Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study.

Head and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, is a cause of substantial global morbidity and mortality. Strategies to reduce disease burden include discovery of novel therapies and repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibiting HMG-CoA reductase (HMGCR). Results from some observational studies suggest that statin use may reduce HNSCC risk. We appraised the relationship of genetically-proxied cholesterol-lowering drug targets and other circulating lipid traits with oral (OC) and oropharyngeal (OPC) cancer risk using two-sample Mendelian randomization (MR). For the primary analysis, germline genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR were used to proxy the effect of low-density lipoprotein cholesterol (LDL-C) lowering therapies. In secondary analyses, variants were used to proxy circulating levels of other lipid traits in a genome-wide association study (GWAS) meta-analysis of 188,578 individuals. Both primary and secondary analyses aimed to estimate the downstream causal effect of cholesterol lowering therapies on OC and OPC risk. The second sample for MR was taken from a GWAS of 6,034 OC and OPC cases and 6,585 controls (GAME-ON). Analyses were replicated in UK Biobank, using 839 OC and OPC cases and 372,016 controls and the results of the GAME-ON and UK Biobank analyses combined in a fixed-effects meta-analysis. We found limited evidence of a causal effect of genetically-proxied LDL-C lowering using HMGCR, NPC1L1, CETP or other circulating lipid traits on either OC or OPC risk. Genetically-proxied PCSK9 inhibition equivalent to a 1 mmol/L (38.7 mg/dL) reduction in LDL-C was associated with an increased risk of OC and OPC combined (OR 1.8 95%CI 1.2, 2.8, p = 9.31 x10-05), with good concordance between GAME-ON and UK Biobank (I2 = 22%). Effects for PCSK9 appeared stronger in relation to OPC (OR 2.6 95%CI 1.4, 4.9) than OC (OR 1.4 95%CI 0.8, 2.4). LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of OC and OPC combined (OR 0.7, 95%CI 0.5, 1.0, p = 0.006). A series of pleiotropy-robust and outlier detection methods showed that pleiotropy did not bias our findings. We found limited evidence for a role of cholesterol-lowering in OC and OPC risk, suggesting previous observational results may have been confounded. There was some evidence that genetically-proxied inhibition of PCSK9 increased risk, while lipid-lowering variants in LDLR, reduced risk of combined OC and OPC. This result suggests that the mechanisms of action of PCSK9 on OC and OPC risk may be independent of its cholesterol lowering effects; however, this was not supported uniformly across all sensitivity analyses and further replication of this finding is required.

A risk prediction model for head and neck cancers incorporating lifestyle factors, HPV serology and genetic markers.

Head and neck cancer is often diagnosed late and prognosis for most head and neck cancer patients remains poor. To aid early detection, we developed a risk prediction model based on demographic and lifestyle risk factors, human papillomavirus (HPV) serological markers and genetic markers. A total of 10 126 head and neck cancer cases and 5254 controls from five North American and European studies were included. HPV serostatus was determined by antibodies for HPV16 early oncoproteins (E6, E7) and regulatory early proteins (E1, E2, E4). The data were split into a training set (70%) for model development and a hold-out testing set (30%) for model performance evaluation, including discriminative ability and calibration. The risk models including demographic, lifestyle risk factors and polygenic risk score showed a reasonable predictive accuracy for head and neck cancer overall. A risk model that also included HPV serology showed substantially improved predictive accuracy for oropharyngeal cancer (AUC = 0.94, 95% CI = 0.92-0.95 in men and AUC = 0.92, 95% CI = 0.88-0.95 in women). The 5-year absolute risk estimates showed distinct trajectories by risk factor profiles. Based on the UK Biobank cohort, the risks of developing oropharyngeal cancer among 60 years old and HPV16 seropositive in the next 5 years ranged from 5.8% to 14.9% with an average of 8.1% for men, 1.3% to 4.4% with an average of 2.2% for women. Absolute risk was generally higher among individuals with heavy smoking, heavy drinking, HPV seropositivity and those with higher polygenic risk score. These risk models may be helpful for identifying people at high risk of developing head and neck cancer.

Genome-wide Association Study for Vitamin D Levels Reveals 69 Independent Loci.

We aimed to increase our understanding of the genetic determinants of vitamin D levels by undertaking a large-scale genome-wide association study (GWAS) of serum 25 hydroxyvitamin D (25OHD). To do so, we used imputed genotypes from 401,460 white British UK Biobank participants with available 25OHD levels, retaining single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) > 0.1% and imputation quality score > 0.3. We performed a linear mixed model GWAS on standardized log-transformed 25OHD, adjusting for age, sex, season of measurement, and vitamin D supplementation. These results were combined with those from a previous GWAS including 42,274 Europeans. In silico functional follow-up of the GWAS results was undertaken to identify enrichment in gene sets, pathways, and expression in tissues, and to investigate the partitioned heritability of 25OHD and its shared heritability with other traits. Using this approach, the SNP heritability of 25OHD was estimated to 16.1%. 138 conditionally independent SNPs were detected (p value < 6.6 × 10-9) among which 53 had MAF < 5%. Single variant association signals mapped to 69 distinct loci, among which 63 were previously unreported. We identified enrichment in hepatic and lipid metabolism gene pathways and enriched expression of the 25OHD genes in liver, skin, and gastrointestinal tissues. We observed partially shared heritability between 25OHD and socio-economic traits, a feature which may be mediated through time spent outdoors. Therefore, through a large 25OHD GWAS, we identified 63 loci that underline the contribution of genes outside the vitamin D canonical metabolic pathway to the genetic architecture of 25OHD.

Are childhood oral health behaviours and experiences associated with dental anxiety in adolescence?

BACKGROUND: Dental anxiety is associated with untreated dental caries. Understanding which childhood behaviours or experiences have the strongest association with later dental anxiety may help focus preventive strategies, subsequently limiting the burden of dental caries and anxiety. AIM: The aim of this study was to explore whether behaviours and experiences during childhood were associated with adolescent dental anxiety. DESIGN: Data were obtained from the Avon Longitudinal Study of Parents and Children (ALSPAC). Multivariable logistic regression was used to explore associations between adolescent dental anxiety and childhood behaviours and experiences. 1791 participants answered questions about oral health behaviours and experiences at 8 years of age and dental anxiety questions aged 17 years. RESULTS: Children with experience of invasive dental treatment were more likely to have dental anxiety at 17 years of age than those who had not experienced dental treatment (OR 1.63; 95% CI: 1.12, 2.37; p = .011). Irregular dental attenders in childhood had over three times the odds of dental anxiety by adolescence, compared with regular attenders (OR 3.67 95% CI: 1.52, 8.88; p = .004). CONCLUSIONS: Adolescent dental anxiety is associated with invasive treatment and irregular dental attendance in childhood. A history of irregular attendance or invasive treatment may serve as a useful predictor when considering dental anxiety in young adult patients. Early preventive care supports good attendance and oral health. These actions may have secondary effects of reducing future dental anxiety.

Investigating the effect of sexual behaviour on oropharyngeal cancer risk: a methodological assessment of Mendelian randomization.

BACKGROUND: Human papilloma virus infection is known to influence oropharyngeal cancer (OPC) risk, likely via sexual transmission. However, sexual behaviour has been correlated with other risk factors including smoking and alcohol, meaning independent effects are difficult to establish. We aimed to evaluate the causal effect of sexual behaviour on the risk of OPC using Mendelian randomization (MR). METHODS: Genetic variants robustly associated with age at first sex (AFS) and the number of sexual partners (NSP) were used to perform both univariable and multivariable MR analyses with summary data on 2641 OPC cases and 6585 controls, obtained from the largest available genome-wide association studies (GWAS). Given the potential for genetic pleiotropy, we performed a number of sensitivity analyses: (i) MR methods to account for horizontal pleiotropy, (ii) MR of sexual behaviours on positive (cervical cancer and seropositivity for Chlamydia trachomatis) and negative control outcomes (lung and oral cancer), (iii) Causal Analysis Using Summary Effect estimates (CAUSE), to account for correlated and uncorrelated horizontal pleiotropic effects, (iv) multivariable MR analysis to account for the effects of smoking, alcohol, risk tolerance and educational attainment. RESULTS: In univariable MR, we found evidence supportive of an effect of both later AFS (IVW OR = 0.4, 95%CI (0.3, 0.7), per standard deviation (SD), p = < 0.001) and increasing NSP (IVW OR = 2.2, 95%CI (1.3, 3.8) per SD, p = < 0.001) on OPC risk. These effects were largely robust to sensitivity analyses accounting for horizontal pleiotropy. However, negative control analysis suggested potential violation of the core MR assumptions and subsequent CAUSE analysis implicated pleiotropy of the genetic instruments used to proxy sexual behaviours. Finally, there was some attenuation of the univariable MR results in the multivariable models (AFS IVW OR = 0.7, 95%CI (0.4, 1.2), p = 0.21; NSP IVW OR = 0.9, 95%CI (0.5 1.7), p = 0.76). CONCLUSIONS: Despite using genetic variants strongly related sexual behaviour traits in large-scale GWAS, we found evidence for correlated pleiotropy. This emphasizes a need for multivariable approaches and the triangulation of evidence when performing MR of complex behavioural traits.

Survival advantage in patients with human papillomavirus-driven oropharyngeal cancer and variation by demographic characteristics and serologic response: Findings from Head and Neck 5000.

BACKGROUND: Patients with human papillomavirus (HPV)-driven oropharyngeal cancer (OPC) experience better survival than those with HPV-negative OPC. It is unclear whether this benefit varies by demographic characteristics and serologic response. METHODS: Records from 1411 patients with OPC who had HPV serology data were analyzed. HPV status was based on HPV type 16 (HPV16) E6 serology. Participants were followed for a median of 5.9 years, and Cox proportional hazards models were used to estimate hazard ratios (HRs). The association between HPV status and overall survival was analyzed by age group, sex, smoking status, tumor site, HPV antibody levels, and HPV antibody pattern. Models were adjusted for age, sex, smoking status, and comorbidity. RESULTS: For the overall association between HPV status and survival, the fully adjusted HR was 0.43 (95% CI, 0.33-0.56). The HR was 0.19 (95% CI, 0.10-0.35) for participants aged ≤54 years, 0.38 (95% CI, 0.25-0.56) for those aged 55 to 64 years, and 0.73 (95% CI, 0.47-1.13) for those aged ≥65 years (P for interaction = .023). There was no clear evidence for an interaction by sex, smoking status, or tumor site. Survival did not differ according to E6 antibody levels in those who were seropositive. All seropositivity patterns were associated with increased survival compared with a pattern of seronegativity for all antibodies. Patients who are positive for E1, E2, E6, and E7 may experience better survival. CONCLUSIONS: HPV status confers a survival advantage across all groups. This survival advantage is more marked for younger patients. The HPV antibody pattern, but not the antibody level, may also affect survival.

Consortium-based genome-wide meta-analysis for childhood dental caries traits.

Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5-18.0 years from nine contributing centres. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage and the results were combined using fixed-effects meta-analysis. Analysis included up to 19 003 individuals (7530 affected) for primary teeth and 13 353 individuals (5875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth [intronic within ALLC, odds ratio (OR) 0.85, effect allele frequency (EAF) 0.60, P 4.13e-8] and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, P 1.63e-8) for permanent teeth. Consortium-wide estimated heritability of caries was low [h2 of 1% (95% CI: 0%: 7%) and 6% (95% CI 0%: 13%) for primary and permanent dentitions, respectively] compared with corresponding within-study estimates [h2 of 28% (95% CI: 9%: 48%) and 17% (95% CI: 2%: 31%)] or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure.

Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis.

Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10-88). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10-12). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10-5) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.

Assessing the causal association between 25-hydroxyvitamin D and the risk of oral and oropharyngeal cancer using Mendelian randomization.

Circulating 25-hydroxyvitamin D (25OHD) is an appealing potential intervention for cancer risk and has been associated with oral and oropharyngeal cancer risk but evidence is inconsistent. The availability of genetic variants, uncorrelated with known confounders, but predictive of 25OHD and genetic data in a large oral and oropharyngeal cancer collaboration aids causal inference when assessing this association. A total of 5,133 oral and oropharyngeal cancer cases and 5,984 controls with genetic data were included in the study. Participants were based in Europe, North America and South America and were part of the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network. Five genetic variants reliably associated with circulating 25OHD were used to create a relative genetic measure of 25OHD. In the absence of measured 25OHD, two-sample Mendelian randomization using individual level outcome data were used to estimate causal odds ratios (OR) for cancer case status per standard deviation increase in log25OHD. Analyses were replicated in an independent population-based cohort (UK Biobank). In the GAME-ON study, there was little evidence of a causal association between circulating 25OHD and oral cancer (OR = 0.86 [0.68;1.09], p = 0.22), oropharyngeal cancer (OR = 1.28 [0.72;2.26], p = 0.40) or when sites were combined (OR = 1.01 [0.74;1.40], p = 0.93). Replication in UK Biobank and pooled estimates produced similar results. Our study suggests that a clinically relevant protective effect of 25OHD on oral and oropharyngeal cancer risk is unlikely and supplementation of the general population with 25OHD is unlikely to be beneficial in preventing these cancers.

Microbiological assessment of aerosol generated during debond of fixed orthodontic appliances.

INTRODUCTION: The aims of this study were to describe bacterial load and diversity of the aerosol created during enamel cleanup after the removal of fixed orthodontic appliances and to assess the effect of a preprocedural mouth rinse. METHODS: The study involved the sampling of ambient air adjacent to the patient's mouth during adhesive removal using a slow-speed handpiece and a spiral fluted tungsten carbide bur without water irrigation. Sampling was carried out during enamel cleanup with or without a preprocedural mouth rinse of either sterile water or chlorhexidine. Airborne particles were collected using a viable inertial impactor simulating the human respiratory tree. The bacteria collected were analyzed using both culture and molecular techniques. RESULTS: Bacteria produced during debond and enamel cleanup can reach all levels of the respiratory tree. The use of a preprocedural mouth rinse, either sterile water or chlorhexidine, increased the numbers and diversity of the bacteria in the air. CONCLUSIONS: When using a slow-speed handpiece and a spiral fluted tungsten carbide bur for enamel cleanup after orthodontic treatment, the bacterial load and diversity of the aerosol produced are lower when a preprocedural mouth rinse is not used.

Development and external validation of a head and neck cancer risk prediction model.

BACKGROUND: Head and neck cancer (HNC) incidence is on the rise, often diagnosed at late stage and associated with poor prognoses. Risk prediction tools have a potential role in prevention and early detection. METHODS: The IARC-ARCAGE European case-control study was used as the model development dataset. A clinical HNC risk prediction model using behavioral and demographic predictors was developed via multivariable logistic regression analyses. The model was then externally validated in the UK Biobank cohort. Model performance was tested using discrimination and calibration metrics. RESULTS: 1926 HNC cases and 2043 controls were used for the development of the model. The development dataset model including sociodemographic, smoking, and alcohol variables had moderate discrimination, with an area under curve (AUC) value of 0.75 (95% CI, 0.74-0.77); the calibration slope (0.75) and tests were suggestive of good calibration. 384 616 UK Biobank participants (with 1177 HNC cases) were available for external validation of the model. Upon external validation, the model had an AUC of 0.62 (95% CI, 0.61-0.64). CONCLUSION: We developed and externally validated a HNC risk prediction model using the ARCAGE and UK Biobank studies, respectively. This model had moderate performance in the development population and acceptable performance in the validation dataset. Demographics and risk behaviors are strong predictors of HNC, and this model may be a helpful tool in primary dental care settings to promote prevention and determine recall intervals for dental examination. Future addition of HPV serology or genetic factors could further enhance individual risk prediction.

Poor oral health influences head and neck cancer patient survival: an International Head and Neck Cancer Epidemiology Consortium pooled analysis.

BACKGROUND: Poor oral health has been identified as a prognostic factor potentially affecting the survival of patients with head and neck squamous cell carcinoma. However, evidence to date supporting this association has emanated from studies based on single cohorts with small-to-modest sample sizes. METHODS: Pooled analysis of 2449 head and neck squamous cell carcinoma participants from 4 studies of the International Head and Neck Cancer Epidemiology Consortium included data on periodontal disease, tooth brushing frequency, mouthwash use, numbers of natural teeth, and dental visits over the 10 years prior to diagnosis. Multivariable generalized linear regression models were used and adjusted for age, sex, race, geographic region, tumor site, tumor-node-metastasis stage, treatment modality, education, and smoking to estimate risk ratios (RR) of associations between measures of oral health and overall survival. RESULTS: Remaining natural teeth (10-19 teeth: RR = 0.81, 95% confidence interval [CI] = 0.69 to 0.95; ≥20 teeth: RR = 0.88, 95% CI = 0.78 to 0.99) and frequent dental visits (>5 visits: RR = 0.77, 95% CI = 0.66 to 0.91) were associated with better overall survival. The inverse association with natural teeth was most pronounced among patients with hypopharyngeal and/or laryngeal, and not otherwise specified head and neck squamous cell carcinoma. The association with dental visits was most pronounced among patients with oropharyngeal head and neck squamous cell carcinoma. Patient-reported gingival bleeding, tooth brushing, and report of ever use of mouthwash were not associated with overall survival. CONCLUSIONS: Good oral health as defined by maintenance of the natural dentition and frequent dental visits appears to be associated with improved overall survival among head and neck squamous cell carcinoma patients.

Smoking and alcohol by HPV status in head and neck cancer: a Mendelian randomization study.

HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are recognized as distinct entities. There remains uncertainty surrounding the causal effects of smoking and alcohol on the development of these two cancer types. Here we perform multivariable Mendelian randomization (MR) to evaluate the causal effects of smoking and alcohol on the risk of HPV-positive and HPV-negative HNSCC in 3431 cases and 3469 controls. Lifetime smoking exposure, as measured by the Comprehensive Smoking Index (CSI), is associated with increased risk of both HPV-negative HNSCC (OR = 3.03, 95%CI:1.75-5.24, P = 7.00E-05) and HPV-positive HNSCC (OR = 2.73, 95%CI:1.39-5.36, P = 0.003). Drinks Per Week is also linked with increased risk of both HPV-negative HNSCC (OR = 7.72, 95%CI:3.63-16.4, P = 1.00E-07) and HPV-positive HNSCC (OR = 2.66, 95%CI:1.06-6.68, P = 0.038). Smoking and alcohol independently increase the risk of both HPV-positive and HPV-negative HNSCC. These findings have important implications for understanding the modifying risk factors between HNSCC subtypes.

An introduction to the UK care pathway for children born with a cleft of the lip and/or palate.

Cleft lip and/or palate includes a spectrum of congenital disorders affecting union on the lip, alveolus, hard and/or soft palate. The management of children born with an orofacial cleft requires a complex process from a multidisciplinary team (MDT) to restore form and function. Since the Clinical Standards Advisory Group (CSAG) report in 1998, the UK has reformed and restructured cleft services to improve the outcomes for children born with a cleft.The spectrum of cleft conditions, the members of the MDT and a chronological description of the stages of cleft management from diagnosis to adulthood are described using a clinical example. This paper forms the introduction to a series of more detailed papers which span all major aspects of cleft management. The papers will cover the following topics: dental anomalies; associated medical conditions among children; orthodontic management of patients; speech assessment and intervention; role of the clinical psychologist; challenges for the paediatric dentist; genetics and orofacial clefts; surgery - primary and secondary; restorative dentistry; and global perspectives.

Long-term treatment outcomes with zygomatic implants: a systematic review and meta-analysis.

PURPOSE: The purpose of this study was to perform a systematic review with meta-analysis on the long-term survival rates of zygomatic implants (ZI). ZI success, prostheses survival and success, sinus pathology and patient reported outcomes were also investigated. METHODS: Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines were followed. Embase and OvidMedline databases were searched alongside the grey literature. The systematic review was recorded in PROSPERO (CRD42022358024). Studies reporting titanium/titanium alloy ZI survival data, ZI-supported prosthesis data, ZIs directly compared to any other implant therapy including grafted sites, a minimum follow-up time of 3 years and a minimum number of 10 patients were included. All study designs were considered if they met the inclusion criteria. Studies not involving ZIs, ZIs not made from titanium/titanium alloy, a follow-up time of < 3 years or < 10 patients, animal studies and in vitro studies were excluded. Long-term follow-up has not been defined in the literature. A minimum of 3 years follow-up was considered acceptable to capture survival after initial healing, alongside in-function prosthesis data via delayed or immediate load protocols. ZI success, was predominantly defined as ZI survival without biological or neurological complications. Meta-analyses were performed for ZI survival, ZI failure incidence, ZI success, loading protocol, prosthesis survival, and prevalence of sinusitis using random effects models. Descriptive analysis was used for ZI success, prosthesis success and patient reported outcome measures. RESULTS: Five hundred and seventy-four titles were identified, of which 18 met the inclusion criteria. Eligible studies included 1349 ZIs in 623 patients. Mean follow-up period was 75.4 months (range 36-141.6). The mean survival of ZIs was 96.2% [95% CI: 93.8; 97.7] at 6 years. Mean survival for delayed loading was 95% [95% CI: 91.7; 97.1] and 98.1% [95% CI: 96.2; 99.0] for immediate loading (p = 0.03). Annual incidence rate of ZI failure was 0.7% [95% CI 0.4; 1.0]. Mean ZI success was 95.7% [95% CI 87.8; 98.6]. Mean prosthesis survival was 94% [95% CI 88.6; 96.9]. Sinusitis prevalence was 14.2% [95% CI 8.8; 22.0] at 5 years. Patients' reported increased satisfaction with ZIs. CONCLUSIONS: ZIs have long-term survival comparable to conventional implants. Immediate loading showed a statistically significant increase in survival over delayed loading. Prosthesis survival was similar to that of prostheses supported by conventional implants, with similar complications. Sinusitis was the most frequently encountered biological complication. Patients reported improved outcome measures with ZI use.

Evaluating the effect of metabolic traits on oral and oropharyngeal cancer risk using Mendelian randomization.

A recent World Health Organization report states that at least 40% of all cancer cases may be preventable, with smoking, alcohol consumption, and obesity identified as three of the most important modifiable lifestyle factors. Given the significant decline in smoking rates, particularly within developed countries, other potentially modifiable risk factors for head and neck cancer warrant investigation. Obesity and related metabolic disorders such as type 2 diabetes (T2D) and hypertension have been associated with head and neck cancer risk in multiple observational studies. However, adiposity has also been correlated with smoking, with bias, confounding or reverse causality possibly explaining these findings. To overcome the challenges of observational studies, we conducted two-sample Mendelian randomization (inverse variance weighted [IVW] method) using genetic variants which were robustly associated with adiposity, glycaemic and blood pressure traits in genome-wide association studies (GWAS). Outcome data were taken from the largest available GWAS of 6034 oral and oropharyngeal cases, with 6585 controls. We found limited evidence of a causal effect of genetically proxied body mass index (BMI; OR IVW = 0.89, 95% CI 0.72-1.09, p = 0.26 per 1 standard deviation in BMI [4.81kg/m2]) on oral and oropharyngeal cancer risk. Similarly, there was limited evidence for related traits including T2D and hypertension. Small effects cannot be excluded given the lack of power to detect them in currently available GWAS.

Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types.

BACKGROUND: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity across 4 cancer types (prostate, head and neck, breast, and lung). METHODS: A genome-wide association study meta-analysis was performed using 19 cohorts totaling 12 042 patients. Acute standardized total average toxicity (STATacute) was modelled using a generalized linear regression model for additive effect of genetic variants, adjusted for demographic and clinical covariates (rSTATacute). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV-formerly SNP)-based heritability of rSTATacute in all patients and for each cancer type. RESULTS: Shared SNV-based heritability of STATacute among all cancer types was estimated at 10% (SE = 0.02) and was higher for prostate (17%, SE = 0.07), head and neck (27%, SE = 0.09), and breast (16%, SE = 0.09) cancers. We identified 130 suggestive associated SNVs with rSTATacute (5.0 × 10‒8 < P < 1.0 × 10‒5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size ‒0.17; P = 1.7 × 10‒7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified 'RNA splicing via endonucleolytic cleavage and ligation' (P = 5.1 × 10‒6, P = .079 corrected) as the top gene set associated with rSTATacute among all patients. In silico gene expression analysis showed that the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed P = .004 corrected; sun exposed P = .026 corrected). CONCLUSIONS: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future meta-genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.

An observational analysis of risk factors associated with symptomatic third molar teeth.

BACKGROUND: Third molar teeth (wisdom teeth) are a common cause of pain and infection in young adults. The study aimed to describe the prevalence of symptomatic third molar teeth and identify factors which predispose to third molar symptoms in a birth cohort. METHODS: An observational study was undertaken nested in the Avon Longitudinal Study of Parents and Children (ALSPAC), a birth cohort based in south west England. The main outcomes were self-reported third molar pain, swelling and treatment for third molar problems, taken from questionnaires completed at age 23 years. The exposures including sex, dental history, socioeconomic status, diet, and genetic factors were obtained from earlier ALSPAC data. RESULTS: In total 4,222 ALSPAC participants responded to one or more questions about third molar teeth. The final sample included more female participants than male participants. The majority of participants (56.6%) reported at least one episode of pain associated with their third molars. Females had greater odds than males of reporting swelling (adjusted odds ratio (OR) 1.97; 95%confidence interval (CI) 1.56, 2.51), pain (adjusted OR=1.96; 95%CI 1.56, 2.51) and receiving both non-surgical and surgical treatment (adjusted OR=2.30; 95%CI 1.62, 3.35, adjusted OR=1.54; 95%CI 1.17, 2.06 respectively). Participants with previously filled teeth had greater odds of third molar extraction. There were no strong associations between index of multiple deprivation (IMD) score or sugar intake and the third molar outcomes. There was weak evidence for a genetic contribution to third molar pain. CONCLUSIONS: Symptomatic third molars are common in this age group, with over half of the participants reporting pain or other symptoms. Female participants had greater odds for third molar pain, swelling and treatment.

Did the March 2020 lockdown cause an increase in patients presenting to the emergency department with odontogenic pain and infection? A single centre, retrospective analysis.

On the 25 March 2020 the Chief Dental Officer (CDO) published guidance to restrict the provision of routine dental care in England due to the rapid spread of the severe acute respiratory syndrome Coronavirus 2 (COVID-19). We analysed the impact of the pandemic on the number of patients presenting with odontogenic pain and infection to the emergency department (ED) of an urban-based teaching hospital, the Bristol Royal Infirmary (BRI). Furthermore, we investigated the severity of infection at first presentation to the ED. The study period encompassed three phases that represented the stages of pandemic restrictions: phase 1 prior to lockdown measures, with no restrictions to dental practice; phase 2 during the government lockdown, with the severest restrictions on dental practices; and phase 3 following the ease of lockdown measures, with return to limited dental services. Data were collected retrospectively from electronic patient records (EPR) regarding adult patients presenting to the ED with dental pain. The rate of presentations (per week) was calculated for each timepoint and compared. A severity score was assigned to each patient using a grading system based on signs of clinical infection and treatment modality. Patients' presentations were analysed at each phase of the pandemic. There was a 42.8% increase in attendance with oral facial pain and infection to ED from phases 1 to 3. The COVID-19 pandemic resulted in restrictions to routine primary dental care services, which were deemed necessary to reduce the spread of the virus. However, this increased demand on secondary care services, as patients increasingly struggled to access primary dental care to manage dental pain.