patients were included with an average age of 37.5 (17-74) years and average follow-up of 56.8 (6-240) months. The AOFAS Ankle/Hindfoot score was obtained pre- and postoperatively in 6 of the studies and had significant improvements in each (p < .05). Similarly, the VAS pain score was evaluated in 5 studies and showed significant decreases from pre- to postoperatively (p < .05). While there were no reported short-term complications, 21.6% of patients required minor subsequent procedures, most commonly arthroscopic debridement and hardware removal. The aggregate graft survival rate was 86.6%. Based on these findings, osteochondral allograft transplantation for OLTs results in positive outcomes with high rates of graft survival and patient satisfaction at intermediate follow-up.

Loss of RAD9B impairs early neural development and contributes to the risk for human spina bifida.

DNA damage response (DDR) genes orchestrating the network of DNA repair, cell cycle control, are essential for the rapid proliferation of neural progenitor cells. To date, the potential association between specific DDR genes and the risk of human neural tube defects (NTDs) has not been investigated. Using whole-genome sequencing and targeted sequencing, we identified significant enrichment of rare deleterious RAD9B variants in spina bifida cases compared to controls (8/409 vs. 0/298; p = .0241). Among the eight identified variants, the two frameshift mutants and p.Gln146Glu affected RAD9B nuclear localization. The two frameshift mutants also decreased the protein level of RAD9B. p.Ser354Gly, as well as the two frameshifts, affected the cell proliferation rate. Finally, p.Ser354Gly, p.Ser10Gly, p.Ile112Met, p.Gln146Glu, and the two frameshift variants showed a decreased ability for activating JNK phosphorylation. RAD9B knockdowns in human embryonic stem cells profoundly affected early differentiation through impairing PAX6 and OCT4 expression. RAD9B deficiency impeded in vitro formation of neural organoids, a 3D cell culture model for human neural development. Furthermore, the RNA-seq data revealed that loss of RAD9B dysregulates cell adhesion genes during organoid formation. These results represent the first demonstration of a DDR gene as an NTD risk factor in humans.

Surgeon-Performed High-Dose Bupivacaine Periarticular Injection With Intra-Articular Saphenous Nerve Block Is Not Inferior to Adductor Canal Block in Total Knee Arthroplasty.

BACKGROUND: Periarticular injection or anesthesiologist-performed adductor canal block are commonly used for pain management after total knee arthroplasty. A surgeon-performed, intra-articular saphenous nerve block has been recently described. There is insufficient data comparing the efficacy and safety of these methods. METHODS: This is a retrospective two-surgeon cohort study comparing short-term perioperative outcomes after primary total knee arthroplasty, in 50 consecutive patients with surgeon-performed high-dose periarticular injection and intra-articular saphenous nerve block (60 mL 0.5% bupivacaine, 30 mL saline, 30mg ketorolac) and 50 consecutive patients with anesthesiologist-performed adductor canal catheter (0.25% bupivacaine 6 mL/h infusion pump placed postoperatively with ultrasound guidance). Chart review assessed pain scores through POD #1, opioid use, length of stay, and short-term complications, including local anesthetic systemic toxicity. Statistical analysis was performed with two-tailed Student's T-test. RESULTS: The high-dose periarticular injection cohort had significantly lower pain scores in the postanesthesia care unit (mean difference 1.4, P = .035), on arrival to the inpatient ward (mean difference 1.7, P = .013), and required less IV narcotics on the day of surgery (mean difference 6.5 MME, P = .0004). There was no significant difference in pain scores on POD #1, total opioid use, day of discharge, or short-term complications. There were no adverse events related to the high dose of bupivacaine. CONCLUSION: Compared with postoperative adductor canal block catheter, an intraoperative high-dose periarticular block demonstrated lower pain scores and less IV narcotic use on the day of surgery. No difference was noted in pain scores on POD #1, time to discharge, or complications. There were no cardiovascular complications (local anesthetic systemic toxicity) despite the high dose of bupivacaine injected. LEVEL OF EVIDENCE: III.

MiR-302 Regulates Glycolysis to Control Cell-Cycle during Neural Tube Closure.

Neural tube closure is a critical early step in central nervous system development that requires precise control of metabolism to ensure proper cellular proliferation and differentiation. Dysregulation of glucose metabolism during pregnancy has been associated with neural tube closure defects (NTDs) in humans suggesting that the developing neuroepithelium is particularly sensitive to metabolic changes. However, it remains unclear how metabolic pathways are regulated during neurulation. Here, we used single-cell mRNA-sequencing to analyze expression of genes involved in metabolism of carbon, fats, vitamins, and antioxidants during neurulation in mice and identify a coupling of glycolysis and cellular proliferation to ensure proper neural tube closure. Using loss of miR-302 as a genetic model of cranial NTD, we identify misregulated metabolic pathways and find a significant upregulation of glycolysis genes in embryos with NTD. These findings were validated using mass spectrometry-based metabolite profiling, which identified increased glycolytic and decreased lipid metabolites, consistent with a rewiring of central carbon traffic following loss of miR-302. Predicted miR-302 targets Pfkp, Pfkfb3, and Hk1 are significantly upregulated upon NTD resulting in increased glycolytic flux, a shortened cell cycle, and increased proliferation. Our findings establish a critical role for miR-302 in coordinating the metabolic landscape of neural tube closure.

Comparison of 3D Printed Spherical Implants versus Femoral Head Allografts for Tibiotalocalcaneal Arthrodesis.

Successful tibiotalocalcaneal (TTC) arthrodesis can be difficult to achieve in patients with bulk bone defects even with the use of femoral head allograft. Retrograde intramedullary nail placement through custom 3-dimensional (3D) spherical implants is an innovative option for these patients. The purpose of this study was to compare fusion rates, graft resorption, and complication rates between patients undergoing TTC fusion with 3D sphere implants versus femoral head allografts. Patients who underwent TTC arthrodesis with an intramedullary nail along with a 3D spherical implant (n = 8) or femoral head allograft (n = 7) were included in this study. The rate of successful fusion of the tibia, calcaneus, and talar neck to the 3D sphere or femoral head allograft was compared between the groups. The rate of total fused articulations was significantly higher in the 3D sphere group (92%) than the femoral head allograft group (62%; p = .018). The number of patients achieving successful fusion of all 3 articulations was higher in the 3D sphere group (75%) than the femoral head allograft group (42.9%, p = .22). The rate of graft resorption was significantly higher in the femoral head allograft group (57.1%) than the 3D sphere group (0%, p = .016). There were no significant differences between the groups in terms of complications. These data demonstrate that the use of a custom 3D printed sphere implant is safe in patients with severe bone loss undergoing TTC arthrodesis with a retrograde intramedullary nail and may result in improved rates of successful arthrodesis.

MRI-guided laser interstitial thermal thalamotomy for medically intractable tremor disorders.

INTRODUCTION: Medically intractable tremors are a common, difficult clinical situation. Deep brain stimulation decreases Parkinson's disease resting tremor and essential tremor, but not all patients are candidates from a diagnostic, medical, or social standpoint, prompting the need for alternative surgical strategies. METHODS: We describe 13 patients with medically intractable tremor treated with laser interstitial thermal thalamotomy performed under general anesthesia using live MRI-guidance and the Clearpoint stereotactic system. RESULTS: All patients had a dramatic decrease in tremor immediately postoperatively, which has been sustained through follow-up (3-17 months) in all but 1 patient (mean tremor score reduction of 62%; 10.33 ± 2.69 to 3.89 ± 3.1). Objective side effects were transient and included imbalance and paresthesia. CONCLUSION: Medically intractable tremor treated with laser interstitial thermal thalamotomy may be a useful addition to the treatment armamentarium for medically intractable tremor disorders. © 2018 International Parkinson and Movement Disorder Society.

The Arabidopsis mediator complex subunits MED16, MED14, and MED2 regulate mediator and RNA polymerase II recruitment to CBF-responsive cold-regulated genes.

The Mediator16 (MED16; formerly termed SENSITIVE TO FREEZING6 [SFR6]) subunit of the plant Mediator transcriptional coactivator complex regulates cold-responsive gene expression in Arabidopsis thaliana, acting downstream of the C-repeat binding factor (CBF) transcription factors to recruit the core Mediator complex to cold-regulated genes. Here, we use loss-of-function mutants to show that RNA polymerase II recruitment to CBF-responsive cold-regulated genes requires MED16, MED2, and MED14 subunits. Transcription of genes known to be regulated via CBFs binding to the C-repeat motif/drought-responsive element promoter motif requires all three Mediator subunits, as does cold acclimation-induced freezing tolerance. In addition, these three subunits are required for low temperature-induced expression of some other, but not all, cold-responsive genes, including genes that are not known targets of CBFs. Genes inducible by darkness also required MED16 but required a different combination of Mediator subunits for their expression than the genes induced by cold. Together, our data illustrate that plants control transcription of specific genes through the action of subsets of Mediator subunits; the specific combination defined by the nature of the stimulus but also by the identity of the gene induced.

Defining neurodegeneration on Guam by targeted genomic sequencing.

OBJECTIVE: Amyotrophic lateral sclerosis/parkinsonism-dementia complex has been described in Guam, Western Papua, and the Kii Peninsula of Japan. The etiology and pathogenesis of this complex neurodegenerative disease remains enigmatic. METHODS: In this study, we have used targeted genomic sequencing to evaluate the contribution of genetic variability in the pathogenesis of amyotrophic lateral sclerosis, parkinsonism, and dementia in Guamanian Chamorros. RESULTS: Genes previously linked to or associated with amyotrophic lateral sclerosis, parkinsonism, dementia, and related neurodegenerative syndromes were sequenced in Chamorro subjects living in the Mariana Islands. Homozygous PINK1 p.L347P, heterozygous DCTN1 p.T54I, FUS p.P431L, and HTT (42 CAG repeats) were identified as pathogenic mutations. INTERPRETATION: The findings explain the clinical, pathologic, and genetic heterogeneity observed in some multi-incident families and contribute to the excess incidence of neurodegeneration previously reported on Guam.