A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade.

Immune checkpoint inhibitors (ICIs) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusive. Here, we leveraged single-cell RNA sequencing (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states that promote immune evasion. We identified a resistance program expressed by malignant cells that is associated with T cell exclusion and immune evasion. The program is expressed prior to immunotherapy, characterizes cold niches in situ, and predicts clinical responses to anti-PD-1 therapy in an independent cohort of 112 melanoma patients. CDK4/6-inhibition represses this program in individual malignant cells, induces senescence, and reduces melanoma tumor outgrowth in mouse models in vivo when given in combination with immunotherapy. Our study provides a high-resolution landscape of ICI-resistant cell states, identifies clinically predictive signatures, and suggests new therapeutic strategies to overcome immunotherapy resistance.

Prognosis of oral epithelial dysplasia in individuals with and without oral lichen planus.

OBJECTIVES: To investigate the role of oral lichen planus (OLP) on the long-term prognosis of oral epithelial dysplasia (OED). METHODS: Retrospective single-centre cohort study using the 2007-2019 database of the Head and Neck Cancer and Oral Medicine units of University College London Hospital. The exposure of interest was the presence of OLP, and the prognostic outcomes included the development of new primary episodes of OED, progression to malignancy and mortality. Cox proportional hazard and Poisson regression models were performed. RESULTS: A total of 299 patients, of whom 144 had OED arising on the background of OLP (OLP/OED) and 155 had OED without underlying OLP (non-OLP/OED), were included. A pre-existing diagnosis of OLP was significantly associated with a twofold increased risk of subsequent primary OED events (HR = 2.02, p = 0.04), which also developed faster (1.46 vs. 2.96 years, p = 0.04) and with more involvement of non-cancer-prone sites (p = 0.001) than in the non-OLP/OED group. There was no difference between groups in the progression to malignancy or mortality. CONCLUSIONS: Oral lichen planus/OED patients are at higher risk of multiple episodes of primary OED, which can develop faster and at non-cancer-prone sites as compared to non-OLP/OED individuals. Further research is needed to clarify the effects of OLP upon progression to OSCC and mortality.

The development and cognitive testing of a patient-reported experience measure for patients with chronic pain of temporomandibular disorders.

INTRODUCTION: The importance of the patients' clinical experience has been reinforced several times over the last decade by healthcare organisations and policy makers. Routine gathering of experience data can help in enhancing patient-centred care and provide guidance to quality improvement schemes. Patient-reported experience measures can help to that end. The aim of this study was to develop a patient-reported experience measure to evaluate the experience of patients with temporomandibular disorders while receiving healthcare. METHODS: Input from several sources was utilised to develop the tool; previous literature, patients with temporomandibular disorders, and experts in the field. A qualitative study was conducted following the COnsensus-based Standards for the selection of health Measurement Instruments guidance to generate the items of the questionnaire, which subsequently underwent cognitive testing. RESULTS: Seventeen patients took part in the qualitative study, in addition to six healthcare professionals. The preliminary questionnaire consisted of 28 questions with six response options. CONCLUSIONS: This patient-reported experience measure is a brief tool to evaluate the clinical experience of patients with temporomandibular disorders. Patients' involvement ensured face and content validity of the questionnaire, in addition to the relevance, comprehensibility and comprehensiveness of the items.

Healthcare priorities in patients with chronic facial pain of temporomandibular disorders.

OBJECTIVES: To explore the experiences of patients with temporomandibular disorders (TMDs) with the National Health Service and to discover their healthcare priorities when seeking treatment. METHODS: Semi-structured interviews were used. They were directed using a topic guide covering subjects such as initial visits in primary care, referrals to secondary care, and the effect on symptoms. The discussions were audiotaped and transcribed verbatim. Thematic analysis was utilised to analyse the data. RESULTS: In total, 15 participants took part in three focus groups. Six themes were identified: "access to appropriate care", "organised and coordinated care", "receiving a diagnosis and enough information", "interaction with the clinical staff", "treatment strategies and having an 'action plan'" and "support and social networks". CONCLUSIONS: The participants gave accounts of the difficulties encountered in healthcare in general terms and specific to TMD. Most notable was the struggle to access appropriate care, receive a diagnosis and be understood. Our findings suggest that delays in delivering appointments with people of expertise may have caused the worsening of symptoms. However, when a pleasant experience was encountered, access to care was fast, the clinician was understanding and communication with the clinical team was good. These provided positive experiences and were appreciated by the patients.

Validity and internal consistency of four scales in patients with TMD: PHQ8, GAD7, PHQ15 and JFLS20.

OBJECTIVES: The aim of this cross-sectional study was to explore the structural validity and internal consistency reliability of General Anxiety Disorder-7, Patient Health Questionnaire-8, 15 and Jaw Functional Limitation Scale-20 in patients with chronic pain of temporomandibular disorders. MATERIALS AND METHODS: Validity and reliability were assessed in 129 patients diagnosed according to the diagnostic criteria for temporomandibular disorders. Structural validity was explored using factor analysis, and internal consistency by calculating Cronbach α. RESULTS: Confirmatory factor analysis revealed a suitable 2-factor model for Patient Health Questionnaire-8, with Cronbach α of 0.89, and 0.86. One and 2-factor models were suitable for General Anxiety Disorder-7, with overall Cronbach α of 0.93 for the 1-factor model, and 0.91 and 0.84 for both factors in a 2-factor model. A 4-factor solution was appropriate for Patient Health Questionnaire-15, with Cronbach α of 0.72, 0.57, 0.71 and 0.73 for each factor separately. Exploratory factor analysis was conducted to explore the factor structure of Jaw Functional Limitation Scale 20, and a 3-factor solution was appropriate. CONCLUSIONS: This study provides positive evidence of structural validity and internal consistency of these questionnaires in patients with pain of temporomandibular disorders. However, additional testing is required to explore further psychometric properties.

A proof of concept pilot trial of probiotics in symptomatic oral lichen planus (CABRIO).

OBJECTIVE: To preliminary evaluate the clinical effects of probiotics in individuals with symptomatic oral lichen planus and the possible mechanisms of action. SUBJECTS AND METHODS: A group of 30 individuals with symptomatic oral lichen planus were recruited in a randomised double-blind parallel group controlled (1:1) proof-of-concept pilot trial of probiotic VSL#3 vs placebo. Efficacy outcomes included changes in pain numeric rating scale, oral disease severity score and the chronic oral mucosal disease questionnaire. Adverse effects, home diary and withdrawals were assessed as feasibility outcomes. Mechanistic outcomes included changes in salivary and serum levels of CXCL10 and IFN-γ and in oral microbial composition. RESULTS: The probiotic VSL#3 was safe and well tolerated. We observed no statistically significant change in pain, disease activity, quality of life, serum/salivary CXCL10 or oral microbial composition with respect to placebo. Salivary IFN-γ levels demonstrate a trend for a reduced level in the active group (p = 0.082) after 30 days of probiotic consumption. CONCLUSIONS: The present proof-of-concept study provides some weak not convincing indication of biological and clinical effects of probiotic VSL#3 in individuals with painful oral lichen planus. Further research in this field is needed, with the current study providing useful information to the design of future clinical trials.

Candida species in patients with oral dysesthesia: A comparison of carriage among oral disease states.

OBJECTIVES: Oral dysesthesia (burning mouth syndrome) is characterized by a burning-like sensation of the oral mucosa. The etiology of this disorder is still unknown, however, associations with oral fungal carriage have been proposed and applied clinically. The aim of the this study was to compare oral Candida carriage in patients with oral dysesthesia with Candida carriage in patients with other commonly diagnosed oral diseases to clarify the relationship between Candida and oral dysesthesia. SUBJECTS AND METHODS: In total, 441 patients in total including 79 patients diagnosed with oral dysesthesia were included in this study. A retrospective analysis of mycological investigations undertaken in patients with clinically diagnosed oral dysesthesia compared with other oral conditions was undertaken. RESULTS: Oral carriage of Candida was found in 63.3% (50 of 79) of patients with oral dysesthesia. The frequency of carriage and oral load of Candida were not significantly increased in patients with oral dysesthesia relative to the other conditions assessed. Patients with clinical signs of fungal infection or xerostomia presented with increased carriage of Candida. CONCLUSION: There is no association between oral dysesthesia and the presence or load of oral Candida.

Comparative genomics and transcriptomics of Pichia pastoris.

BACKGROUND: Pichia pastoris has emerged as an important alternative host for producing recombinant biopharmaceuticals, owing to its high cultivation density, low host cell protein burden, and the development of strains with humanized glycosylation. Despite its demonstrated utility, relatively little strain engineering has been performed to improve Pichia, due in part to the limited number and inconsistent frameworks of reported genomes and transcriptomes. Furthermore, the co-mingling of genomic, transcriptomic and fermentation data collected about Komagataella pastoris and Komagataella phaffii, the two strains co-branded as Pichia, has generated confusion about host performance for these genetically distinct species. Generation of comparative high-quality genomes and transcriptomes will enable meaningful comparisons between the organisms, and potentially inform distinct biotechnological utilies for each species. RESULTS: Here, we present a comprehensive and standardized comparative analysis of the genomic features of the three most commonly used strains comprising the tradename Pichia: K. pastoris wild-type, K. phaffii wild-type, and K. phaffii GS115. We used a combination of long-read (PacBio) and short-read (Illumina) sequencing technologies to achieve over 1000X coverage of each genome. Construction of individual genomes was then performed using as few as seven individual contigs to create gap-free assemblies. We found substantial syntenic rearrangements between the species and characterized a linear plasmid present in K. phaffii. Comparative analyses between K. phaffii genomes enabled the characterization of the mutational landscape of the GS115 strain. We identified and examined 35 non-synonomous coding mutations present in GS115, many of which are likely to impact strain performance. Additionally, we investigated transcriptomic profiles of gene expression for both species during cultivation on various carbon sources. We observed that the most highly transcribed genes in both organisms were consistently highly expressed in all three carbon sources examined. We also observed selective expression of certain genes in each carbon source, including many sequences not previously reported as promoters for expression of heterologous proteins in yeasts. CONCLUSIONS: Our studies establish a foundation for understanding critical relationships between genome structure, cultivation conditions and gene expression. The resources we report here will inform and facilitate rational, organism-wide strain engineering for improved utility as a host for protein production.

Automated pipeline for rapid production and screening of HIV-specific monoclonal antibodies using pichia pastoris.

Monoclonal antibodies (mAbs) that bind and neutralize human pathogens have great therapeutic potential. Advances in automated screening and liquid handling have resulted in the ability to discover antigen-specific antibodies either directly from human blood or from various combinatorial libraries (phage, bacteria, or yeast). There remain, however, bottlenecks in the cloning, expression and evaluation of such lead antibodies identified in primary screens that hinder high-throughput screening. As such, "hit-to-lead identification" remains both expensive and time-consuming. By combining the advantages of overlap extension PCR (OE-PCR) and a genetically stable yet easily manipulatable microbial expression host Pichia pastoris, we have developed an automated pipeline for the rapid production and screening of full-length antigen-specific mAbs. Here, we demonstrate the speed, feasibility and cost-effectiveness of our approach by generating several broadly neutralizing antibodies against human immunodeficiency virus (HIV).

Efficacy and safety of low dose subcutaneous diclofenac in the management of acute pain: a randomized double-blind trial.

OBJECTIVE: Diclofenac is an effective and well-tolerated nonsteroidal anti-inflammatory drug (NSAID) frequently used in the treatment of acute pain. Marketed formulations for parenteral administration usually contain 75 mg/3 mL of diclofenac sodium, which provide limited dosing flexibility, and are usually given intramuscularly. METHODS: We present a randomized, double-blind, active comparator- and placebo-controlled, parallel-group phase III multicenter study, investigating efficacy and tolerability of a new 1 mL-volume formulation of diclofenac sodium (25, 50 or 75 mg) containing hydroxypropyl-ß-cyclodextrin (HPßCD) as a solubility enhancer. This low-volume formulation allows subcutaneous (SC), in addition to intramuscular (IM) administration. Patients developing moderate-to-severe pain (≥ 50 mm on Visual Analogue Scale) after third molar extraction under local anesthesia were randomized to one of the 4 SC injections: 25 mg diclofenac HPßCD (n = 77), 50 mg diclofenac HPßCD (n = 76), 75 mg diclofenac HPßCD (n = 78), or placebo (n = 75). RESULTS: Mean pain intensity difference at 1.5 hours postdose (primary endpoint) was higher in all diclofenac-treated groups than placebo group. The adjusted means (95% CI) were 36.5 (31.7 to 41.2) in diclofenac 25 mg group, 37.3 (32.6 to 42.1) in diclofenac 50 mg group, 37.7 (33.0 to 42.4) in diclofenac 75 mg group, and 12.3 (7.44 to 17.1) in placebo group. Both 25 and 50 mg doses of diclofenac produced significantly greater pain relief than placebo (P < 0.001 in both comparisons). CONCLUSION: Single SC doses of diclofenac HPßCD of 25 and 50 mg are effective and well tolerated for relieving pain compared with placebo.

Patient-Reported Outcome Measures Used in Temporomandibular Disorders: A Review of the Literature.

AIMS: To identify the range of patient-reported outcome measures (PROMs) used in TMD studies, summarize the available evidence for their psychometric properties, and provide guidance for the selection of such measures. METHODS: A comprehensive search was conducted to retrieve articles published between 2009 and 2018 containing a patient-reported measure of the effects of TMDs. Three databases were searched: MEDLINE, Embase, and Web of Science. RESULTS: A total of 517 articles containing at least one PROM were included in the review, and 57 additional studies were also located describing the psychometric properties of some tools in a TMD population. A total of 106 PROMs were identified and fell into the following categories: PROMs describing the severity of symptoms; PROMs describing psychologic status; and PROMs describing quality of life and general health. The most commonly used PROM was the visual analog scale. However, a wide range of verbal descriptors was employed. The Oral Health Impact Profile-14 and Beck Depression Inventory were the most commonly used PROMs describing the effect of TMDs on quality of life and psychologic status, respectively. Additionally, the Oral Health Impact Profile (various versions) and the Research Diagnostic Criteria Axis ll questionnaires were the instruments most repeatedly tested in a TMD population, and these instruments have undergone cross-cultural validation in several languages. CONCLUSION: A wide range of PROMs have been used to describe the impact of TMDs on patients. Such variability may limit the ability of researchers and clinicians to evaluate the efficacy of different treatments and make meaningful comparisons.

A Meta-Synthesis of the Experience of Chronic Temporomandibular Disorder Patients Within Health Care Services

Aims: To systematically review the qualitative evidence related to experiences of patients with temporomandibular disorders (TMD) and to explore their journeys within health care services. Methods: A systematic search of the following databases was conducted: MEDLINE, Embase, PsycINFO, Web of Science, CINAHL Complete, and the Cochrane database. Thematic synthesis was used to analyze and synthesize the data from qualitative studies that explored the journeys of TMD patients within health care services. The Critical Appraisal Skills Programme (CASP) tool was used to critically appraise the quality of the included studies. Results: The search strategies yielded 4,563 articles across all databases, and 18 articles were eventually included. Six themes were derived: care-seeking attitudes; expectations and health care experience; the patient-clinician interaction; diagnosis as a stepping stone for improvement; management; and social support. Conclusion: The journey within health care services may play a valuable role in the ability to cope with chronic TMDs. Receiving a diagnosis, being listened to, and being believed are among the most important elements making for a positive clinical experience.

The Expanding Dissemination and Distribution Patterns of Diverse CRISPR Plasmids by Addgene.

CRISPR-based technologies have rapidly enabled the democratization of genome editing in academic institutions through distribution by Addgene over the past decade. Recently, several distribution milestones have been reached, with a collection of >15,000 plasmids deposited by >1,000 laboratories spanning ∼40 countries now shipped 300,000 times to ∼5,000 organizations traversing ∼100 countries. Yet, both deposits of and requests for CRISPR plasmids continue to rise for this disruptive technology. Distribution patterns revealed robust demand for three distinct classes of CRISPR effectors, namely nucleases (e.g., Cas9 and Cas12), modulators (deactivated CRISPR nucleases fused to transcriptional regulators and epigenome modifiers), and chimeric effectors (Cas proteins fused to enzymes carrying out other activities such as deamination, reverse transcription, transposition, and integration). Yearly deposits over the past decade are requested in near-even proportions, reflecting continuous technological development and requests for novel constructs. Though it is unclear whether the slowing rate of requests is inherent to a pandemic operational lag or a transition from emerging to mature technology, it is noteworthy that the relative proportion of requests from plasmids deposited in the previous year remains stable, suggesting robust development of novel tools concurrent with continued adoption of editing, base editing, prime editing, and more. Predictably, most requested plasmids are designed for mammalian genome manipulation, presumably for medical research and human health pursuits, reflecting investments in therapeutic applications. Concurrently, requests for plant and microbial constructs are on the rise, especially in regions of the world more reliant on local agricultural inputs and focused on food and feed applications, illustrating continued diversification of genome editing applications.

A single-cell landscape of high-grade serous ovarian cancer.

Malignant abdominal fluid (ascites) frequently develops in women with advanced high-grade serous ovarian cancer (HGSOC) and is associated with drug resistance and a poor prognosis1. To comprehensively characterize the HGSOC ascites ecosystem, we used single-cell RNA sequencing to profile ~11,000 cells from 22 ascites specimens from 11 patients with HGSOC. We found significant inter-patient variability in the composition and functional programs of ascites cells, including immunomodulatory fibroblast sub-populations and dichotomous macrophage populations. We found that the previously described immunoreactive and mesenchymal subtypes of HGSOC, which have prognostic implications, reflect the abundance of immune infiltrates and fibroblasts rather than distinct subsets of malignant cells2. Malignant cell variability was partly explained by heterogeneous copy number alteration patterns or expression of a stemness program. Malignant cells shared expression of inflammatory programs that were largely recapitulated in single-cell RNA sequencing of ~35,000 cells from additionally collected samples, including three ascites, two primary HGSOC tumors and three patient ascites-derived xenograft models. Inhibition of the JAK/STAT pathway, which was expressed in both malignant cells and cancer-associated fibroblasts, had potent anti-tumor activity in primary short-term cultures and patient-derived xenograft models. Our work contributes to resolving the HSGOC landscape3-5 and provides a resource for the development of novel therapeutic approaches.

Physical properties and biocompatibility effects of doping SiO2 and TiO2 into phosphate-based glass for bone tissue engineering.

Phosphate glass is continuing to gain more attention as potential bone substitutes. The ternary (P2O5-CaO-Na2O) is investigated in terms of both physical properties and biocompatibility by doping different percentages of SiO2 and TiO2. Two groups were prepared; the first has different percentages of TiO2 and SiO2, whereas the second group compositions have 5 mol% TiO2 and 5 mol% SiO2 being added to compensate the network-forming oxide P2O5 and the network-modifying oxide CaO. Density, mass loss, pH, DTA, XRD, and cation release experiments were performed to study the physicochemical properties of the compositions, while MG63 and hMS cells were used within in vitro cell culture to study their biocompatibility. Results showed that an increase in TiO2 content correlated with an increase in glass density, decreased mass loss, increased trend of Tg and Tm values, and Na+ and Ca2+ release in group 1. There was no improvement in the MG63 viability or the ability of hMSCs to differentiate into osteoblasts where TiO2 decreased in favour of SiO2. Furthermore, in group 2, 50P2O5-25CaO was less dense than 45P2O5-30CaO, degraded dramatically less, had lower Tg and Tm values and released less Na+ and Ca(2+). The synergistic effect of doping 5 mol% TiO2 and 5 mol% SiO2 increased the MG63 viability in both compositions and was found 45P2O5-30CaO to have promising results in terms of the ability of hMSCs to differentiate into osteoblasts. To conclude, substituting TiO2 in place of SiO2 improved the physical properties and the biocompatibility of (P2O5-CaO-Na2O) glass system, whereas doping 5 mol% SiO2 and 5 mol% TiO2 together in place of P2O5 and CaO had a synergistic effect in controlling their degradation rate and improving their biological responses.

Dyloject, a novel injectable diclofenac formulation, offers greater safety and efficacy than voltarol for postoperative dental pain.

BACKGROUND AND OBJECTIVES: Voltarol for injection (a diclofenac sodium formulation employing polyethylene glycol and benzyl alcohol [PG-BA] as excipients) is marketed in Europe but not in North America. A suspension, PG-BA diclofenac sodium, requires preparation for each patient and slow IV infusion to minimize venous irritation. Dyloject, a novel diclofenac formulation, employs hydroxypropyl beta-cyclodextrin (HPbetaCD) to solubilize diclofenac in a small volume. We compared the efficacy and safety of an IV HPbetaCD diclofenac sodium bolus, a 30-minute PG-BA diclofenac sodium infusion, and placebo in post-molar extraction pain. METHODS: A total of 155 adult patients were randomized to receive HPbetaCD diclofenac sodium 75 mg, PG-BA diclofenac sodium 75 mg, or placebo. Primary endpoints were superiority of HPbetaCD diclofenac sodium to placebo and noninferiority of HPbetaCD diclofenac sodium to PG-BA diclofenac sodium with respect to total pain relief over 4 hours (TOTPAR4) on a 0 to 100-mm visual analog scale (VAS). Secondary endpoints included categorical TOTPAR4, VAS and categorical TOTPAR up to 8 hours, other measures of pain intensity and relief, patient global evaluation, and time to rescue medication. RESULTS: HPbetaCD diclofenac sodium had efficacy superior to both placebo and PG-BA diclofenac sodium. At 15 minutes, more patients given HPbetaCD diclofenac sodium than PG-BA diclofenac sodium reported 30% reduction in pain intensity (52% vs. 21%, P = .0022). Both diclofenac products had a 6-hour duration of effect and were well tolerated. Patient global evaluations of HPbetaCD diclofenac sodium were high, superior to placebo, and similar to PG-BA diclofenac sodium. The adverse event (AE) incidence was similar for HPbetaCD diclofenac sodium and PG-BA diclofenac sodium, except that in the current trial and in integrated safety results from the present and prior studies, phlebitis was more common with PG-BA diclofenac sodium. No cardiac or renal AEs or gastrointestinal bleeding were reported or observed. CONCLUSIONS: IV bolus HPbetaCD diclofenac sodium produced analgesia more quickly than, and with equal duration as, the 30-minute PG-BA diclofenac sodium infusion. Pooled data on thrombophlebitis from the present investigation and our prior studies of the novel formulation indicate this adverse effect is less frequent and less severe with HPbetaCD diclofenac sodium than with PG-BA diclofenac sodium.

Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors.

Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing.

A randomized, controlled study to investigate the analgesic efficacy of single doses of the cannabinoid receptor-2 agonist GW842166, ibuprofen or placebo in patients with acute pain following third molar tooth extraction.

OBJECTIVES: To evaluate the postoperative analgesic efficacy of GW842166, a noncannabinoid CB2 agonist, in patients undergoing third molar tooth extraction. METHODS: This randomized, double-blind, placebo-controlled study compared the analgesic efficacy of single doses of GW842166 (100 or 800 mg) or ibuprofen with placebo in patients undergoing extraction of at least 1 fully or partially impacted third molar tooth. Eligible participants were dosed preoperatively within 1 hour of surgery. Participants allocated to active comparator received a second dose of ibuprofen (400 mg), 4 hours after the first 800 mg dose. Participants in the GW842166 and placebo groups received placebo at 4 hours. Procedures for the assessment of efficacy included a visual analog scale and verbal rating scale for scoring pain up to 10 hours postsurgery, duration of analgesia, patient global evaluation, proportion of patients requiring rescue medication, and elapsed time to rescue analgesia. Analysis of covariance was used to compare efficacy variables. Patient global evaluation was analyzed using Wilcoxon rank-sum tests and time to data was analyzed using the log-rank test. RESULTS: Ibuprofen was significantly more effective than placebo across all endpoints. Trends for an improvement in pain scores for GW842166 800 mg failed to be of either clinical or statistical significance. GW842166 100 mg showed little separation from placebo. There was no evidence for any beneficial adjunctive effect after coadministration of rescue analgesia with GW842166. All treatments were well tolerated. DISCUSSION: In comparison to ibuprofen, single doses of GW842166 (100 and 800 mg) failed to demonstrate clinically meaningful analgesia in the setting of acute dental pain.