KCH Dental Fostering Research Seminar Series Tara Renton

KCH Dental ‘Fostering Research’ Seminar Series Tara Renton

New Government Strategy 2006

The NIHR Clinical Research Network The National Institute for Health Research (NIHR) Clinical Research Network is an essential element in achieving the government’s vision “to create a health research system in which the NHS supports outstanding individuals, working in world-class facilities, conducting leading-edge research focused on the needs of patients and the public. ”

NHS = largest clinical trial centre world wide

National Institute for Health Research - LCRN Faculty Investigators & Senior Investigators Associates Trainees Infrastructure Universities Research Clinical Research Networks NHS Trusts Research Projects & Programmes Patients & Public Clinical Research Facilities & Centres Research Governance Systems Research Units & Schools Research Information Systems

UK Health Research income 2008 £ 7. 4 B spent on health research in UK (75% industrial and 75% health specific) R&D levy £ 21 m GSTT and £ 11 m KCH Future emphasis on Research funding Best performing clinical academic partnerships in translational and applied research (AHSCs) Continued focus on cancer / cardiac but also on high burden diseases (dental? ) Education and training MPET and HEFCE

NIHR Research Programmes Translating research evidence into NHS practice Basic Research (Biomedical, population, Social Science& engineering & technology) Proof of concept Experimental Medicine Efficacy Effectiveness and costeffectiveness Knowledg e transfer for NHS Research Centres Programme Grants Healthcare Technology Cooperatives Health Technology Assessment Service Delivery and Organisation Research for Patient Benefit Research for Innovation, Speculation and Creativity New & Emerging Applications of NICE Tech. Health Technology Devices Adoption into the service

Structure NIHR Clinical research network Six “topic” Clinical Research Networks, which focus on specific disease areas: Cancer, Diabetes, Dementias and Neurodegenerative Diseases, Medicines for Children, Mental Health, and Stroke A Primary Care Research Network The CCRN is made up of 25 Comprehensive Local Research Networks (CLRNs) which cover the whole of England by region. These locally based Research Networks coordinate and facilitate the conduct of clinical research and provide a wide range of support to the local research community. 18 health specialty groups

Map

Activity by health group

Activity by health group

What is a portfolio study? Studies eligible for NIHR Clinical Research Network support include; National competition Commercial Non-commercial studies including those that are automatically make up the greatest proportion of studies on the NIHR Adoption process You can opt into existing open recruiting studies NRES tick section 59 a

How to get adoption of study

KCH Portfolio Activity 117 portfolio studies: 76 Interventional (gain £ 1600 per pt) 41 Observational (gain £ 3 -600 per pt)

Oral dental Specialty Group

Oral and dental Supports portfolio studies Covers wide range of conditions oral cancer – orthodontic Development of prevention and management strategies for all oral diseases Promotion oral health Design and evaluation services of successful and cost effective delivery of oral health care

Oral and Dental UK group Our membership CLRN Northumberland, Tyne and Wear: CHAIR Professor Jimmy Steele Birmingham and the Black Country Professor Thomas Dietrich Central and East London Professor John Galloway London (North West) Manolis Heliotis London (South) Professor Tara Renton Northumberland, Tyne and Wear Professor Jimmy Steele South Yorkshire Professor Peter Robinson (Deputy Chair) West Anglia Chi-Hwa Chan Western Dr Anthony Ireland West Yorkshire Dr James Mc. Caul Professor Paul Brunton Scotland Professor Jeremy Bagg Dr Jan Clarkson Wales Professor Stephen Richmond

Oral and dental studies Low dose intravenous immunoglobulin or 0. 9 sodium chloride in the treatment of primary trigeminal neuralgia refractory to Carbamazepine. A randomised double blind parrallel placebo controlled multicentre trial in an outpatient setting Monitoring of Oral Cancer Patients Using Novel Lab-On-A-Chip Ensembles Timing of Primary Surgery for Cleft Palate (TOPS) v 1. 1 The role of selective neck dissection in patients with early oral squamous cell carcinoma (1 -3 cm primary size) and no clinical evidence of lymph node metastases in the neck (N 0) Are microimplants as effective at providing orthodontic anchorage as conventional methods Chewing gum and orthodontic pain Development of technique to assist with culture of stem cells from oral mucosa & dental pulp Treatment of Periodontitis and metabolic control in patients with Type 2 Diabetes Mellitus Dielectrophoresis as a prognostic tool for potentially malignant and malignant disease of the mouth A comparison of pre medication with oral paracetamol versus intravenous paracetamol given at time of induction for postoperative analgesia following wisdom tooth extraction A study evaluating (selected) saliva biomarkers to validate their predictive capability in diagnosing clinical periodontal disease Genetic and psychometric role in post surgical acute pain using ASL/regional cerebral blood (r. CBF) flow Analysis of the Saliva Proteome for Diagnostic Markers of Gingivitis and Periodontitis using FT-ICR-MS/MS. An analysis of the effect of photographic intervention on medical dialogue within pain consultations. An exploration of photographic portraiture with patients and clinicians from oral and dental medicin Human tonsil cellular response to infection IMPROVDENT: Improving Dentures for Patient Benefit A cross over randomised clinical trial comparing impression materials for complete dentures Eliminating periodontal infection in patients with type 2 diabetes. X-ray microtomography study of carious teeth and comparison of its removal by various techniques INTERVAL Dental Recalls Trial [Investigation of NICE Technologies for Enabling Risk-Variable-Adjusted-Length Dental Recall Trial] Odontogenesis: a paradigm for mammalian biomineralisation and the role of extracellular matrix in the control of crystal deposition and growth Effect of nitrite in saliva on gastro-oesophageal reflux Seal or Varnish? A randomised trial to determine the relative cost and effectiveness of pit and fissure sealants and fluoride varnish in preventing dental decay

So what studies are happening at KCH Dental? Mapping pain in man using f. MRI Culture of stem cells from human teeth Intervention to assess drivers for Paedodontic GA extractions More?

Trigeminal pain research in KHP

Trigeminal nerve Vth cranial nerve Sensory supply to face, scalp and mouth Homunculus

M 3 M surgery The Patient Network District MCN Macro system EPR Databse Local commissioning Local guidelines Best practice Micro system Website for pts

Neurovascular Classification of Chronic orofacial pain Neuropathic Primary Trigeminal N / ATN Glossopharyngeal N Tension HA Migraine Cluster HA Giant cell arteritis SUNCT SUNA 25 Secondary PHN, DM, MS, HIV, Tx Post surgical N Lingual inferior alveolar nerve injuries Burning Mouth S Persistent idiopathic (ATFP / ATO) TMJ pain

The Team clinical Dental Institute Clinical Orofacial pain clinics at KCHFT Professor Tara Renton Oral Surgery KCL / Hon Cons KCHFT / GSTFT Cathy Bryant NHS consultant Oral Surgery Liaison staff at Oral surgery pain clinics Dr Sam Chong Neurology Consultant KCHFT Dr Tom Smith Pain management consultant Dr Lisa Page Liaison Psychiatrist Hon Cons Sarah Barker Liaison clinical Psychologist Nicky James Health psychologist Peter Bullock and Sinan Barazi Neurosurgeons Other staff involved in orofacial pain Dr Michael Escudier Consultant Oral Medicine GSTFT Dr Tim Poate Consultant Oral Medicine KCHFT Dr Helen Mac Pharlane Staff Grade Oral Medicine GSTFT Professor Ray Chaudery Neurology Consultant KCHFT Prof Manjit Kothari Neurology Queens Square UCL Prof Mike Gleeson ENT KCL

The Team academic Clinical Non Clinical Tara Renton Zehra Yilmaz Post Doc IAT Ph. Ds Nadine Khawaja Obi Ebugnegwe KCL Kiran Beneng Wolfson Norazah Bakar Andy Grant Post Doc Collaborations Imaging Prof Manjit Kothari UCL Steve Williams Prof Io. P Prof Praveen Anand IC Matt Howard Io. P Post Doc Prof Vishal Aggrawal QMUL Kristina Krause Io. P Ph. D student

Phenotyping of patients Imaging Genetic Pain Neurological Functional Psychometric Patient demograph

Peripheral receptors Central pain pathway Genetics

Work ongoing Trigeminal pain: an update Inflammatory nociceptive pain Dental Pain Peripheral + genetics Post surgical pain Genetics, Peripheral and central Neuropathic pain Post Traumatic Neuropathy Genetics, Peripheral and central Trigeminal autonomic cephalgias Genetics, Peripheral and central Trigeminal neuralgia Genetics, Peripheral and central Burning mouth Genetics, Peripheral and central

Unravelling toothache Immortalised cell line of odontoblastic +ve markers TRPA 1, TRPV 1 and TRPV 4. Microarray, RT-PCR, flow cytometry and Calcium imaging studies Obi Egbuniwe Ph. D St Prof Lucy Di Silvio Dr Andy Grant P 16/P 53 expression and telomerase activity in immortalized human dental pulp cells Egbuniwe O. , Idowu BD, Funes JM, Grant AD, Renton T, Di Silvio L ( Tissue Engineering (IF = 4. 5)

Gene expression novel targets The microaaray data we got from painful and non painful teeth showed an up regulation of certain inflammatory markers and cytokines. We are looking at the effect of Substance P exposure on cellular activity Work with Prof Steve Mac. Mahon & Dr Andy Grant

We need to recruit patients to donate teeth!

BMS Dr Kiran Beneng Ph. D St Prof Praveen Anand Dr Michael Escudier Ongoing work TRPM 8 CB 1, P 2 X 3 and GABA receptors Imaging central pathways (CNS) Dr Matt Howard NGF TRPV 1 NF NF Bar charts of the mean ± SEM of epithelial nerve fibres per papilla in control and BMS tongue. * P <0. 0001. P =0. 0006, Spearman r =0. 55

Third molar surgery 35

Psychological features Depression Anger Post traumatic stress disorder Victim of abuse Loss of ability to trust 36

Imaging central pathways Post surgical pain Post Perfalgen Post dicolfenac Burning mouth syndrome before and after Rx Migraines Trigeminal neuralgia Trigeminal autonomic cephalgias Cluster headache SUNCT SUNA

Imaging post surgical pain • TME most frequent model in acute pain trials (Moore et al. , 2005) • 30 -80% of patients suffer moderate to severe pain post-operatively (Popping 2008 & Apfelbaum 2003). Prof Steve Williams Io. P KCL Center Neuroscience imaging Matt Howard, Kristina Krause, Anbarasu Lourdusamy Gunter Schumann SGDP Io. P Nadine Khawaja IA Ph. D St

Significant increases in post-surgical regional CBF in brain regions previously associated with pain (pain neuromatrix) ACC PCC S 1 S 2 THAL INS • Additional amygdala, hippocampus, brainstem, and V 5 ROIs

Results Significant increases in post surgical r. CBF observed in; S 1, S 2, Thalamus, Insula, Anterior cingulate cortex Also in Amygdala and Hippocampus But NOT in control region Largest change seen in Thalamus No first or second order interaction of surgery for all ROIs Presusrgery /post surgery Side (left or right) Hemisphere (left or right)

Post surgical pain Gene expression & VAS score relationships Correlation between 38 genes and VAS scores RED up regulated GREEN down regulated Left side correlation with VAS score for all 6 c. ASL maps Highest correlation reveals a gene BMX involved in regulation of IL 6 in pts with RA 41

Clinical, imaging and genetic characterisation of Cluster headaches Dr Norazah Bakar Ph. D St Prof Manjit Matharu UCL Mat Howard Io. P KCl Steve Williams Io. P KCL Dr Sam Chong KCH Trigeminal autonomic cephalgias Cluster headaches SUNCT and SUNA

Grants Private donation Prevention trigeminal nerve injuries 2011 £ 50 K KCH NHS Trust/KCL Joint Research Committee 2010 59 K Functional MRI evaluation of brain response BMS MRC translational project grants Shortlisted 2011 £ 388 K Proof of concept studies on the development of a pain biomarker in man Pfizer support for Ph. D students in lab based work 2011 £ 60 K British Pain Society Mildred B Clulow 2010 £ 68 K Proof of concept studies on the development of a pain biomarker in man BRC Oral Health 2010 £ 8 K Consumables For Odontoblast progenitor cell project London central research fund 2009 10 K Development of model to culture neural progenitor cells for human dental pulp.

Primary care SELDOC GMPs headaches Io. P CNS Clinical Neuroimaging Biomarker for acute pain Dental. RA, Back pain Dental 2 y and 3 y care Acute /chronic V Pain related Anxiety Post surgical pain STH Input breast Neurosurgery Charlotte Wilson Jones Neurology Richard Selway Neuromodulation Ashkan Keymours 42 neurologists Back pain Peter Bullock Sam Chong Headaches Primary Care Back pain Psychosexual clinic TN Pain management Vulvadynia Leone Ridsdale Joan Hester + Tom Smith Pain Rheumatology Diabetic. Palliative care Knee pain burning. Sue Peat Medical education foot Ernest Choy David Bennett Prof Bjornsson Dave Edmonds Palliative Care Birth CNS Gastroenterology Joan Hester Myelination of brain first 7 months St Christophers IBS Hospice IOP 4 specialist GPSI in headaches

IPE PAIN EDUCATION Masters Neuroscience Io. P Sue Peat and Joan Hester UG Medicine Nursing Emma Briggs Nightingale Institute Tara Renton Mike Escudier UG dental Mick Thacker Wolfson Masters degree pain neurosciences

Publications Yilmaz Z, Renton T, Yiangou Y, Zakrzewska J, Chessell IP, Bountra C, Anand P. Burning mouth syndrome as a trigeminal small fibre neuropathy: Increased heat and capsaicin receptor TRPV 1 in nerve fibres correlates with pain score. J Clin Neurosci. 2007 Sep; 14(9): 864 -71. Renton T. An update on pain. Br Dent J. 2008 Mar 22; 204(6): 335 -8. Renton T Summary of: Unexplained orofacial pain - is an early diagnosis possible? Br Dent J. 2008 Aug 9; 205(3): 140 -141 Coulthard P, Esposito M, Renton T, Worthington HV. Surgical techniques for the removal of mandibular wisdom teeth (protocol). Cochrane Databa of Systematic Reviews 2003, Issue 3. Art. No: CD 004345. www. cochrane. org Khawaja N, Renton T. Case studies on implant removal influencing the resolution of inferior alveolar nerve injury. Br Dent J. 2009 Apr 11; 206(7): 36 70 Seymour RA, Moore U, Hawkesford J, Coulthard P, Jackson-Leech D, Thomas D, Hill M, Combs ML, Renton T, Mc. Gurk M. An investigation into th efficacy of intravenous diclofenac in post-operative dental pain. Eur J Clin Pharmacol. 2000 Sep; 56(6 -7): 447 -52. Renton T. Prevention of iatrogenic inferior alveolar nerve injuries in relation to dental procedures. Dent Update. 2010 Jul-Aug; 37(6): 350 -2, 354 -6, 3 60 Beneng K, Renton T, Yilmaz Z, Yiangou Y, Anand P. Sodium channel Nav 1. 7 immunoreactivity in painful human dental pulp and burning mouth syndrome. BMC Neurosci. 2010 Jun 8; 11(1): 71. [Epub ahead of print]PMID: 20529324 Beneng K, Yilmaz Z, Yiangou Y, Mc. Pharland H, Anand P, Renton T. Sensory purinergic receptor P 2 X(3) is elevated in burning mouth syndrome. In Oral Maxillofac Surg. 2010 Apr 24. [Epub ahead of print] Beneng K, Renton T, Yilmaz Z, Yiangou Y, Anand P. Cannabinoid receptor CB 1 -immunoreactive nerve fibres in painful and non-painful human too pulp. J Clin Neurosci. 2010 Nov; 17(11): 1476 -9. Epub 2010 Aug 11 Frafjord R & Renton T. Update on Coronectomy J Oral Surgery; 2010: vol 3 (1 -2) 1 -7 Renton T, Adey-Viscuso D, Meechan JG, Yilmaz Z. Trigeminal nerve injuries in relation to the local anaesthesia in mandibular injections. Br Dent J 2010 Nov; 209(9): E 15 Renton T. Prevention of iatrogenic inferior alveolar nerve injuries in relation to dental procedures. SADJ. 2010 Sep; 65(8): 342 -4, 346 -8, 350 -1 Renton T Summary of: Experience in third molar surgery: an update. Br Dent J. 2010 Jul 10; 209(1): 36 -7. Howard M, Khawaja N, Krause K, Schumann G, Williams S, Renton T. ASL labeling or central pain pathways in post third molar surgical pain. A pi study. PLOS 1 accepted Feb 2011 Lourdusamy A, Krause K, Howard M, Khawaja N, Renton T, Schumann G, Williams S, Analysis of dental pain gene expression related to third mol surgery. Submitted Am J Human Genetics N Khawaja, Renton T. Case Studies illustrating the management of trigeminal neuropathic pain using topical 5% Lidocaine patches. Accepted JOS June 2010

Publications YILMAZ, Z, ZAKRZEWSKA, J, HARDING, L, RENTON, T. Identification of allodynia and hypoalgesia using quantitative thermal threshold testing in burning mouth syndrome and lingual nerve injury. Accepted European Journal of Pain. Impact factor = 3. 714 Renton T, Yilmaz Z. Experience of the management of trigeminal nerve injuries Accepted JOMS Nov 2010 Gaballah K, Khawaja N, Renton T. Factors contributing to needle stick injuries trainee dentists and nurses in a dental school. Submitted J Dent Education Nov 2010 Renton T, Dawood A, Shah A, Yilmaz Z. Trigeminal nerve injuries in relation to dental implants. Accepted Clinical research in Implantology Accepted Nov 2010 Renton T Frafjord R. Notes on coronectomy. Accepted BDJ Renton. T. Coronectomy update. Accepted Dental Update Renton T. A systematic review of haematological screening for BMS. accepted Elsevier Renton T A systematic review of histological evaluation for BMS. accepted Elsevier T Renton, Z Yilmaz ‘Numb chin’ syndrome an update and case series Submitted J Oral Surgery June 2010 T Renton. Z Yilmaz S Chong. A series of medication over use orofacial pain Submitted Pain Jan 2011 T Renton. Z Yilmaz S Chong. Lacosamide for chronic oro-facial pain: a case series. Submitted Neurology Jan 2011 Mehdi I Yilmaz Z, Renton T, Page L The treatment goals of patients attending an orofacial pain clinic. Comparsion of psochological morbidity of headaches and chronic orofacial pain. Submitted J Oral Surgery Dec 2010 Renton T, Z Yılmaz Profiling of patients with iatrogenic trigeminal nerve injuries Accepted J Orofacial Pain Jan 2011 Renton T Foot N, Yilmaz Z. Endodontic related trigeminal nerve injuries. J Endodontics submitted Jan 2011 Renton T Gabbalah K, Yilmaz Z Trigeminal nerve injuries in relation to third molar surgery. How do we minimize these? Submitted IJOMS

So how can you get involved?

So how can you get involved? Collaborate. . . whats happening locally? KCH KCL GSTT Primary care Opportunities Local support Staff Patients

Huge patient cohort Kings College Hospital Walk in acute pain Dental extractions Surgical extractions Third molar surgery Biopsy 30 K per annum 1500 per week 1100 per week 600 per week 50 per week Guys and St Thomas’ Dental extractions Surgical extractions Third molar surgery Biopsy 500 per week 350 per week 175 per week 15 per week

Local opportunities Related AHSC health research King’s PSSQ Research Centre Joint clinical trials office Education and training Central Biomed Social care workforce Medical law and ethics Friendly R&D dental team! Tara Zehra & Sue

What dental research themes ‘dovetail’ in with KCH or AHSC? Main themes Pain neuroscience Medically compromised Trauma Secondary themes Cancer Clinical trials Prevention disease Cardiac stroke DM Alcohol abuse / smoking

What’s the big question in your area? Restorative Ortho Paedo Spec care dentistry Oral surgery PDC Max. Fac How can you improve? Service delivery Patient access Health outomes Teaching Training

Potential research areas for Dental? Clinical trials Facial trauma Medically compromised patient ADC CHD DM risk study Liver disease in kids Parkinsons / MS/ OFP Smoking alcohol cessation Others WB TR TR MTH JG LZ Oncology Improved oral health of KCH in patients Anxiety Sedation paedo / adult Bisphonate therapy Potential areas SD SW JC TN Imaging US CBCT Dentoalveolar trauma Orthodontic RX Paedo dentoalveolar surgery Primary care movement of 40% services from 2 dry to 1 ry care TMJ pain

Potential strategy to increase NHS consultant research activity Identify themes for dental Link up KCL leads with NHS interested staff Free up time for KCH staff Local grant applications Cochrane review topics IA Trainee applications recommended for Encourage Ph. Ds and masters (OSeas? ) Updated information systems to assist research and development Dedicated staff to assist with review, papers, grants

What does this mean for the ‘jobbing’ NHS staff? Increased recognised Research activity PAs for Research Cochrane reviews –local support Walport posts IATs More funding for your trust Collaborative research activity More satisfied patients

What does this mean for the ‘jobbing’ NHS staff? MORE FUN!

All positive Best research for best health Current GOLD standard is not necessarily good enough! Constant improvement of health services provision

We look forward to your support in developing clinical research THANK YOU Thanks to Septodont for sponsorship of this meeting

Dental Clinical KCH > GSTT dental approx 200 K pts / year KCH > GSTT Dental, liver, gastrointestinal and neurosciences KCH 46% of clinical activity Research income for dental GSTT >KCH Dental top seven KCL groups over £ 5 m income Medical>Io. P>BHS>dental>nursing Dental dropping from 23 -11% of income 2005 -08 Clinical academic staff KCH 12 vs GSTT 29 GSTT 60% AHSC overall income (more Research)