search
Back to results

Peripheral TMD Pain Mechanisms and the Effect by Botulinum Toxin A

Primary Purpose

Temporomandibular Disorders

Status
Recruiting
Phase
Phase 2
Locations
Sweden
Study Type
Interventional
Intervention
Botulinum toxin type A
Isotonic saline 0,9%
Sponsored by
Karolinska Institutet
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Temporomandibular Disorders focused on measuring Temporomandibular Disorders, Botulinum Toxin A, Myalgia, Randomized, Clinical Trial, Pain, Gene, Neural Plasticity

Eligibility Criteria

20 Years - 45 Years (Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria: a diagnosis of TMDM myalgia or myofascial pain according to the DC/TMD criteria females with adequate contraceptives and a negative pregnancy test pain upon digital palpation of at least one of the masseter muscle a characteristic pain intensity of > 40/100. Exclusion Criteria: difficulties understanding the Swedish language systemic inflammatory connective tissue diseases widespread pain neuromuscular disorders diagnosed or severe psychiatric disease neuropathic pain pain of dental origin history of trauma to the face, head or neck pregnancy or nursing known allergy to botulinum toxin or antibiotics use of muscle relaxants, antidepressant, neuropsychiatric, anticoagulant drugs, or aminoglycoside antibiotics previous treatment with botulinum toxin during the last 12 months use of analgesic or anti-inflammatory medication during the 48 hours preceding biopsy skin infection over injection/biopsy site

Sites / Locations

  • Department of Dental Medicine, Karolinska InstitutetRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Botulinum toxin

Isotonic saline

Arm Description

Single bilateral injection into three standardized points of the masseter muscles and two of the anterior temporalis muscle. The total dose administered is 100 U (10 U/point) which is dissolved in 1 mL of isotonic saline. Thus, 0.1 ml of botulinum toxin solution is injected in each point.

Single injection of 1 mL isotonic saline (0.9 mg/mL) into the same five points per side in a similar manner as for botulinum toxin.

Outcomes

Primary Outcome Measures

Change of gene expression measured with bulk RNA-seq
Gene expression in the anterior tibialis muscle (internal control) will be subtracted from the masseter and the patients will then be clustered according to DEGs and compared to baseline.
Change of epigenetic signature measured with ATAC
The epigenetic signature in the anterior tibialis muscle (internal control) will be subtracted from the masseter and the patients will then be clustered according to DEGs and compared to baseline.
Change of expression of sensory neuron markers measured with IHC
The expression will be measured as the change of frequency (%) of selected sensory neuron markers.

Secondary Outcome Measures

Change of pain intensity compared to baseline using 0-10 numeric rating scales (NRS)
Assessed with the Brief Pain Inventory and includes assessment of the current and the worst, average, and least pain intensity during the last week, each scored on 0-10 numeric rating scale. The worst, average, and current pain can be used to calculate the Characteristic Pain Intensity (0-100) which is the mean score of the three assessments multiplied with ten.
Global improvement using Patient Global Impression of Change Scale (PGIC)
Assessed with the 7-point PGIC with the alternatives: 0 = eliminated, 1 = much improved, 2 = improved, 3 = unchanged, 4 = impaired, 5 =much impaired and 6 = very much impaired.
Change of pain quality compared to baseline using the McGill Pain questionnaire (MPQ)
Assessed with the MPQ Short-Form which includes 15 adjectives that can be used to describe pain, each scored according to severity (0-3). The total score is calculated.
Number of participants with adverse events assessed with questionnaire
The participant lists any adverse event occurring during the week after injection and rate them as mild, moderate or severe.
Number of participants with adverse events assessed with questionnaire
The participant lists any adverse event occurring since the last visit and rate them as mild, moderate or severe.
Change of physical function assessed with questionnaire
Assessed with the Axis II questionnaire included in the DC/TMD. Includes the The Brief Pain Inventory (7 items, score ranges 0-100 for each), the Jaw Function Limitation Scale (20 items, score ranges 0-10), and the Oral Behavior Checklist (21 items, score ranges 0-84). A lower score indicates a better outcome for all instruments.
Change of emotional function assessed with questionnaire
Assessed with the Axis II questionnaire included in the DC/TMD. Includes the Beck's Depression inventory (21 items, score ranges 0-63), the Generalized Anxiety Disorder (7 items, score ranges 0-21), the Patient Health Questionnaire (15 items, score ranges 0-30), the Pain Catastrophizing Scale (13 items, score ranges 0-52), the Perceived Stress Scale (1o items, score ranges 0-40), and the Insomnia Severity Index (7 items, score ranges 0-28). A lower score indicates a better outcome for all instruments.

Full Information

First Posted
January 7, 2023
Last Updated
October 3, 2023
Sponsor
Karolinska Institutet
search

1. Study Identification

Unique Protocol Identification Number
NCT05720065
Brief Title
Peripheral TMD Pain Mechanisms and the Effect by Botulinum Toxin A
Official Title
Peripheral TMD Pain Mechanisms and the Effect by Botulinum Toxin A. A Randomized, Controlled, Double-blind Study
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 20, 2023 (Actual)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
August 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Karolinska Institutet

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The goal of this clinical trial is to investigate the effect of botulinum toxin on neurons' plasticity in the masseter muscle in humans with and without painful myogenous temporomandibular disorders (TMDM). The main questions it aims to answer are: does treatment with botulinum toxin alter gene expressions, epigenetic signatures, and cells plasticity in the masseter muscles of TMDM patients? do any such changes differ between patients with local and regional TMDM? does treatment with botulinum toxin influence pain characteristics (intensity, frequency, and sensibility) and other variables in patients with TMDM and are there correlations between significantly changed expression of biomarkers and other variables? Participants will be examined with a questionnaire, clinical examination, and biopsy sampling from one of the masseter and are then randomized to treatment with botulinum toxin or control (isotonic saline). Follow-ups occur after one, three, and six months with questionnaire, clinical examination, and collection of post-treatment microbiopsies to see if botulinum toxin alter peripheral molecular events and clinical variables.
Detailed Description
Patient recruitment: The patients will be recruited among those referred to the Specialist Clinic for Orofacial Pain and Jaw Function at the University Dental Clinic, Karolinska Institutet, Huddinge, Sweden, or via advertisement. Randomization: Patients will be randomly assigned to treatment by a random generator (www.randomization.com). For each participant the treatment will be written on a note and placed in a sealed envelope by a researcher not involved in any other part of data collection. A second person not involved in patient examination will open the envelope, prepare the syringe with the randomized solution, and place it in the examination room before the examiner and patient enters it. Botulinum toxin and saline have identical appearance so the participant and investigator will be masked to treatment assignment. Procedure: The participants complete an extended and slightly modified version of the Swedish Axis II questionnaire included in the Diagnostic Criteria for TMD (DC/TMD) before the first visit. The Axis II questionnaire contains sociodemographic question, questions regarding TMD symptoms and headache (presence, duration, and frequency) used for diagnostic purposes (Symptom Questionnaire), and validated instruments to assess physical and emotional function. A clinical examination is then performed according to the DC/TMD Axis I which also includes recordings of pressure pain threshold, temporal summation pain, and conditioned pain modulation. After having ensured that the participant fulfils the eligible criteria biopsies are obtained from a painful and a non-painful site for later analysis. At least one week hereafter treatment are given. Biopsies: Microbiopsies will be obtained from the masseter and anterior tibialis muscle (a non-treated pain-free internal control). The microbiopsies are taken through the skin overlaying the most prominent part of the muscle under skin surface anesthesia. A disposable biopsy instrument with a penetration depth of 11 mm and a diameter of 18 gauche (G) (masseter) or 16G (tibialis) will be used. The biopsy instrument will be guided with a coaxial needle, that will be inserted to a depth of 10 mm. Three to four microbiopsies will be taken from each muscle to ensure that sufficient muscle tissue is obtained. The coaxial needle will be inserted along the long axis of the muscles until the fascia is penetrated and the biopsy instrument is then inserted through the coaxial needle and a piece of the muscle with a size of approximately 0.12 cm * 1.1 cm is collected. The muscle section will be removed from the biopsy instrument using a sterile probe and immediately put in a cryotube which is snap frozen in liquid nitrogen. After removal of the muscle section the biopsy instrument will be rinsed with isotonic saline. This procedure will be repeated two to three times. Each time the biopsy instrument will be rotated 45° so that the microbiopsy would be taken from a new portion of the muscle. The biopsies will be stored (-80º) in Karolinska Institutet's dental biobank until analysis. Analyses of biopsies: The biopsies will be analyzed with bulk ribonucleic acid sequencing (RNA-seq), Multiome (combined single-cell Assay for Transposase-Accessible Chromatin (ATAC) and RNA-seq), immunohistochemistry (IHC), light sheet microscopy, and flow cytometry (FC) at University of Texas Health Science Center in San Antonio (UTHSCSA) and at the Live Cell Imaging Facility at Karolinska Institutet, Huddinge, Sweden. Data of the non-painful site (anterior tibialis will be subtracted from data of the painful site (masseter) for every patient. Then, these data can be clustered. For bulk RNA seq, differentially expressed genes (DEGs) will be selected and then paired analysis will be run within empirical analysis of DEGs in R (edgeR) software to select significantly different (p<0.05) DEGs. This is an established and well standardized approach. Selection criteria for further analysis are fold charge (FC)>1.5 and Reads Per Kilobase of transcript per Million mapped reads (RPKM)>10. Finally, biological processes will be defined by www.pantherdb.org on base of DEGs. Substation of internal controls from experimental data will also be done, followed by clustering of patients using DEGs. Both approaches produce similar results. Power analysis based on preliminary results from skin biopsies showed that 19 paired samples will obtain 83.6% power with a standard deviation (SD) of 0.8. However, RNA from muscle tissue is usually of higher quality than skin samples. Hence, the investigators anticipate that bulk RNA-seq will have lesser SD and require 14 paired samples per group; this includes samples after treatments. Combined gene and epigenetic signature plasticity on cellular levels will be evaluated by Multiome using Genomic x10 platform. Multiome analysis is standardized by Genomic x10. For visual presentation Seurat will be used. Power analysis for Multiome showed that 3-4 paired samples per group is needed. Currently accepted analysis is that paired samples belonging to the same participant group combined and multiple t-test-like analysis for each cell cluster run against another group. The IHC analysis will focus on sensory neurite plasticity using markers for subsets of sensory neurons and use Light Sheet microscopy to measure neurite length and branching for whole biopsies. The investigators also plan to use the Glyclick method which generates stable and homogenous antibody conjugates for immunoglobin G from several species and subclasses. If possible, also proteomics will be done. FC will be used to profile immune and vasculature cells. Power analysis showed that 8 samples per group will be needed for IHC and FC. Analyses of clinical data: P<0.05 will be used as significance level. The Shapiro-Wilk's test will test for normality of data. Mean (SD) or median (interquartile range, IQR), depending on normality, will be used to describe the data. For normally distributed and continuous data repeated measures Analysis of Variance (ANOVA) will be used to analyze differences in treatment effect with Group and Time as factors. If significant differences are found these will be further analyzed with Dunnet's posthoc test. Data that are skewed or ordinal will be analyzed with Friedman ANOVA for each group separately with Dunn's test as posthoc test for time differences. The Mann-Whitney U-test will be used to analyze differences between groups at different time points, using Bonferroni correction for multiple testing. Multivariate statistics will be used to identify correlations between significantly changed biomarkers and other variables. Principal component analysis (PCA) will be used to identify moderate or strong outliers. Orthogonal partial least squares discriminant analysis (OPLS-DA) will then be used to regress group membership using the biomarkers as regressors. For correlations between biomarkers and clinical variables OPLS modelling will be performed. The Variable Influence on Projection (VIP) value indicates the relevance of each X-variable pooled over all dimensions and the Y-variables indicate the group of variables that best explain Y. VIP > 1.0 is considered significant. R2 describes the goodness of fit, i.e., the fraction of sum of squares of all the variables explained by a principal component whereas Q2 describes the goodness of prediction, i.e., the fraction of the total variation of the variables that can be predicted by a principal component using cross validation methods. R2 should not be considerably higher than Q2, if substantially higher (>0.3) the robustness of the model is poor. To validate the model, an obtained cross-validated analysis of variance (CV-ANOVA) p-value will be used. The OPLS-DA model is considered of significant importance if the CV-ANOVA has a p-value < 0.05.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Temporomandibular Disorders
Keywords
Temporomandibular Disorders, Botulinum Toxin A, Myalgia, Randomized, Clinical Trial, Pain, Gene, Neural Plasticity

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Botulinum toxin
Arm Type
Active Comparator
Arm Description
Single bilateral injection into three standardized points of the masseter muscles and two of the anterior temporalis muscle. The total dose administered is 100 U (10 U/point) which is dissolved in 1 mL of isotonic saline. Thus, 0.1 ml of botulinum toxin solution is injected in each point.
Arm Title
Isotonic saline
Arm Type
Placebo Comparator
Arm Description
Single injection of 1 mL isotonic saline (0.9 mg/mL) into the same five points per side in a similar manner as for botulinum toxin.
Intervention Type
Drug
Intervention Name(s)
Botulinum toxin type A
Other Intervention Name(s)
Botox®️ (100 U, AbbVie AB, Solna, Sweden)
Intervention Description
Randomized double-blind administration
Intervention Type
Drug
Intervention Name(s)
Isotonic saline 0,9%
Other Intervention Name(s)
Natriumklorid Braun (0,9 mg/mL, B. Braun Medical AB, Danderyd, Sweden)
Intervention Description
Randomized double-blind administration
Primary Outcome Measure Information:
Title
Change of gene expression measured with bulk RNA-seq
Description
Gene expression in the anterior tibialis muscle (internal control) will be subtracted from the masseter and the patients will then be clustered according to DEGs and compared to baseline.
Time Frame
1-6 months
Title
Change of epigenetic signature measured with ATAC
Description
The epigenetic signature in the anterior tibialis muscle (internal control) will be subtracted from the masseter and the patients will then be clustered according to DEGs and compared to baseline.
Time Frame
1-6 months
Title
Change of expression of sensory neuron markers measured with IHC
Description
The expression will be measured as the change of frequency (%) of selected sensory neuron markers.
Time Frame
1-6 months
Secondary Outcome Measure Information:
Title
Change of pain intensity compared to baseline using 0-10 numeric rating scales (NRS)
Description
Assessed with the Brief Pain Inventory and includes assessment of the current and the worst, average, and least pain intensity during the last week, each scored on 0-10 numeric rating scale. The worst, average, and current pain can be used to calculate the Characteristic Pain Intensity (0-100) which is the mean score of the three assessments multiplied with ten.
Time Frame
1-3 months
Title
Global improvement using Patient Global Impression of Change Scale (PGIC)
Description
Assessed with the 7-point PGIC with the alternatives: 0 = eliminated, 1 = much improved, 2 = improved, 3 = unchanged, 4 = impaired, 5 =much impaired and 6 = very much impaired.
Time Frame
1-3 months
Title
Change of pain quality compared to baseline using the McGill Pain questionnaire (MPQ)
Description
Assessed with the MPQ Short-Form which includes 15 adjectives that can be used to describe pain, each scored according to severity (0-3). The total score is calculated.
Time Frame
1-3 months
Title
Number of participants with adverse events assessed with questionnaire
Description
The participant lists any adverse event occurring during the week after injection and rate them as mild, moderate or severe.
Time Frame
1 week
Title
Number of participants with adverse events assessed with questionnaire
Description
The participant lists any adverse event occurring since the last visit and rate them as mild, moderate or severe.
Time Frame
1-3 months
Title
Change of physical function assessed with questionnaire
Description
Assessed with the Axis II questionnaire included in the DC/TMD. Includes the The Brief Pain Inventory (7 items, score ranges 0-100 for each), the Jaw Function Limitation Scale (20 items, score ranges 0-10), and the Oral Behavior Checklist (21 items, score ranges 0-84). A lower score indicates a better outcome for all instruments.
Time Frame
1-3 months
Title
Change of emotional function assessed with questionnaire
Description
Assessed with the Axis II questionnaire included in the DC/TMD. Includes the Beck's Depression inventory (21 items, score ranges 0-63), the Generalized Anxiety Disorder (7 items, score ranges 0-21), the Patient Health Questionnaire (15 items, score ranges 0-30), the Pain Catastrophizing Scale (13 items, score ranges 0-52), the Perceived Stress Scale (1o items, score ranges 0-40), and the Insomnia Severity Index (7 items, score ranges 0-28). A lower score indicates a better outcome for all instruments.
Time Frame
1-3 months
Other Pre-specified Outcome Measures:
Title
Change of pressure pain threshold (PPT) compared to baseline
Description
The PPT (kPa) will be recorded over the masseter muscle with an electronic algometer as the average of three recordings
Time Frame
1-3 months
Title
Change of conditioned pain modulation (CPM) compared to baseline
Description
During CPM the participant immerse her hand and wrist into a cold water bath during 60s. The PPT (kPa) is recorded immediately before and after hand immersion. The percent change (%) before-after is used as CPM value.
Time Frame
1-3 months
Title
Change of temporal summation pain compared to baseline
Description
Temporal summation will be evoked with a 1.0 kg palpometer. The stimulus will be applied 10 times at the masseter muscle for 2 s with 1 s interval and pain intensity will be recorded after the 1st, 5th, and 10th stimulation on a 0-10 NRS.
Time Frame
1-3 months

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: a diagnosis of TMDM myalgia or myofascial pain according to the DC/TMD criteria females with adequate contraceptives and a negative pregnancy test pain upon digital palpation of at least one of the masseter muscle a characteristic pain intensity of > 40/100. Exclusion Criteria: difficulties understanding the Swedish language systemic inflammatory connective tissue diseases widespread pain neuromuscular disorders diagnosed or severe psychiatric disease neuropathic pain pain of dental origin history of trauma to the face, head or neck pregnancy or nursing known allergy to botulinum toxin or antibiotics use of muscle relaxants, antidepressant, neuropsychiatric, anticoagulant drugs, or aminoglycoside antibiotics previous treatment with botulinum toxin during the last 12 months use of analgesic or anti-inflammatory medication during the 48 hours preceding biopsy skin infection over injection/biopsy site
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Malin Ernberg, PhD
Phone
+46706368236
Email
malin.ernberg@ki.se
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Malin Ernberg
Organizational Affiliation
Karolinska Institutet
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Dental Medicine, Karolinska Institutet
City
Huddinge
State/Province
Stockholm
ZIP/Postal Code
SE14104
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Malin Ernberg
Phone
0706368236
Email
malin.ernberg@ki.se

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Deidentified genetic data will be entered into a database at the National Institute of Health (NIH) that only contains genetic data, sex, age, and TMD diagnosis. No other health data is disclosed.
IPD Sharing Time Frame
Data will be available after study termination and saved in the databases for 10 years whereafter they are discarded.
IPD Sharing Access Criteria
The database is made available to other researchers only for non-commercial research that has permission from the ethics committee after approval by the research leader (controlled access). Data is also uploaded into a database of aggregated genomic data that is shared with the research community (unlimited access).
Citations:
PubMed Identifier
24482784
Citation
Schiffman E, Ohrbach R, Truelove E, Look J, Anderson G, Goulet JP, List T, Svensson P, Gonzalez Y, Lobbezoo F, Michelotti A, Brooks SL, Ceusters W, Drangsholt M, Ettlin D, Gaul C, Goldberg LJ, Haythornthwaite JA, Hollender L, Jensen R, John MT, De Laat A, de Leeuw R, Maixner W, van der Meulen M, Murray GM, Nixdorf DR, Palla S, Petersson A, Pionchon P, Smith B, Visscher CM, Zakrzewska J, Dworkin SF; International RDC/TMD Consortium Network, International association for Dental Research; Orofacial Pain Special Interest Group, International Association for the Study of Pain. Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) for Clinical and Research Applications: recommendations of the International RDC/TMD Consortium Network* and Orofacial Pain Special Interest Groupdagger. J Oral Facial Pain Headache. 2014 Winter;28(1):6-27. doi: 10.11607/jop.1151.
Results Reference
background
PubMed Identifier
21514731
Citation
Ernberg M, Hedenberg-Magnusson B, List T, Svensson P. Efficacy of botulinum toxin type A for treatment of persistent myofascial TMD pain: a randomized, controlled, double-blind multicenter study. Pain. 2011 Sep;152(9):1988-1996. doi: 10.1016/j.pain.2011.03.036. Epub 2011 Apr 22.
Results Reference
background
PubMed Identifier
35065194
Citation
Mecklenburg J, Wangzhou A, Hovhannisyan AH, Barba-Escobedo P, Shein SA, Zou Y, Weldon K, Lai Z, Goffin V, Dussor G, Tumanov AV, Price TJ, Akopian AN. Sex-dependent pain trajectories induced by prolactin require an inflammatory response for pain resolution. Brain Behav Immun. 2022 Mar;101:246-263. doi: 10.1016/j.bbi.2022.01.016. Epub 2022 Jan 19.
Results Reference
background
PubMed Identifier
32812765
Citation
Srzentic K, Fornelli L, Tsybin YO, Loo JA, Seckler H, Agar JN, Anderson LC, Bai DL, Beck A, Brodbelt JS, van der Burgt YEM, Chamot-Rooke J, Chatterjee S, Chen Y, Clarke DJ, Danis PO, Diedrich JK, D'Ippolito RA, Dupre M, Gasilova N, Ge Y, Goo YA, Goodlett DR, Greer S, Haselmann KF, He L, Hendrickson CL, Hinkle JD, Holt MV, Hughes S, Hunt DF, Kelleher NL, Kozhinov AN, Lin Z, Malosse C, Marshall AG, Menin L, Millikin RJ, Nagornov KO, Nicolardi S, Pasa-Tolic L, Pengelley S, Quebbemann NR, Resemann A, Sandoval W, Sarin R, Schmitt ND, Shabanowitz J, Shaw JB, Shortreed MR, Smith LM, Sobott F, Suckau D, Toby T, Weisbrod CR, Wildburger NC, Yates JR 3rd, Yoon SH, Young NL, Zhou M. Interlaboratory Study for Characterizing Monoclonal Antibodies by Top-Down and Middle-Down Mass Spectrometry. J Am Soc Mass Spectrom. 2020 Sep 2;31(9):1783-1802. doi: 10.1021/jasms.0c00036. Epub 2020 Aug 19.
Results Reference
background
PubMed Identifier
25261281
Citation
Christidis N, Kang I, Cairns BE, Kumar U, Dong X, Rosen A, Kopp S, Ernberg M. Expression of 5-HT3 receptors and TTX resistant sodium channels (Na(V)1.8) on muscle nerve fibers in pain-free humans and patients with chronic myofascial temporomandibular disorders. J Headache Pain. 2014 Sep 26;15(1):63. doi: 10.1186/1129-2377-15-63.
Results Reference
background
PubMed Identifier
23999822
Citation
Wheelock AM, Wheelock CE. Trials and tribulations of 'omics data analysis: assessing quality of SIMCA-based multivariate models using examples from pulmonary medicine. Mol Biosyst. 2013 Nov;9(11):2589-96. doi: 10.1039/c3mb70194h.
Results Reference
background
Links:
URL
http://www.jerrydallal.com/random/randomize.htm
Description
Random generator

Learn more about this trial

Peripheral TMD Pain Mechanisms and the Effect by Botulinum Toxin A

We'll reach out to this number within 24 hrs