Does surgical volume correlate with outcomes in TMJ replacement surgery?

OBJECTIVE: To survey oral and maxillofacial surgeons (OMS) who perform temporomandibular joint replacement (TMJR) to determine whether length of surgery, specific TMJR protocols, or the incidence of complications are related to experience and case volume. STUDY DESIGN: An anonymous electronic survey was emailed to 407 surgeon members of the American Association of Oral and Maxillofacial Surgeons, American Society of Temporomandibular Joint Surgeons, and European Society of Temporomandibular Joint Surgeons known to have TMJR experience via publications or reputation. The descriptive survey contained multiple choice and open-ended questions. Descriptive statistics were computed for each variable for data analysis. RESULTS: Forty-nine surgeons completed the survey. The average stock TMJR cases included 54.6% unilateral and 50.5% bilateral cases. The average custom TMJR cases included 50.5% unilateral and 49.5% bilateral cases. Average procedure time for stock TMJR was 2.86 hours for unilateral, and 5.30 hours for bilateral cases. The average procedure time for a custom TMJR was 2.75 hours for unilateral, and 4.87 hours for bilateral cases. Average duration of hospital stay for stock and custom TMJR cases was 1.49 and 1.41 days (unilateral), and 1.98 and 1.95 days (bilateral). CONCLUSIONS: This study provides some pilot data that demonstrates that the length of surgery, specific TMJR surgical protocols, and the incidence of complications may be related to surgeon TMJR experience and case volume.

Alloplastic TMJ replacement in the skeletally immature patient - A systematic review.

This study assessed the current evidence for the use of TMJR reconstruction in skeletally immature patients. A systematic review was conducted according to PRISMA guidelines. An electronic search in PubMed and Embase was performed. Meta-analysis randomized controlled trials (RCTs), cohort studies, observational studies, case series, and case reports were eligible for inclusion. Case reports were also included due to the limited number of publications identified with the predefined terms. Exclusion criteria were: (1) studies written in a language other than English; (2) full-text unavailability (i.e., posters and conference abstracts). The selected studies were assessed for risk of bias. A meta-analysis was not performed as it necessitates a substantial between-study design homogeneity; hence, a descriptive synthesis of data was performed. There were 9 TMJR device reconstruction studies involving 14 subjects 13 years of age or younger. Follow-up ranged from 7 months to 120 months. All papers reported significant decrease in pain and improvement of diet. All prostheses were functional. No material failures of the prosthesis components were observed. The mandible continued to show limited growth following TMJR and most of the cases required no secondary or revision surgery even when the patient reached skeletal maturity. This systematic review had some limitations. The studies included had a low level of evidence and a high risk of bias. Most of the studies had a small patient sample, and no study had a control group. The literature reviewed supports the use of TMJR devices in the restoration of mandibular function and form in skeletally immature patients.

Selective concentration of iron, titanium, and zirconium substrate minerals within Gregory's diverticulum, an organ unique to derived sand dollars (Echinoidea: Scutelliformes).

Gregory's diverticulum, a digestive tract structure unique to a derived group of sand dollars (Echinoidea: Scutelliformes), is filled with sand grains obtained from the substrate the animals inhabit. The simple methods of shining a bright light through a specimen or testing response to a magnet can reveal the presence of a mineral-filled diverticulum. Heavy minerals with a specific gravity of >2.9 g/cm3 are selectively concentrated inside the organ, usually at concentrations one order of magnitude, or more, greater than found in the substrate. Analyses of diverticulum content for thirteen species from nine genera, using optical mineralogy, powder X-ray diffraction, scanning electron microscopy and energy dispersive X-ray spectroscopy, as well as micro-computed tomography shows the preference for selection of five major heavy minerals: magnetite (Fe3O4), hematite (Fe2O3), ilmenite (FeTiO3), rutile (TiO2), and zircon (ZrSiO4). Minor amounts of heavy or marginally heavy amphibole, pyroxene and garnet mineral grains may also be incorporated. In general, the animals exhibit a preference for mineral grains with a specific gravity of >4.0 g/cm3, although the choice is opportunistic and the actual mix of mineral species depends on the mineral composition of the substrate. The animals also select for grain size, with mineral grains generally in the range of 50 to 150 µm, and do not appear to alter this preference during ontogeny. A comparison of analytical methods demonstrates that X-ray attenuation measured using micro-computed tomography is a reliable non-destructive method for heavy mineral quantification when supported by associated analyses of mineral grains extracted destructively from specimens or from substrate collected together with the specimens. Commonalities in the electro-chemical surface properties of the ingested minerals suggest that such characteristics play an important role in the selection process.

Drug-Polymer Nanodroplet Formation and Morphology Drive Solubility Enhancement of GDC-0810.

Nanodroplet formation is important to achieve supersaturation of active pharmaceutical ingredients (APIs) in an amorphous solid dispersion. The aim of the current study was to explore how polymer composition, architecture, molar mass, and surfactant concentration affect polymer-drug nanodroplet morphology with the breast cancer API, GDC-0810. The impact of nanodroplet size and morphology on dissolution efficacy and drug loading capacity was explored using polarized light microscopy, dynamic light scattering, and cryogenic transmission electron microscopy. Poly(N-isopropylacrylamide-stat-N,N-dimethylacrylamide) (PND) was synthesized as two linear derivatives and two bottlebrush derivatives with carboxylated or PEGylated end-groups. Hydroxypropyl methylcellulose acetate succinate grade MF (HPMCAS-MF) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) were included as commercial polymer controls. We report the first copolymerization synthesis of a PVPVA bottlebrush copolymer, which was the highest performing excipient in this study, maintaining 688 µg/mL GDC-0810 concentration at 60 wt % drug loading. This is likely due to strong polymer-drug noncovalent interactions and the compaction of GDC-0810 along the PVPVA bottlebrush backbone. Overall, it was observed that the most effective formulations had a hydrodynamic radius less than 25 nm with tightly compacted nanodroplet morphologies.

Surgical complications of vagus nerve stimulation surgery: A 14-years single-center experience.

Introduction: Vagus nerve stimulation (VNS) is the most frequently used neuromodulation treatment for Drug-Resistant Epilepsy (DRE) patients. Complications of VNS surgery include surgical site infection and unilateral vocal cord paresis. Complication rates vary across studies. Research question: What is the safety profile of VNS related surgeries? Materials and methods: Retrospective cohort study using patient files of DRE-patients who had undergone primary implantation of a VNS-system, replacement of the VNS pulse generator, replacement of the lead, replacement of both pulse generator and lead, or VNS removal surgery in the Maastricht UMC+. Multiple Imputation was used for missing data. Univariable and multivariable logistic regression analysis were performed to analyze possible risk factors, in case of a small sample size, an independent-samples t-test and Fisher's exact test or Pearson's X2-test were used. The complication rate was calculated as percentage. Results: This study included a total of 606 VNS surgical procedures, leading to 67 complications of which 3 permanent complications. Complication rate after primary implantation was 13.4%; 2,5% for pulse generator replacement; 21.4% for lead revision and 27.3% for complete VNS removal. No statistically significant results were found when analyzing the results of adults and children <18 years separately. Discussion and conclusion: Complication rates of VNS-related surgeries in our own institutional series are low and comparable to previously reported series. VNS surgery is a relatively safe procedure. The complication rate differs per type of surgery and mean surgery duration was longer for patients with complications after lead revision surgery compared to patients without complications.

Alloplastic temporomandibular joint replacement - past, present, and future: "Learn from the past, prepare for the future, live in the present." Thomas S. Monson.

Based on evidence from the orthopaedic, biomedical engineering, and oral and maxillofacial surgical literature, this paper discusses reported successes and failures of past alloplastic temporomandibular joint (TMJ) devices that have led to the development of present total temporomandibular joint replacement (TMJR) devices. The paper concludes with discussion of the ongoing research that will lead to future embodiment (materials, designs, and manufacture) advances in TMJR management of severe and debilitating end-stage TMJ disease, further improving patients' mandibular function, form, and overall quality of life.

Recommendations on the Use of Oral Orthotic Occlusal Appliance Therapy for Temporomandibular Joint Disorders: Current Evidence and Clinical Practice.

Background: 'Temporomandibular joint disorders (TMDs)' denote an umbrella term that includes arthritic, musculoskeletal and neuromuscular conditions involving the temporomandibular joint, the masticatory muscles, and the associated tissues. Occlusal devices are one of the common treatment modalities utilized in the conservative management of TMDs. The indications for the available 'oral splints' or 'oral orthotic occlusal devices' remain ambiguous. Methods: A joint international consortium was formulated involving the subject experts at TMJ Foundation, to resolve the current ambiguity regarding the use of oral orthotic occlusal appliance therapy for the temporomandibular joint disorders based on the current scientific and clinical evidence. Results: The recommendations and the conclusion of the clinical experts of the joint international consort has been summarized for understanding the indications of the various available oral orthotic occlusal appliances and to aid in the future research on oral occlusal orthotics. Conclusion: The use of the oral orthotic occlusal appliances should be based on the current available scientific evidence, rather than the archaic protocols.

Resective Epilepsy Surgery, QUality of life and Economic evaluation (RESQUE): the change in quality of life after resective epilepsy surgery-protocol for a multicentre, prospective cohort study.

INTRODUCTION: Resective epilepsy surgery is often seen as a last resort when treating drug-resistant epilepsy. Positive results on quality of life (QoL) and economic benefits after surgery argue for a less restrictive attitude towards epilepsy surgery for drug-resistant epilepsy. QoL and economic benefits are country-dependent. The objective of the Resective Epilepsy Surgery, QUality of life and Economic evaluation (RESQUE) trial is to evaluate the change in QoL before and after epilepsy surgery in Dutch people with drug-resistant epilepsy. The results will form part of an economic evaluation of epilepsy surgery in people with epilepsy (PWE) in The Netherlands. METHODS AND ANALYSIS: A longitudinal prospective multicentre cohort study involving 100 PWE undergoing epilepsy surgery between 2019 and 2025 is being performed in three Dutch academic hospitals. Excluded are PWE who have a lower level of intelligence (TIQ<70) or who do not master the Dutch language. Before surgery and 3, 6, 12 and 24 months after surgery, PWE receive validated online questionnaires (QOLIE-31, EQ-5D, iMCQ and iPCQ) on QoL, cost of care, expectations and satisfaction. Primary outcome is the change in QoL. Secondary outcomes are change in generic QoL, seizure reduction (International League Against Epilepsy Outcome Classification), medical consumption, productivity, the correlation between QoL and seizure reduction and expectation of and satisfaction with the surgery. ETHICS AND DISSEMINATION: The study design has been approved by the Medical Ethics Review Committee (METC) of Maastricht UMC+ (2019-1134) and the Amsterdam UMC (vu). At the time of writing, UMC Utrecht is in the process of considering approval. The study will be conducted according to the Dutch Medical Research Involving Human Subjects Act and the Declaration of Helsinki. The results will be publicly disclosed and submitted for publication in international peer-reviewed scientific journals. There is no veto on publication by the involved parties. TRIAL REGISTRATION: NL8278; Pre-results.

Does Emotional State Improve Following Temporomandibular Joint Total Joint Replacement?

BACKGROUND: Temporomandibular joint total joint replacement (TMJTJR) offers patients the opportunity for improved function and reduced pain. TMJTJR also has the potential to affect a patient's emotions in a positive or negative manner. PURPOSE: The purpose of this study was to evaluate changes in emotional state for subjects undergoing TMJTJR. STUDY DESIGN, SETTING, SAMPLE: The authors implemented a retrospective cohort study. Subjects who received TMJTJR were identified from the TMJ Inter Network, which is a study group comprising more than 130 temporomandibular joint surgeons. Subjects between the ages of 18 and 65 years with complete medical records and pre/post TMJTJR video/audio recordings were enrolled in the study. PREDICTOR VARIABLE: The predictor variable was time (preoperative and postoperative). MAIN OUTCOME VARIABLES: The primary outcome variable is change in the emotional state. All subjects had preoperative (T0) recorded interview as well as a postoperative (T1) interview at 3 to 6 months. The eight-category emotional state was classified as neutral, happy, sad, angry, fearful, disgusted, surprised, and bored. The three-category emotional state was classified as neutral, positive, and negative. The emotional state was measured using artificial intelligence at T0 and T1. The secondary outcome variable was pain score and maximal interincisal opening. COVARIATES: The covariates are gender, age, diagnosis, prosthetic side, TMJTJR design, and TMJTJR type. ANALYSES: The relationship between emotional state change and covariates was examined using both the χ2 test and the Kruskal-Wallis H test. The significance of the change in categorical data after surgery was examined using the McNemar-Bowker test. P values < .05 were considered statistically significant. RESULTS: Thirty-three subjects were included in the study. The mean age was 30.09 ± 8.69 with 15 males (45%) and 18 females (55%). The percentage of subjects with preoperative neutral, happy, sad, angry, and fearful emotional states was 24, 15, 24, 9, and 27%, respectively. The percentage of subjects with postoperative neutral, happy, sad, angry, and fearful emotional states was 21, 39, 21, 12, and 6%, respectively. The change in emotional state was statistically significant (P = .037). There was no statistically significant relationship between covariates and emotional state changes (P > .05). CONCLUSION: According to the assessment of artificial intelligence, TMJTJR improves the emotional state of patients.

Chemokine Regulation in Temporomandibular Joint Disease: A Comprehensive Review.

Temporomandibular joint disorders (TMDs) are conditions that affect the muscles of mastication and joints that connect the mandible to the base of the skull. Although TMJ disorders are associated with symptoms, the causes are not well proven. Chemokines play an important role in the pathogenesis of TMJ disease by promoting chemotaxis inflammatory cells to destroy the joint synovium, cartilage, subchondral bone, and other structures. Therefore, enhancing our understanding of chemokines is critical for developing appropriate treatment of TMJ. In this review, we discuss chemokines including MCP-1, MIP-1α, MIP-3a, RANTES, IL-8, SDF-1, and fractalkine that are known to be involved in TMJ diseases. In addition, we present novel findings that CCL2 is involved in ß-catenin-mediated TMJ osteoarthritis (OA) and potential molecular targets for the development of effective therapies. The effects of common inflammatory factors, IL-1ß and TNF-α, on chemotaxis are also described. In conclusion, this review aims to provide a theoretical basis for future chemokine-targeted therapies for TMJ OA.

Helicobacter pylori World Gastroenterology Organization Global Guideline.

Helicobacter pylori remains a major health problem worldwide, causing considerable morbidity and mortality due to peptic ulcer disease and gastric cancer. The burden of disease falls disproportionally on less well-resourced populations. As with most infectious diseases, the largest impact on reducing this burden comes from improvement in socioeconomic status, which interrupts transmission. This has been observed in many regions of the world, but the prevalence of infection remains high in many regions where improvements in living standards are slow to occur. Meanwhile, the optimal clinical management and treatment pathways remain unsettled and are evolving with changing antimicrobial resistance patterns. Despite decades of research and clinical practice, major challenges remain. The quest for the most effective, safe, and simple therapy remains the major issue for clinicians. The search for an effective vaccine appears to be elusive still. Clinical guidelines do not infrequently proffer discordant advice. A major challenge for guidelines is for relevance across a variety of populations with a varying spectrum of disease, antimicrobial resistance rates, and vastly different resources. As local factors are central to determining the impact and management strategies for H. pylori infection, it is important that pathways are based on the best available local knowledge rather than solely extrapolating from guidelines formulated in other regions, which may be less applicable. To this end, this revision of the World Gastroenterology Organisation (WGO) H. pylori guideline uses a "Cascades" approach that seeks to summarize the principles of management and offer advice for pragmatic, relevant and achievable diagnostic and treatment pathways based on established key treatment principles and using local knowledge and available resources to guide regional practice.

Drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains.

The design of compounds that can discriminate between closely related target proteins remains a central challenge in drug discovery. Specific therapeutics targeting the highly conserved myosin motor family are urgently needed as mutations in at least six of its members cause numerous diseases. Allosteric modulators, like the myosin-II inhibitor blebbistatin, are a promising means to achieve specificity. However, it remains unclear why blebbistatin inhibits myosin-II motors with different potencies given that it binds at a highly conserved pocket that is always closed in blebbistatin-free experimental structures. We hypothesized that the probability of pocket opening is an important determinant of the potency of compounds like blebbistatin. To test this hypothesis, we used Markov state models (MSMs) built from over 2 ms of aggregate molecular dynamics simulations with explicit solvent. We find that blebbistatin's binding pocket readily opens in simulations of blebbistatin-sensitive myosin isoforms. Comparing these conformational ensembles reveals that the probability of pocket opening correctly identifies which isoforms are most sensitive to blebbistatin inhibition and that docking against MSMs quantitatively predicts blebbistatin binding affinities (R2=0.82). In a blind prediction for an isoform (Myh7b) whose blebbistatin sensitivity was unknown, we find good agreement between predicted and measured IC50s (0.67 µM vs. 0.36 µM). Therefore, we expect this framework to be useful for the development of novel specific drugs across numerous protein targets.

A first-in-human phase I/IIa gene transfer clinical trial for Duchenne muscular dystrophy using rAAVrh74.MCK.GALGT2.

In a phase 1/2, open-label dose escalation trial, we delivered rAAVrh74.MCK.GALGT2 (also B4GALNT2) bilaterally to the legs of two boys with Duchenne muscular dystrophy using intravascular limb infusion. Subject 1 (age 8.9 years at dosing) received 2.5 × 1013 vector genome (vg)/kg per leg (5 × 1013 vg/kg total) and subject 2 (age 6.9 years at dosing) received 5 × 1013 vg/kg per leg (1 × 1014 vg/kg total). No serious adverse events were observed. Muscle biopsy evaluated 3 or 4 months post treatment versus baseline showed evidence of GALGT2 gene expression and GALGT2-induced muscle cell glycosylation. Functionally, subject 1 showed a decline in 6-min walk test (6MWT) distance; an increase in time to run 100 m, and a decline in North Star Ambulatory Assessment (NSAA) score until ambulation was lost at 24 months. Subject 2, treated at a younger age and at a higher dose, demonstrated an improvement over 24 months in NSAA score (from 20 to 23 points), an increase in 6MWT distance (from 405 to 478 m), and only a minimal increase in 100 m time (45.6-48.4 s). These data suggest preliminary safety at a dose of 1 × 1014 vg/kg and functional stabilization in one patient.

Is Heterotopic Ossification Removal From Alloplastic Temporomandibular Joint Prosthesis Using Er,Cr:YSGG Laser Superior to Conventional Methods?

PURPOSE: Heterotopic ossification (HO) formed over the major components and fixation screw heads of an alloplastic temporomandibular joint replacement (TMJR) prosthesis can result in decreased quality of life, limited function, prosthesis failure, and hinder prosthesis revision, replacement, or removal. This study simulated HO removal from the major components and fixation screw heads of alloplastic TMJR prostheses using an erbium, chromium-doped yttrium, scandium, gallium, and garnet (Er,Cr:YSGG) laser and compared the results to conventional methods of HO removal. The surface morphology and chemical structure of the exposed components were analyzed. The investigators hypothesize that HO removal with an Er,Cr:YSGG laser causes less damage to TMJR prosthesis components compared to conventional HO removal methods. METHODS: This multiple test descriptive analysis simulated HO removal from TMJR prostheses mounted to stereolithic models. Simulated HO removal was completed using a novel Er,Cr:YSGG laser method and conventional methods which utilized a fissure carbide bur in a high-speed rotary instrument, a standard osteotome, and an ultrasonic aspirator. Surfaces exposed on the TMJR prostheses were analyzed for morphological or chemical change using scanning electron microscopy, energy dispersive X-ray spectroscopy, and Raman spectroscopy. RESULTS: The Er,Cr:YSGG laser did not adversely affect the titanium screws or titanium components of the TMJR prostheses, while conventional methods of HO removal did. HO removal using the Er,Cr:YSGG laser and conventional methods both inflicted surface damage to the fossa ultrahigh molecular weight polyethylene component of the TMJR prostheses. CONCLUSION: Damage inflicted to titanium alloy or commercially pure titanium components of TMJR prostheses by conventional HO removal methods can be avoided by instead removing HO with an Er,Cr:YSGG laser. However, long exposure of the Er,Cr:YSGG laser to ultrahigh molecular weight polyethylene surfaces should be avoided. Additional research to expand on applications to other procedures and in other surgical fields is encouraged.

Islet primary cilia motility controls insulin secretion.

Primary cilia are specialized cell-surface organelles that mediate sensory perception and, in contrast to motile cilia and flagella, are thought to lack motility function. Here, we show that primary cilia in human and mouse pancreatic islets exhibit movement that is required for glucose-dependent insulin secretion. Islet primary cilia contain motor proteins conserved from those found in classic motile cilia, and their three-dimensional motion is dynein-driven and dependent on adenosine 5'-triphosphate and glucose metabolism. Inhibition of cilia motion blocks beta cell calcium influx and insulin secretion. Human beta cells have enriched ciliary gene expression, and motile cilia genes are altered in type 2 diabetes. Our findings redefine primary cilia as dynamic structures having both sensory and motile function and establish that pancreatic islet cilia movement plays a regulatory role in insulin secretion.

Generation of ciliary beating by steady dynein activity: the effects of inter-filament coupling in multi-filament models.

The structure of the axoneme in motile cilia and flagella is emerging with increasing detail from high-resolution imaging, but the mechanism by which the axoneme creates oscillatory, propulsive motion remains mysterious. It has recently been proposed that this motion may be caused by a dynamic 'flutter' instability that can occur under steady dynein loading, and not by switching or modulation of dynein motor activity (as commonly assumed). In the current work, we have built an improved multi-filament mathematical model of the axoneme and implemented it as a system of discrete equations using the finite-element method. The eigenvalues and eigenvectors of this model predict the emergence of oscillatory, wave-like solutions in the absence of dynein regulation and specify the associated frequencies and waveforms of beating. Time-domain simulations with this model illustrate the behaviour predicted by the system's eigenvalues. This model and analysis allow us to efficiently explore the potential effects of difficult to measure biophysical parameters, such as elasticity of radial spokes and inter-doublet links, on the ciliary waveform. These results support the idea that dynamic instability without dynamic dynein regulation is a plausible and robust mechanism for generating ciliary beating.

Polycation Architecture Affects Complexation and Delivery of Short Antisense Oligonucleotides: Micelleplexes Outperform Polyplexes.

Herein, we examine the complexation and biological delivery of a short single-stranded antisense oligonucleotide (ASO) payload with four polymer derivatives that form two architectural variants (polyplexes and micelleplexes): a homopolymer poly(2-dimethylaminoethyl methacrylate) (D), a diblock polymer poly(ethylene glycol)methylether methacrylate-block-poly(2-dimethylaminoethyl methacrylate) (ObD), and two micelle-forming variants, poly(2-dimethylaminoethyl methacrylate)-block-poly(n-butyl methacrylate) (DB) and poly(ethylene glycol)methylether methacrylate-block-poly(2-dimethylaminoethyl methacrylate)-block-poly(n-butyl methacrylate) (ObDB). Both polyplexes and micelleplexes complexed ASOs, and the incorporation of an Ob brush enhances colloidal stability. Micellplexes are templated by the size and shape of the unloaded micelle and that micelle-ASO complexation is not sensitive to formulation/mixing order, allowing ease, versatility, and reproducibility in packaging short oligonucleotides. The DB micelleplexes promoted the largest gene silencing, internalization, and tolerable toxicity while the ObDB micelleplexes displayed enhanced colloidal stability and highly efficient payload trafficking despite having lower cellular uptake. Overall, this work demonstrates that cationic micelles are superior delivery vehicles for ASOs denoting the importance of vehicle architecture in biological performance.

Modification of an extended total temporomandibular joint replacement (eTMJR) classification system.

The aims of this paper were to validate a modification of an extended total temporomandibular joint replacement (eTMJR) classification system and develop a classification schematic for ease of reference. High-volume TMJ surgeons were asked to score 20 separate eTMJR devices using the updated classification system, and inter-rater variability was calculated. Using the modified classification system developed, a Conger's kappa (κ) coefficient of 0.53 was returned, suggesting moderate to good levels of agreement. The final classification system was then developed in a series of standardised graphic illustrations as visual representations of the different subcategories of eTMJR devices.