Martin H. Thornhill

Incidence of infective endocarditis in England, 2000-13: a secular trend, interrupted time-series analysis.

BACKGROUND Antibiotic prophylaxis given before invasive dental procedures in patients at risk of developing infective endocarditis has historically been the focus of infective endocarditis prevention. Recent changes in antibiotic prophylaxis guidelines in the USA and Europe have substantially reduced the number of patients for whom antibiotic prophylaxis is recommended. In the UK, guidelines from the National Institute for Health and Clinical Excellence (NICE) recommended complete cessation of antibiotic prophylaxis for prevention of infective endocarditis in March, 2008. We aimed to investigate changes in the prescribing of antibiotic prophylaxis and the incidence of infective endocarditis since the introduction of these guidelines. METHODS We did a retrospective secular trend study, analysed as an interrupted time series, to investigate the effect of antibiotic prophylaxis versus no prophylaxis on the incidence of infective endocarditis in England. We analysed data for the prescription of antibiotic prophylaxis from Jan 1, 2004, to March 31, 2013, and hospital discharge episode statistics for patients with a primary diagnosis of infective endocarditis from Jan 1, 2000, to March 31, 2013. We compared the incidence of infective endocarditis before and after the introduction of the NICE guidelines using segmented regression analysis of the interrupted time series. FINDINGS Prescriptions of antibiotic prophylaxis for the prevention of infective endocarditis fell substantially after introduction of the NICE guidance (mean 10,900 prescriptions per month [Jan 1, 2004, to March 31, 2008] vs 2236 prescriptions per month [April 1, 2008, to March 31, 2013], p<0·0001). Starting in March, 2008, the number of cases of infective endocarditis increased significantly above the projected historical trend, by 0·11 cases per 10 million people per month (95% CI 0·05-0·16, p<0·0001). By March, 2013, 35 more cases per month were reported than would have been expected had the previous trend continued. This increase in the incidence of infective endocarditis was significant for both individuals at high risk of infective endocarditis and those at lower risk. INTERPRETATION Although our data do not establish a causal association, prescriptions of antibiotic prophylaxis have fallen substantially and the incidence of infective endocarditis has increased significantly in England since introduction of the 2008 NICE guidelines. FUNDING Heart Research UK, Simplyhealth, and US National Institutes of Health.

New developments and opportunities in oral mucosal drug delivery for local and systemic disease

The oral mucosas accessibility, excellent blood supply, by-pass of hepatic first-pass metabolism, rapid repair and permeability profile make it an attractive site for local and systemic drug delivery. Technological advances in mucoadhesives, sustained drug release, permeability enhancers and drug delivery vectors are increasing the efficient delivery of drugs to treat oral and systemic diseases. When treating oral diseases, these advances result in enhanced therapeutic efficacy, reduced drug wastage and the prospect of using biological agents such as genes, peptides and antibodies. These technologies are also increasing the repertoire of drugs that can be delivered across the oral mucosa to treat systemic diseases. Trans-mucosal delivery is now a favoured route for non-parenteral administration of emergency drugs and agents where a rapid onset of action is required. Furthermore, advances in drug delivery technology are bringing forward the likelihood of transmucosal systemic delivery of biological agents.

Impact of the NICE guideline recommending cessation of antibiotic prophylaxis for prevention of infective endocarditis: before and after study

Objective To quantify the change in prescribing of antibiotic prophylaxis before invasive dental procedures for patients at risk of infective endocarditis, and any concurrent change in the incidence of infective endocarditis, following introduction of a clinical guideline from the National Institute for Health and Clinical Excellence (NICE) in March 2008 recommending the cessation of antibiotic prophylaxis in the United Kingdom. Design Before and after study. Setting England. Population All patients admitted to hospital in England with a primary or secondary discharge diagnosis of acute or subacute infective endocarditis. Main outcome measures Monthly number of prescriptions for antibiotic prophylaxis consisting of a single 3 g oral dose of amoxicillin or a single 600 mg oral dose of clindamycin, and monthly number of cases of infective endocarditis, infective endocarditis related deaths in hospital, or cases of infective endocarditis with a possible oral origin for streptococci. Results After the introduction of the NICE guideline there was a highly significant 78.6% reduction (P<0.001) in prescribing of antibiotic prophylaxis, from a mean 10 277 (SD 1068) prescriptions per month to 2292 (SD 176). Evidence that the general upward trend in cases of infective endocarditis before the guideline was significantly altered after the guideline was lacking (P=0.61). Using a non-inferiority test, an increase in the number of cases of 9.3% or more could be excluded after the introduction of the guideline. Similarly an increase in infective endocarditis related deaths in hospital of 12.3% or more could also be excluded. Conclusion Despite a 78.6% reduction in prescribing of antibiotic prophylaxis after the introduction of the NICE guideline, this study excluded any large increase in the incidence of cases of or deaths from infective endocarditis in the two years after the guideline. Although this lends support to the guideline, ongoing data monitoring is needed to confirm this, and further clinical trials should determine if antibiotic prophylaxis still has a role in protecting some patients at particularly high risk.

Tissue-engineered Oral Mucosa: a Review of the Scientific Literature

Tissue-engineered oral mucosal equivalents have been developed for clinical applications and also for in vitro studies of biocompatibility, mucosal irritation, disease, and other basic oral biology phenomena. This paper reviews different tissue-engineering strategies used for the production of human oral mucosal equivalents, their relative advantages and drawbacks, and their applications. Techniques used for skin tissue engineering that may possibly be used for in vitro reconstruction of human oral mucosa are also discussed.

Increased Prevalence of Dysplastic and Malignant Lip Lesions in Renal-Transplant Recipients

BACKGROUND Renal-transplant recipients are known to have increased rates of skin cancer associated with exposure to the sun. Little is known, however, about the prevalence and histologic features of lesions of the lips in these patients, or about risk factors for such lesions. METHODS We examined the lips of 160 renal-transplant recipients (105 men and 55 women; mean [+/- SD] age, 48 +/- 13 years) and 160 normal subjects matched with the transplant recipients for age, sex, and skin type. The mean length of time between transplantation and the examination was 69 +/- 52 months; 58 percent of the recipients had received their grafts more than 60 months earlier. RESULTS Among the 160 renal-transplant recipients, 21 (13 percent) had leukoplakia; in 2 (1.2 percent) the leukoplakia contained squamous-cell carcinoma. In contrast, only one normal subject (0.6 percent) had leukoplakia. Histologically, 13 of the 21 leukoplakias (62 percent) in the renal-transplant recipients who underwent biopsy were dysplastic, and 2 (10 percent) contained squamous-cell carcinoma. Actinic change was evident in 91 percent of the dysplastic lesions but not in the nondysplastic lesions (P < 0.001). Exposure to the sun and smoking were risk factors for dysplastic and malignant lip lesions in the renal-transplant recipients (P < 0.001 and P = 0.003, respectively). Among these recipients, only men had dysplastic or malignant lip lesions (P = 0.006); lipstick was used frequently by 73 percent of the women. The clinical appearance of lip lesions did not predict the presence of dysplasia or cancer. CONCLUSIONS Renal-transplant recipients have an increased prevalence of leukoplakia, dysplasia, and cancer of the lip.

Prevalence and risk factors associated with leukoplakia, hairy leukoplakia, erythematous candidiasis, and gingival hyperplasia in renal transplant recipients

The aims of this study were to determine the prevalence of intraoral lesions in renal transplant recipients and to identify possible risk factors. The oral mucosa of 159 renal transplant recipients and 160 control patients was examined. The most common lesion in renal transplant recipients was cyclosporin-induced gingival hyperplasia (prevalence 22%) and patients with gingival hyperplasia were found to be taking significantly more cyclosporin-A than those without (p < 0.001). The prevalence of hairy leukoplakia and leukoplakia in renal transplant recipients was 11.3% and 10.7%, respectively, compared with 0% and 5.6% in the controls. Oral candidiasis was observed in 9.4% of renal transplant recipients compared with 2.5% of the controls; 3.8% of renal transplant recipients exhibited erythematous candidiasis, but this was not seen in the controls. Renal transplant recipients had a significantly increased risk of developing gingival hyperplasia (p < 0.0001), oral candidiasis (p < 0.0005), and two other conditions that have a well-established association with the immune suppression accompanying HIV infection, hairy leukoplakia (p < 0.0001) and erythematous candidiasis (p < 0.01).

A systematic review of placebo‐controlled randomized clinical trials of treatments used in oral lichen planus

Background  Oral lichen planus (OLP) is one of the commoner conditions seen in oral medicine clinics. Current treatments are palliative rather than curative. Numerous treatments have been tried but many have not been evaluated in randomized controlled trials (RCTs).

IL-1B and IL-6 gene polymorphisms encode significant risk for the development of recurrent aphthous stomatitis (RAS)

Recurrent aphthous stomatitis (RAS) is an, ulcerative condition of the mouth, with a polygenic mode of inheritance in which cytokines are thought to play an important role. Ninety-one RAS patients and 91 controls were genotyped for known IL-1A, IL-1B, IL-1RN and IL-6 gene polymorphisms. Inheritance of the G allele of the IL-1B −511 polymorphism was strongly associated with RAS (OR = 2.5, P < 0.00002), with increased numbers of G/G homozygotes (OR = 4.5, P < 0.0005). The G allele of IL-6 −174 also occurred more frequently in RAS (OR = 2.6, P < 0.0001) with greatest risk associated with G/G homozygosity (OR = 3.4, P < 0.0001). IL-1RN VNTR 1/1 homozygotes also occurred more frequently in RAS (OR = 2.0, P < 0.02). Inheritance of the G/G genotype of both IL-1B and IL-6 was a particularly strong predictor for RAS (OR = 8.5).

Polymersome-Mediated Delivery of Combination Anticancer Therapy to Head and Neck Cancer Cells: 2D and 3D in Vitro Evaluation

Polymersomes have the potential to encapsulate and deliver chemotherapeutic drugs into tumor cells, reducing off-target toxicity that often compromises anticancer treatment. Here, we assess the ability of the pH-sensitive poly 2-(methacryloyloxy)ethyl phosphorylcholine (PMPC)- poly 2-(diisopropylamino)ethyl methacrylate (PDPA) polymersomes to encapsulate chemotherapeutic agents for effective combinational anticancer therapy. Polymersome uptake and ability to deliver encapsulated drugs into healthy normal oral cells and oral head and neck squamous cell carcinoma (HNSCC) cells was measured in two and three-dimensional culture systems. PMPC-PDPA polymersomes were more rapidly internalized by HNSCC cells compared to normal oral cells. Polymersome cellular uptake was found to be mediated by class B scavenger receptors. We also observed that these receptors are more highly expressed by cancer cells compared to normal oral cells, enabling polymersome-mediated targeting. Doxorubicin and paclitaxel were encapsulated into pH-sensitive PMPC-PDPA polymersomes with high efficiencies either in isolation or as a dual-load for both singular and combinational delivery. In monolayer culture, only a short exposure to drug-loaded polymersomes was required to elicit a strong cytotoxic effect. When delivered to three-dimensional tumor models, PMPC-PDPA polymersomes were able to penetrate deep into the center of the spheroid resulting in extensive cell damage when loaded with both singular and dual-loaded chemotherapeutics. PMPC-PDPA polymersomes offer a novel system for the effective delivery of chemotherapeutics for the treatment of HNSCC. Moreover, the preferential internalization of PMPC polymersomes by exploiting elevated scavenger receptor expression on cancer cells opens up the opportunity to target polymersomes to tumors.

Leucocyte Endothelial Cell Adhesion: a Study comparing Human Umbilical Vein Endothelial Cells and the Endothelial Cell Line EA‐hy‐926

EA‐hy‐926 is a cell line produced by hybridizing human umbilical vein endothelial cells (HUVEC) and the epithelial cell line A549. To establish whether EA‐hy‐926 could be used as a model for endothelial cells (EC) in leucocyte‐EC adhesion interactions, the effect of interleukin‐4 (IL‐4), tumour necrosis factor (TNF) or interferon‐γ (IFN) stimulation on their adhesiveness and expression of E‐selectin, vascular cell adhesion molecule‐1 (VCAM‐1) and intercellular adhesion molecule‐1 (ICAM‐1) was compared with that of HUVEC and A549. Although HUVEC exhibited increased adhesiveness and adhesion molecule expression with IL‐4, TNF or IFN, EA‐hy‐926 exhibited these responses only with TNF. CD11/CD 18‐dependent binding accounted for a significant component of basal binding to HUVEC and EA‐hy‐926, but did not account for the increased binding of T cells, JY, J6, ICH‐BJ or ICH‐KM cell lines to TNF‐stimulated monolayers. At least part of the CD1l/CD18‐independent adhesion was attributable to VCAM‐1 induction on HUVFC and FA‐hy‐926. TNF‐stimulation also induced F‐selectin expression on EA‐hy‐926 and HUVEC and an accompanying increase in neutrophil (PMN) binding. The EA‐hy‐926 cells used in this study, therefore, showed responses similar to HUVEC when stimulated with TNF but not when stimulated with IL‐4 or IFN.