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Although recent evidence has suggested the value of operative therapy for the management of medication-related osteonecrosis of the jaw (MRONJ), its effectiveness remains controversial. The purpose of this study was to measure and compare MRONJ disease resolution and changes to the quality of life (QoL) between operative and nonoperative management of MRONJ.This is a prospective cohort study. Consecutive MRONJ patients presenting to Mount Sinai Hospital and Sunnybrook Health Sciences Center (September 2016 to August 2020) were recruited and divided by the treatments provided into operative and nonoperative groups. The primary and secondary outcome variables were disease resolution and QoL at 6 months, respectively. Disease resolution was defined as mucosal coverage with an absence of pain, and QoL was measured via the MRONJ-QoL questionnaire. The primary and secondary outcomes, after adjusting for potential confounders, were assessed via multivariate logistic regression and multivariate linear regression analyses, respectively, with significance set to P .05.Sixty patients were included in this study. Of these, 40 patients received operative treatment, and 20 received nonoperative treatment. In the unadjusted analyses, operative therapy was found to be significantly associated with both disease resolution and improvement in QoL (relative risk 6.75, 95% confidence interval [CI] 1.78 to 25.6, P .001; and MRONJ-QoL score improvement of 3.35, 95% CI 0.16 to 6.54, P = .04). When controlling for potential confounders, operative therapy was found to be significantly associated with disease resolution when compared with nonoperative therapy (adjusted odds ratio 46.2, 95% CI 5.57 to 383.9, P .001). Linear regression analysis also showed operative therapy to be significantly associated with improved QoL compared with nonoperative therapy (adjusted MRONJ-QoL score improvement of 3.72, 95% CI 0.34 to 7.11, P = .03).Our study demonstrated operative therapy to be significantly associated with disease resolution and improvement in QoL.

Masticatory myofascial pain is a musculoligamentous syndrome that can mimic odontogenic pain. Pain referral to odontogenic structures can be traced to hyper-irritated myofascial trigger points (MTrPs). This pragmatic study evaluated the concordance between ultrasonography and palpation in detecting MTrPs in the masseter and temporalis muscles.57 patients suspected of temporomandibular disorder were included. MTrPs were palpated manually by expert clinicians. Ultrasonography was then performed by a blind sonographer. The quantity of MTrPs and involved muscle sections, the pain occurrence, and location of the MTrPs within the muscle sections were compared using mean difference (MD) and concordance statistics [Cohen's kappa (κ) and the interclass correlation coefficient (ICC)] as applicable.Ultrasonography located MTrPs as 2.1±1.3mmUltrasonography and palpation concord moderately to substantially on the quantity of MTrPs and the involved muscle sections, but disagree on the location of the MTrPs within the muscle sections. Ultrasonography has the potentials as a chair-side diagnostic aid to help clinicians determine an accurate diagnosis, enhance patient experience during examination, and avoid unnecessary treatments that can mitigate the risk of iatrogenic damage.

AimTo understand the spatiotemporal dynamics of bacterial succession during gingivitis, and to identify taxa with a critical role in gum health with prognostic value.Materials and methodsLongitudinal microbiome data were collected from 15 individuals after completely discontinuing all forms of oral hygiene, and subsequently reintroducing it for three and two weeks, respectively. Sequences from the 16S rRNA V4-V5 gene region from sub- and supra-gingival plaque, saliva, and tongue sites were annotated and mapped to a reference tree of Human Oral Microbiome Database sequences.ResultsSuspending oral hygiene induced gingivitis, which was resolved after its resumption to baseline. Most significant shifts in bacterial abundance were observed in dental plaque, but not in saliva and tongue sites. During gingivitis-induction, baseline microbiota dominated by Streptococcus, was superseded by increased Prevotella, Fusobacterium, Leptotrichia, and Porphyromonas genera. Converse to its decline during disease-induction, gum health restoration was accompanied by a significant increase in streptococci.ConclusionWe present the most comprehensive, spatiotemporal map of bacterial succession during gingivitis onset and resolution. We have identified taxa with potential as probiotic candidates for gum disease (i.e., perio-probiotics), and suggest tooth-associated plaque and not saliva or tongue plaque should be used in future prognostic tests.

Precooperative children and patients with intellectual disabilities often require intramuscular (IM) sedation prior to the induction of general anesthesia (GA). Ketamine is an effective preinduction sedative but can produce significant adverse side effects. Dexmedetomidine, a sedative with sympatholytic and analgesic properties, may provide advantages when used in combination with ketamine. This retrospective study evaluated the efficacy and safety of IM ketamine with dexmedetomidine for preoperative sedation. We conducted a chart review of all patients (n = 105) treated for dental rehabilitation who received either IM ketamine and dexmedetomidine (study group, n = 74) or IM ketamine and midazolam (control group, n = 31) prior to induction of GA. No significant difference (p = .14) was observed in the time interval from IM administration to operating room entry (median [interquartile range]) between the study and control groups (5 [4–8] vs 5 [2–7] minutes). Patients who received IM dexmedetomidine exhibited significantly lower mean arterial pressures throughout the induction (p = .004) and had lower heart rates (p = .01) throughout the intraoperative period compared with patients who did not receive dexmedetomidine. The combination of dexmedetomidine and ketamine may provide effective and safe IM sedation prior to the induction of GA.

Introduction Loss of the interdental papilla, leading to the formation of black triangular spaces just below the contact area of adjacent teeth, is one of the most challenging periodontal conditions to treat and often requires an interdisciplinary approach by the periodontist, restorative dentist, and orthodontist. Although these "black triangles" may appear quite small from a clinician's standpoint, they can have a significant impact on oral health satisfaction for patients. This case series illustrates a novel minimally invasive approach to restore interdental papilla deficiencies. Case presentation Four interdental papilla defects were treated in three females. No patients were lost to follow-up over 6 months. The surgery consisted of a horizontal incision placed apical to the area of papillary loss in the alveolar mucosa just beyond the mucogingival junction. An interdental subperiosteal tissue space was then created by tunneling toward and under the dental papilla. Once adequate release was achieved, dermal filler was administered into and underneath the deficient papilla. The papillary margins were then sealed with cyanoacrylate and additional dermal filler was injected as needed to achieve ideal papillary fill. Six months after treatment there was an improvement in patient-satisfaction regarding papilla fill demonstrated by a mean increase in visual analogue scale (VAS) measurements of 62.46%. Mean papilla fill was 1.75 mm. Conclusion This surgical technique demonstrates the restoration of deficient interdental papillae between teeth and implants, and perhaps as importantly, a considerable improvement in patient-based outcomes quantified through VASs.

An innovation in the treatment of odontogenic keratocysts (OKCs) is the adjunctive application of 5-fluorouracil (5-FU). Although the original approach remains effective, it may often be a challenge for the patient to return postoperatively and/or tolerate non-resorbable packing removal. The purpose of the present study is to determine whether our refined approach, where we directly apply 5-FU-coated absorbable gelatin sponge to the surgical cavity, would be an effective treatment for OKCs with similar efficacy as with our original approach.A retrospective case series studying the treatment efficacy of our refined topical 5-FU approach on OKCs was reviewed. The study population was composed of all patients presenting for evaluation and management of OKCs with our refined technique between September 1, 2017 and July 1, 2022 at Stony Brook University Hospital. The primary outcomes included 1) time to OKC recurrence, and 2) incidence of trigeminal nerve injury following OKC treatment with the refined topical 5% 5-FU technique. Other study variables included age, gender, tumor location, and tumor size. Data analyses included descriptive statistics reported as median [interquartile range], and Kaplan-Meier survival analysis for time to OKC recurrence.Thirteen patients with 15 OKCs were reviewed (6 women and 7 men). There were no OKC recurrences with a median follow-up time of 28.5 (24) months. Normal bony healing was observed in all cases and there were no adverse local or systemic events, no alterations in sinus function, and no incidences of infraorbital or inferior alveolar nerve paresthesia.Our case series demonstrates that this refinement further increases technical ease, decreases operating time, and precludes the need for packing removal, with similar efficacy as the original approach.

Background Anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDARE) is a multi-stage autoimmune-mediated disease associated with a multitude of neuropsychiatric and dysautonomic features. Orofacial dyskinesias are frequently associated with this condition and manifest as abnormal movements of the orofacial musculature. These involuntary movements may result in significant trauma to the oral and maxillofacial complex including the avulsion of the dentition and orofacial lacerations. Case presentation We describe the course of two female patients with anti-NMDARE in whom significant involuntary self-inflicted maxillofacial trauma was suffered despite the use of complex parenteral sedation regimens. The application of traditional maxillomandibular wiring techniques and pharmacologic strategies, including botulinum toxin, to immobilize the mandible were initially unsuccessful. These difficulties led to the fabrication and wire-based fixation of a patient-specific acrylic oral appliance that maintained the mandible in a depressed position and mitigated all lateral and protrusive movements. Discussion and conclusions These cases illustrate the first known successful use of an appliance-based therapy for managing orofacial dyskinesias in the anti-NMDARE patient population through an adaptation of traditional maxillomandibular fixation techniques. This approach eliminated further orofacial trauma and afforded physicians with safer means to manage and assess patients afflicted with this condition during their protracted intensive care unit admissions.

Introduction The scapula tip free flap has been described for reconstruction of short mandible defects with extensive soft tissue needs. The versatility of this flap has not been extensively described. Methods Retrospective case series of patients who underwent mandibulectomy and reconstruction with the scapula tip free flap from 2005 to 2016. Outcomes include bony union, complications, dental rehabilitation, and donor site morbidity. Results A total of 120 patients were identified. Average harvested bone was 7.7 cm, with 54% undergoing one osteotomy, and 76.7% harvested as a chimeric flap. Radiographically, average inset bone was 6.6 cm. Complete or partial bony union was observed at 74.4% of proximal and 82.6% of distal osteotomies. A 95% of reconstructions met criteria for dental implants. Mean disabilities of the arm, shoulder and hand score was 21.2. Conclusions The scapular tip is an excellent option for reconstruction of segmental mandible defects with the option of osteotomy, excellent bony union rates, low donor site morbidity, and potential for dental rehabilitation.

To investigate and compare the general public's, general dentists', and primary care physicians' level of knowledge of the scope of practice of oral and maxillofacial surgeons (OMSs). We hypothesized that there is a generalized lack of knowledge of the scope of practice of oral-maxillofacial surgery, with the general public being the least informed and the general dentists the most educated.A cross-sectional survey study was conducted via a mail-out survey that was delivered to a random sample of the general public, general dentists, and primary care physicians in Ontario, Canada. A total of 1800 participants were selected. The survey consisted of a demographic screener along with 24 clinical scenarios in which the participants could select all the specialists they thought were capable of completing the treatment. Inferential statistics were computed using a chi-square test to compare responses between the groups and identified any significant differences between subjects for each of the 24 scenarios with P value set at 0.05.Total response rate of 50.1% (n = 902) was achieved. The majority of health professionals (100% dentists, 95.5% primary care physicians) have heard of oral-maxillofacial surgery, in contrast to only 73.7% of the general public (P .001). There was a general lack of awareness of oral-maxillofacial surgery scope of practice by all groups wherein OMSs were selected less than 50% of the time in 10 (general dentists), 14 (primary care physicians), and 16 (general public) of 24 clinical scenarios.Greater than 25% of the general public are unaware of OMS. More concerning, the general public and health professionals as a whole are unfamiliar with the full scope of practice of OMSs. For enhancing access to care by qualified specialists, educational programs highlighting key aspects of oral-maxillofacial surgery should be developed and distributed to all populations.

Multicolumn Electron Beam Lithography (MEBL), a proprietary technology platform developed by Multibeam Corporation, is being applied to enable Security Lithography – a maskless embedding of unique security information into each IC during routine wafer fabrication. This paper focuses on ensuring Secure Chip ID, which provides traceability of a chip throughout its lifecycle and enables confirmation of its unique identity and provenance. The complete MEBL embedding process is disclosed – from chip design to IC fab to verification test. This paper also shows how MEBL hardcoding of the Secure Chip ID “at the silicon level” makes the embedding process cost-efficient and tamperproof.

Tracheopulmonary complications following placement of a nasogastric (NG) feeding tube are uncommon but can cause significant morbidity and mortality. In this case report, an 83-year-old woman of American Society of Anesthesiologists class IV with underlying pulmonary disease required placement of an NG feeding tube after surgical treatment of primary squamous cell carcinoma of the tongue. Malpositioning of the NG feeding tube into the right pleural space was confirmed by computed tomography. Removal of the NG feeding tube resulted in a tension pneumothorax that necessitated chest tube placement. Because of the difficulty of blind NG feeding tube placement in this patient, the subsequently placed NG feeding tube was successfully positioned with the aid of a video laryngoscope. This case report illustrates the risk of NG feeding tube malpositioning in a nasally intubated patient undergoing head and neck surgery and discusses improvements in techniques for proper NG feeding tube placement.

Background: Persistent use of real-time continuous glucose monitoring (CGM) improves diabetes control in individuals with type 1 diabetes (T1D) and type 2 diabetes (T2D). Methods: PRECISE II was a nonrandomized, blinded, prospective, single-arm, multicenter study that evaluated the accuracy and safety of the implantable Eversense CGM system among adult participants with T1D and T2D (NCT02647905). The primary endpoint was the mean absolute relative difference (MARD) between paired Eversense and Yellow Springs Instrument (YSI) reference measurements through 90 days postinsertion for reference glucose values from 40 to 400 mg/dL. Additional endpoints included Clarke Error Grid analysis and sensor longevity. The primary safety endpoint was the incidence of device-related or sensor insertion/removal procedure-related serious adverse events (SAEs) through 90 days postinsertion. Results: Ninety participants received the CGM system. The overall MARD value against reference glucose values was 8.8% (95% confidence interval: 8.1%–9.3%), which was significantly lower than the prespecified 20% performance goal for accuracy (P

Purpose Optimal management approaches for medication-related osteonecrosis of the jaw (MRONJ) using either surgical or nonsurgical approaches remain inconclusive. Our objective was to compare the effects of surgical versus nonsurgical therapy on the resolution of MRONJ. Methods We conducted a retrospective review of eligible patients with a diagnosis of MRONJ at Mount Sinai Hospital, Toronto, Ontario, Canada, who either were seen in the outpatient clinic from January 2014 to December 2016 or received major surgical intervention from January 2011 to December 2016. A multivariate logistic regression was conducted to evaluate the effects of surgical therapy on disease resolution. Results A total of 78 patients were included in this study. Of these, 56 (72%) received surgical therapy. Antiresorptive agents were being taken for the treatment of osteoporosis by 46 patients (82%) in the surgical group compared with 20 nonsurgical patients (91%) (P = .28). The median follow-up period was 15.5 months (interquartile range, 8.0 to 34.3 months) in the surgical group compared with 11.0 months (interquartile range, 8.0 to 20.5 months) in the nonsurgical group (P = .75). Disease resolution occurred in 39 surgical patients (70%) compared with 8 nonsurgical patients (36%). Surgical therapy was associated with disease resolution compared with nonsurgical therapy alone, after adjustment for age, duration of antiresorptive or antiangiogenic therapy, whether the antiresorptive or antiangiogenic agents were used for oncologic purposes, and the stage of MRONJ at initial presentation (adjusted odds ratio, 4.33; 95% confidence interval, 1.28 to 14.60). Conclusions Surgical therapy compared with nonsurgical therapy was associated with disease resolution in patients with MRONJ. High-quality evidence of the superiority of any specific surgical approach in the treatment of MRONJ is needed.

Most cancer patients experience severe pain during their disease course, and the management of cancer pain is a major challenge for patients and the healthcare team. Many diverse translational models of cancer pain in recent years have improved our understanding of cancer-related pain. Cancer and associated cells in the cancer microenvironment may release various peripheral mediators, including ATP, formaldehyde, protons, proteases, endothelin, bradykinin, TNF and NGF, that result in the activation and/or sensitization of peripheral and central neurons, that contribute to the clinical manifestations of cancer-related pain. Identification of these mediators and the peripheral and central mechanisms by which they contribute to cancer-related pain may provide novel therapeutic targets to alleviate cancer patient suffering.

More than half of all cancer patients will suffer significant pain during the course of their disease. The strategic localization of TMPRSS2, a membrane-bound serine protease, on the cancer cell surface may allow it to mediate signal transduction between the cancer cell and its extracellular environment. Here we show TMPRSS2 expression is not only dramatically increased in the primary cancers of patients but TMPRSS2-immunopositivity is also directly correlated with cancer pain severity in these patients. TMPRSS2 induced proteolytic activity, activated trigeminal neurons, and produced marked mechanical hyperalgesia when administered into the hindpaw of wild-type mice but not in PAR2-deficient mice. Co-culture of human cancer cells with murine trigeminal neurons demonstrated co-localization of TMPRSS2 with PAR2. These results point to a novel role for a cell membrane-anchored mediator in cancer pain, as well as pain in general.

The effectiveness of management strategies used for the treatment of medication-related osteonecrosis of the jaw (MRONJ) remains poorly understood. The authors evaluated systematically the effectiveness of the various treatment modalities used for MRONJ.The authors conducted a comprehensive search of MEDLINE, Embase, the Cochrane Library, and Scopus to identify randomized controlled trials, nonrandomized controlled trials, and prospective cohort studies to evaluate comparatively the effectiveness of management strategies for the treatment of MRONJ. The authors conducted the identification of eligible studies in duplicate and synthesized the extracted data by means of a meta-analysis, when feasible.The authors found 13 studies with a medium-to-high risk of bias that met the inclusion criteria of this review. The authors found that, compared with medical treatment of local antimicrobials with or without systemic antimicrobials, the study investigators associated surgical treatment with higher odds of complete resolution of the condition (2 studies; 76 participants; unadjusted odds ratio, 3.55; 95% confidence interval, 1.12 to 11.19). The effectiveness of other therapies, such as bisphosphonate drug holidays, teriparatide, and hyperbaric oxygen, was uncertain.On the basis of the results of an unadjusted analysis, the results of the studies that were deemed to be medium to low quality and to have medium-to-low statistical power suggested that there are higher odds of resolving MRONJ with surgical treatment compared with medical treatment. High-quality research is required for conclusive statements to be made regarding treatment strategies for management of MRONJ.

Oral microbes form a complex and dynamic biofilm community, which is subjected to daily host and environmental challenges. Dysbiosis of the oral biofilm is correlated with local and distal infections and postulating a baseline for the healthy core oral microbiota provides an opportunity to examine such shifts during the onset and recurrence of disease. Here we quantified the daily, weekly, and monthly variability of the oral microbiome by sequencing the largest oral microbiota time-series to date, covering multiple oral sites in ten healthy individuals. Temporal dynamics of salivary, dental, and tongue consortia were examined by high-throughput 16S rRNA gene sequencing over 90 days, with four individuals sampled additionally 1 year later. Distinct communities were observed between dental, tongue, and salivary samples, with high levels of similarity observed between the tongue and salivary communities. Twenty-six core OTUs that classified within Streptococcus, Fusobacterium, Haemophilus, Neisseria, Prevotella, and Rothia genera were present in ≥95% samples and accounted for ~65% of the total sequence data. Phylogenetic diversity varied from person to person, but remained relatively stable within individuals over time compared to inter-individual variation. In contrast, the composition of rare microorganisms was highly variable over time, within most individuals. Using machine learning, an individual's oral microbial assemblage could be correctly assigned to them with 88–97% accuracy, depending on the sample site; 83% of samples taken a year after initial sampling could be confidently traced back to the source subject., Peering into the mouth: Bacterial turnover in plaque and saliva A study of bacteria in the mouth reveals insights into their diversity, stability, and variability among people and over time. By tracking daily, weekly, and monthly fluctuations of plaque and salivary bacteria in ten healthy volunteers, Dilani Senadheera at the Faculty of Dentistry, University of Toronto and co-researchers in Canada reveal significant differences in the “microbiome” present in dental, tongue and saliva samples over time. They found considerable variation in these communities between individuals, sufficient to identify a person with “bacterial fingerprints” using plaque or saliva even after 1 year. The researchers reveal a “core community” that spans different persons, oral sites, and time, suggesting some level of stability. This study is useful to understand the diversity and community drifts in different oral sites over time, which is important when plaque and saliva are used for bacterial analysis in diagnostic, risk-prediction, and forensic applications.

Angiosarcoma and its epithelioid variant are vascular malignancies that rarely affect the facial skeleton. Epithelioid angiosarcoma resembles carcinoma and can be difficult to diagnose. A case is presented of metastatic epithelioid angiosarcoma to the mandible from an angiosarcomatoid portion of renal carcinoma. The diagnostic challenge is outlined and the literature is reviewed.

Purpose The antimetabolite drug, 5-fluorouracil (5-FU), is used in the treatment of various cancers, including basal cell carcinomas (BCCs). The authors hypothesized that keratocystic odontogenic tumors (KOTs) would respond to 5-FU treatment because of their similarities to BCCs in molecular etiopathogenesis. Materials and Methods An ambispective cohort study of the treatment efficacy of topical 5-FU on KOTs was conducted. Independent variables included the topical application of 5% 5-FU or modified Carnoy's solution (MC) after enucleation and peripheral ostectomy at the University of Toronto from 2006 through 2014. Outcome variables included time to recurrence and peripheral nerve injury. KOT specimens in these patients were immunostained with p53, Ki-67, thymidylate synthetase (TS), thymidylate phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD) antibodies. Semiquantitative staining scores were calculated for all immunohistochemistry sections examined. Descriptive statistics were computed using Fisher exact test and Kaplan-Meier analysis as appropriate with the P value set at .05. Results Thirty-two patients with 32 KOTs were reviewed (41% in women and 59% in men). There were no KOT recurrences in the 5-FU group (n = 11), whereas there were 4 recurrences in the MC group (n = 21; P = .190). There was a significantly lower incidence of inferior alveolar nerve paresthesia with 5-FU treatment ( P = .039). Immunohistochemical staining showed upregulation of TP ( P P P > .05) in inflamed KOTs. Conclusions 5-FU effectively treats KOTs with less postoperative morbidity than conventional treatment with MC. Low TS and upregulated TP expressions in inflamed KOTs suggest increased 5-FU efficacy in inflamed KOTs. Topical 5-FU is a novel therapy for KOTs and provides a targeted molecular approach to treatment.

Posterior tongue defects present a unique reconstructive challenge. The various reconstructive options available for treating the defect created by a posterior hemiglossectomy frequently result in a distorted tongue and functional impairment. This paper describes a novel sliding anterior hemitongue flap to allow reconstruction of moderate resection defects (i.e. for T1-T2 tongue squamous cell carcinomas) of the posterior tongue. By mobilizing the anterior tongue, near normal mobility and tongue length are maintained. This surgical technique may be performed alone intraorally or in combination with a neck dissection.

Purpose: We present a strategy to survey proteolytic processes that occur in human cancer microenvironments. Experimental design: In situ microdialysis during oral cancer surgery was combined with mass spectrometry-based proteomics to analyze interstitial fluid surrounding tumors and anatomically matched normal sites. Protease activity-based 18O-profiling was utilized to reveal peptides that were processed by co-collected proteases ex vivo. Results: We demonstrated for the first time the use of microdialysis in humans to collect interstitial fluid from cancer microenvironments. Proteomic profiling identified proteases and inhibitors in the microdialysis samples. A subset of peptides displayed characteristic 18O-isotope patterns that indicated processing by endogenous proteases. Conclusions and clinical relevance: The presented approach provides unprecedented views of in vivo targets of proteases without disrupting the cancer or surrounding tissue. The methodology can be broadly adapted to other physiological conditions in which proteolytic mediators are involved (e.g. arthritic joints, inflamed muscle, other types of cancer) and where a comparison of normal and pathological tissue is sought.

Rodent pain models play an important role in understanding the mechanisms of nociception and have accelerated the search for new treatment approaches for pain. Creating an objective metric for orofacial nociception in these models presents significant technical obstacles. No animal assay accurately measures pain-induced orofacial dysfunction that is directly comparable to human orofacial dysfunction. We developed and validated a high throughput, objective, operant, nociceptive animal assay, and an instrument to perform the assay termed the dolognawmeter, for evaluation of conditions known to elicit orofacial pain in humans. Using the device our assay quantifies gnawing function in the mouse. We quantified a behavioral index of nociception and demonstrated blockade of nociception in three models of orofacial pain: (1) TMJ inflammation, (2) masticatory myositis, and (3) head and neck cancer. This assay will be useful in the study of nociceptive mediators involved in the development and progression of orofacial pain conditions and it will also provide a unique tool for development and assessment of new therapeutic approaches.

We examined the effect of the peripheral application of glutamate and capsaicin to the temporomandibular joint (TMJ) in influencing the activation and central sensitization of TMJ-responsive nociceptive neurons in the trigeminal subnucleus caudalis/upper cervical cord (Vc/UCC). The activity of single neurons activated by noxious mechanical stimulation of the TMJ was recorded in the Vc/UCC of 49 halothane-anesthetized male rats. Cutaneous mechanoreceptive field (RF), cutaneous mechanical activation threshold (MAT), and TMJ MAT of each neuron were assessed before and after injection of 0.5 M glutamate (or vehicle) and 1% capsaicin (or vehicle) into the TMJ. A total of 49 nociceptive neurons (37 nociceptive-specific, 12 wide-dynamic-range) that could be activated by blunt noxious mechanical stimulation of the TMJ were studied. When injected alone, glutamate and capsaicin activated and induced central sensitization (reflected in cutaneous RF expansion and cutaneous and/or TMJ MAT reduction) in most Vc/UCC neurons. Following glutamate injection, capsaicin evoked greater activity and less cutaneous/TMJ MAT reduction compared with capsaicin alone, whereas capsaicin abolished all subsequent glutamate-evoked activity and depressed cutaneous RF expansion in most neurons. Glutamate effects on deep afferents and Vc/UCC neurons were analogous since glutamate sensitized afferent and neuronal responses to capsaicin but the desensitizing effects of capsaicin on glutamate-evoked excitability of Vc/UCC neurons contrast with the lack of capsaicin-induced modulation of glutamate-evoked afferent excitability [Lam, D.K., Sessle, B.J., Hu, J.W., 2008a. Glutamate and capsaicin effects on trigeminal nociception I: activation and peripheral sensitization of deep craniofacial nociceptive afferents. Brain Res. doi:10.1016/j.brainres.2008.11.029], suggesting that peripheral and central sensitization may be differentially involved in the nociceptive effects of glutamate and capsaicin applied to deep craniofacial tissues.

Chemical process systems often need to respond to frequently changing product demands. This motivates the determination of optimal transitions, subject to specification and operational constraints. However, direct implementation of optimal input trajectories would, in general, result in offset in the presence of disturbances and plant/model mismatch. This paper considers reference trajectory optimization of processes controlled by constrained model predictive control (MPC). Consideration of the closed-loop dynamics of the MPC-controlled process in the reference trajectory optimization results in a multi-level optimization problem. A solution strategy is applied in which the MPC quadratic programming subproblems are replaced by their Karush-Kuhn-Tucker optimality conditions, resulting in a single-level mathematical program with complementarity constraints (MPCC). The performance of the method is illustrated through application to two case studies, the second of which considers economically optimal grade transitions in a polymerization process. Les systemes de procedes chimiques doivent souvent repondre a des changements de production frequents. Ceci motive la determination de transitions optimales, soumises a des contraintes de specification et de fonctionnement. Toutefois, l'implantation directe de trajectoires d'entree optimales entraine, en general, un decalage en presence de perturbations et d'une incompatibilite installation/modele. Cet article porte sur l'optimisation des trajectoires pour des procedes controles par le controle predictif par modele contraint (MPC). Le fait de considerer la dynamique en boucle fermee du procede controle par MPC dans l'optimisation des trajectoires de reference cause un probleme d'optimisation a plusieurs niveaux. Une strategie de solution est appliquee dans laquelle les sous-problemes de programmation quadratique du MPC sont remplaces par des conditions d'optimalite de Karush-Kuhn-Tucker. On obtient ainsi un programme mathematique a niveau unique associe a des contraintes de complementarite (MPCC). La performance de la methode est illustree par l'application de deux etudes de cas, le second considerant les transitions de grade optimales en termes economiques dans un procede de polymerisation.

Purpose This report describes a case of a 32-year-old woman who had been diagnosed with a facial arteriovenous malformation during childhood. Because this patient possessed a major risk of perioperative hemorrhage, the use of several local hemostatic measures was thoroughly explored before routine exodontia. Materials and Methods Selective embolization of the right superior thyroid artery was performed intraoperatively and a novel hemostatic technique using a combination of a packing of Gelfoam wrapped in Surgicel was placed within the extraction sites and sealed with SwiftSet. Results Local hemostasis was achieved with a novel technique using a combination of cyanoacrylate and local hemostatic agents despite aggressive hemorrhaging after routine exodontia. Conclusion By exploiting the local properties of these agents, local hemostasis can be achieved with this novel technique even in the most challenging cases of vascular anomalies.

Background The effectiveness of management strategies used for the treatment of medication-related osteonecrosis of the jaw (MRONJ) remains poorly understood. The authors evaluated systematically the effectiveness of the various treatment modalities used for MRONJ. Types of Studies Reviewed The authors conducted a comprehensive search of MEDLINE, Embase, the Cochrane Library, and Scopus to identify randomized controlled trials, nonrandomized controlled trials, and prospective cohort studies to evaluate comparatively the effectiveness of management strategies for the treatment of MRONJ. The authors conducted the identification of eligible studies in duplicate and synthesized the extracted data by means of a meta-analysis, when feasible. Results The authors found 13 studies with a medium-to-high risk of bias that met the inclusion criteria of this review. The authors found that, compared with medical treatment of local antimicrobials with or without systemic antimicrobials, the study investigators associated surgical treatment with higher odds of complete resolution of the condition (2 studies; 76 participants; unadjusted odds ratio, 3.55; 95% confidence interval, 1.12 to 11.19). The effectiveness of other therapies, such as bisphosphonate drug holidays, teriparatide, and hyperbaric oxygen, was uncertain. Conclusions and Practical Implications On the basis of the results of an unadjusted analysis, the results of the studies that were deemed to be medium to low quality and to have medium-to-low statistical power suggested that there are higher odds of resolving MRONJ with surgical treatment compared with medical treatment. High-quality research is required for conclusive statements to be made regarding treatment strategies for management of MRONJ.

Surgical access to tumors involving the posterolateral maxilla and infratemporal region remains a considerable challenge for surgeons. Various surgical approaches for treating posterior maxillary lesions require transcutaneous incisions, such as an upper or lower cheek flap, but they often result in substantial morbidity. This article describes a novel transoral approach involving a curvilinear incision, temporalis myotomy, and coronoidectomy to allow direct visualization of the posterolateral maxilla and infratemporal region. This surgical technique may be used for the surgical resection of maxillary tumors that extend into the posterior maxillary sinus wall and pterygoid plate region via a transoral approach.

Image contrast of line-cut and contact hole features patterned using Complementary E-Beam Lithography (CEBL) at advanced technology nodes are analyzed. The study assumes one beam in each column is used to pattern features less than 20 nm (Full Width Half Maximum, FWHM), consistent with Multibeam’s multi-column vector-scan approach for CEBL patterning. When the feature size approaches the resolution of the e-beam column design, the dose intensity profile follows a Gaussian model. Using Gaussian profiles, the image contrast of line cut or contact hole features can be studied as a function of beam FWHM size, spacing between features, and proximity effect. As expected, the image contrast was dominated by contact hole stepping distance (i.e., spacing between neighboring contact holes) and proximity effect. The plot of image contrast versus contact position becomes very useful in studying the impact of contact spacing, proximity effect and process window in writing line-cut or contact features in CEBL applications. Based on a given design rule of contact hole size and spacing, we can determine the appropriate e-beam size and resist contrast to achieve good image contrast. The relationship between resist contrast and image contrast is discussed to estimate the process window in CEBL applications. Finally, the impact of electron forward scattering in resist is analyzed, including the effects of resist thickness and beam voltage selections. We determined that the influence of back scattered electrons is not a significant factor in CEBL applications when feature pattern density is less than 11%.

Targeted therapy to prevent the progression from acute to chronic pain in cancer patients remains elusive. We developed three novel cancer models in mice that together recapitulate the anatomical, temporal, and functional characteristics of acute and chronic head and neck cancer pain in humans. Using pharmacologic and genetic approaches in these novel cancer models, we identified the interaction between protease-activated receptor 2 (PAR2) and serine proteases to be of central importance. We show that serine proteases such as trypsin induce acute cancer pain in a PAR2-dependent manner. Chronic cancer pain is associated with elevated serine proteases in the cancer microenvironment and PAR2 upregulation in peripheral nerves. Serine protease inhibition greatly reduces the severity of persistent cancer pain in wild-type mice, but most strikingly, the development of chronic cancer pain is prevented in PAR2-deficient mice. Our results demonstrate a direct role for PAR2 in acute cancer pain and suggest that PAR2 upregulation may favor the development and maintenance of chronic cancer pain. Targeting the PAR2–serine protease interaction is a promising approach to the treatment of acute cancer pain and prevention of chronic cancer pain.

Single-column e-beam systems are used in production for the detection of electrical defects, but are too slow to be used for the detection of small physical defects, and can't meet future inspection requirements. This paper presents a multiplecolumn e-beam technology for high throughput wafer inspection. Multibeam has developed all-electrostatic columns for high-resolution imaging. The elimination of magnetic coils enables the columns to be small; e-beam deflection is faster in the absence of magnetic hysteresis. Multiple miniaturecolumns are assembled in an array. An array of 100 columns covers the entire surface of a 300mm wafer, affording simultaneous cross-wafer sampling. Column performance simulations and system architecture are presented. Also provided are examples of high throughput, more efficient, multiple-column wafer inspection.

Developers of e-beam lithography systems are pursuing diverse strategies to bolster throughput. To achieve parallelism, some e-beam efforts focus on building multiple-columns, and others focus on developing columns with multiple beamlets. In this paper, we discuss the benefits and throughput of a multiple column approach for a particular application: Complementary E-Beam Lithography (CEBL). CEBL is a novel approach where the e-beam lithography system is used only to pattern the smallest features. Everything else is patterned with existing optical lithography equipment. By working hand-in-hand with optical lithography, CEBL provides an urgently needed solution to create next-generation microchips. Moreover, CEBL is extendable for multiple technology generations. We show how a multiple column approach is the best way to meet the requirements for CEBL, including high throughput, high resolution and overlay accuracy, without excess complexity or cost.

We present an analysis of the performance of an all electro-static electron-beam column designed for CEBL (Complementary Electron Beam Lithography). To meet the requirements of CEBL at advanced technology nodes (16 nm half-pitch and beyond), a beam size of < 20 nm FWHM (Full Width Half Maximum) and overlay accuracy of < 4 nm are needed. Beam current and beam energy must be optimized to achieve these specifications while meeting throughput requirements. In this paper, we present an in-depth analysis of the resolution of Multibeam's electron beam column as a function of beam energy. We focus on an analysis of beam energy below 30 keV, to avoid wafer heating and improve overlay accuracy. The beam size is analyzed with respect to aperture size and current. Spherical aberrations, chromatic aberrations and other effects at various beam energy levels are analyzed. At 7.5 or 5 keV beam energy, the 2 dominating factors in the beam spot size are the image size of the virtual source of the TFE (thermal field emitter) electron gun, chromatic and spherical aberrations. Performance of the column and process window to meet patterning requirements will be discussed.

Endothelin-1 is a vasoactive peptide that activates both the endothelin A (ET(A)) and endothelin B (ET(B)) receptors, and is secreted in high concentrations in many different cancer environments. Although ET(A) receptor activation has an established nociceptive effect in cancer models, the role of ET(B) receptors on cancer pain is controversial. EDNRB, the gene encoding the ET(B) receptor, has been shown to be hypermethylated and transcriptionally silenced in many different cancers. In this study we demonstrate that EDNRB is heavily methylated in human oral squamous cell carcinoma lesions, which are painful, but not methylated in human oral dysplasia lesions, which are typically not painful. ET(B) mRNA expression is reduced in the human oral squamous cell carcinoma lesions as a consequence of EDNRB hypermethylation. Using a mouse cancer pain model, we show that ET(B) receptor re-expression attenuates cancer-induced pain. These findings identify EDNRB methylation as a novel regulatory mechanism in cancer-induced pain and suggest that demethylation therapy targeted at the cancer microenvironment has the potential to thwart pain-producing mechanisms at the source, thus freeing patients of systemic analgesic toxicity.

The semiconductor industry is moving to highly regular designs, or 1D gridded layouts, to enable scaling to advanced nodes, as well as improve process latitude, chip size and chip energy consumption. The fabrication of highly regular ICs is straightforward. Poly and metal layers are arranged into 1D layouts. These 1D layouts facilitate a two-step patterning approach: a line-creation step, followed by a line-cutting step, to form the desired IC pattern (See Figure 1). The first step, line creation, can be accomplished with a variety of lithography techniques including 193nm immersion (193i) and Self-Aligned Double Patterning (SADP). It appears feasible to create unidirectional parallel lines to at least 11 nm half-pitch, with two applications of SADP for pitch division by four. Potentially, this step can also be accomplished with interference lithography or directed self assembly in the future. The second step, line cutting, requires an extremely high-resolution lithography technique. At advanced nodes, the only options appear to be the costly quadruple patterning with 193i, or EUV or E-Beam Lithography (EBL). This paper focuses on the requirements for a lithography system for "line cutting", using EBL to complement Optical. EBL is the most cost-effective option for line cutting at advanced nodes for HVM.

193nm Optical lithography has powered the industry's growth for the last 10 years and multiple patterning is poised to extend 193nm even further. There is a growing trend in Logic design for manufacturing, with high-volume manufacturing (HVM) firms adopting a layout style using unidirectional single-pitch straight lines in poly and metal layers. These layouts lend themselves to a complementary lithography approach. First, unidirectional lines are patterned with Optical lithography. Second, these lines are "cut" to form the desired layout. In this paper, we present EBDW as a complement to optical lithography for line-cutting. We show how e-beam multiple-column architecture, optimized for line-cutting, is the best for patterning critical layers at advanced nodes as Complementary Lithography.

We investigated the effects of cannabinoid receptor agonists on (1) oral cancer cell viability in vitro and (2) oral cancer pain and tumor growth in a mouse cancer model. We utilized immunohistochemistry and Western blot to show that human oral cancer cells express CBr1 and CBr2. When treated with WIN55,212-2 (non-selective), ACEA (CBr1-selective) or AM1241 (CBr2-selective) agonists in vitro, oral cancer cell proliferation was significantly attenuated in a dose-dependent manner. In vivo, systemic administration (0.013M) of WIN55,212-2, ACEA, or AM1241 significantly attenuated cancer-induced mechanical allodynia. Tumor growth was also significantly attenuated with systemic AM1241 administration. Our findings suggest a direct role for cannabinoid mechanisms in oral cancer pain and proliferation. The systemic administration of cannabinoid receptor agonists may have important therapeutic implications wherein cannabinoid receptor agonists may reduce morbidity and mortality of oral cancer.