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.

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.

Exploring the impact of digital professionalism awareness training on dental undergraduate students.

INTRODUCTION: Since the publication of GDC guidance, there have been small, but rising numbers of Fitness to Practise (FtP) cases made against qualified dentists, relating to the use of social media. Prior to graduation, dental students currently receive training in the appropriate use of social media, but more work is needed to determine the most effective methods do this. The aim of this study is to explore the impact of the digital professionalism awareness training provided at one UK-based institution. MATERIALS AND METHODS: In year 2, a "brown envelope" is compiled using an online publicly available Facebook profile search for every student. All year 2 to 5 dental undergraduate students at one UK dental school who had completed the "brown envelope" were invited to participate in focus groups to examine its impact on behaviour change. A qualitative framework analysis method was applied to the transcripts. RESULTS: Eleven dental undergraduate students participated in two focus groups. All students had experienced the "brown envelope" intervention. Four main themes emerged, including: a clear expression of dental student autonomy and rejection of regulation; that online activity in dentistry is different to medicine; that the intervention is useful and changed online behaviour; and constructive suggestions for improving training. CONCLUSION: The interactive "brown envelope" intervention for digital professionalism awareness training was well received and appeared to result in actionable behavioural change on student profiles (eg alterations in privacy settings or restricting access to their own "friends lists").

Litigation risks despite guideline adherence for acute spinal cord injury: time is spine.

OBJECTIVE: Current guidelines do not specify timing for management of acute spinal cord injury (aSCI) due to lack of high-quality evidence supporting specific intervals for intervention. Randomized prospective trials may be unethical. Nonetheless, physicians have been sued for delays in diagnosis and intervention. METHODS: The authors reviewed both the medical literature supporting the guidelines and the legal cases reported in the Westlaw and Lexis Advance databases from 1972 to 2018 resulting in awards or settlements, to identify whether surgeons are vulnerable to litigation despite the existence of guidelines not mandating specific timing of care. RESULTS: Timing of intervention was related to claims in 59 (36%) of 163 cases involving SCI. All 22 trauma cases identified cited timing of intervention, sometimes related to delayed diagnosis, as a reason for the lawsuit. The mean award of 10 cases in which the plaintiffs' awards were disclosed was $4,294,384. In the majority of cases, award amounts were not disclosed. CONCLUSIONS: Because conduct of a prospective, randomized trial to investigate surgical timing of intervention for aSCI may not be achievable, evidence-based guidelines will be unlikely to mandate specific timing. Nonetheless, surgeons who unreasonably delay intervention for aSCI may be at risk for litigation due to treatment delay. This is increasingly likely in an environment where "complete" SCI is difficult to verify. SCI may at some point be recognized as a surgical emergency, as brain injury generally is, despite a lack of prospective randomized trials supporting this implementation, challenging the feasibility of the US trauma infrastructure to provide care for these patients.

Management of hypertonia in cerebral palsy.

PURPOSE OF REVIEW: The review provides an update on the treatment of hypertonia in cerebral palsy, including physical management, pharmacotherapy, neurosurgical, and orthopedic procedures. RECENT FINDINGS: Serial casting potentiates the effect of Botulinum neurotoxin A injections for spasticity. Deep brain stimulation, intraventricular baclofen, and ventral and dorsal rhizotomy are emerging tools for the treatment of dystonia and/or mixed tone. The long-term results of selective dorsal rhizotomy and the timing of orthopedic surgery represent recent advances in the surgical management of hypertonia. SUMMARY: Management of hypertonia in cerebral palsy targets the functional goals of the patient and caregiver. Treatment options are conceptualized as surgical or nonsurgical, focal or generalized, and reversible or irreversible. The role of pharmacologic therapies is to improve function and mitigate adverse effects. Further investigation, including clinical trials, is required to determine the role of deep brain stimulation, intraventricular baclofen, orthopedic procedures for dystonia, and rhizotomy.

Safety of botulinum toxin injections in children less than one year old: A retrospective chart review.

PURPOSE: Infants can have muscle hypertonia due to cerebral palsy, muscle strength imbalances due to brachial plexus palsy, refractory clubfoot, and torticollis. These muscle problems can cause significant development impairments. A child with severe sialorrhea and dysphagia from leukodystrophy can aspirate, causing respiratory problems. Botulinum toxin (BoNT) injections can improve these conditions but may lead to adverse effects from the toxin spreading to non-targeted muscles, potentially impacting breathing, swallowing, and overall strength. This is particularly concerning in infants. This study assessed the safety of BoNT injections in children less than one year of age. METHODS: This was a retrospective cohort study. RESULTS: Forty-seven patients (22 male, 25 female) received BoNT injections before one year of age (three to 12 months). Thirty-seven received one round of injections and 10 were injected on multiple occasions. Forty-five received onabotulinumtoxinA (15-100 units [U], 1.9-15.2 U/kg), one received abobotulinumtoxinA (70 U, 9.0 U/kg), and one received incobotulinumtoxinA (25 U, 3.5 U/kg). Lower extremities were treated in 15 patients, upper extremities in 38, the sternocleidomastoid in two, and the salivary glands in one. Forty-five patients had no reported complications. One experienced transient fever, vomiting, and diarrhea. The parent of another reported subjective weakness in one muscle. CONCLUSION: BoNT injections in children less than one year of age appear to be safe.

An evaluation of oral surgery referrals to aid development of an integrated service in South West England.

Introduction The number of oral surgery referrals from primary to secondary care has increased, resulting in longer waiting times. A study suggests two-thirds of patients referred to secondary care for oral surgery could be treated by dentists with enhanced skills.Aims To help inform the development of an integrated oral surgery service in South West England by assessing the proportion of inappropriate referrals to Bristol Dental Hospital.Methods A total of 100 non-consecutive written referrals to oral surgery were analysed. Multiple variables were collected, including the complexity of the treatment requested (Level 1, 2 or 3) and patient and referrer locations.Results In total, 94 referrals were included in the analysis: 17% were Level 1 complexity, 35% Level 2, and 48% Level 3. Additionally, 17% of referrals were inappropriate. Almost half (52%) (Levels 1 and 2) could have been treated in primary care. Many referrals had missing clinical details or unacceptable-quality radiographs.Conclusion An effective integrated oral surgery managed clinical network in South West England could reduce waiting times in secondary care and potentially improve patient experience. An electronic referral management system could also improve the quality of referral information.

Contemporary dental student professionalism: moving towards a macro-level perspective.

Defining professionalism and developing educational interventions that foster and assess student professionalism are integral to dental education. Nevertheless, conceptual, methodological and pedagogic differences define the academic field, leaving students, educators and the profession itself struggling to make meaningful progress on how best to elicit and monitor dental student professionalism. This article proposes that more progress can be made on this important issue when a contextualised, sociological assessment of dentistry and dental professionalism is undertaken. We contend that identifying some of the socio-cultural demands in UK dental students' lives, and acknowledging how these pressures shape their interactions with the UK dental education system, provides a nuanced and contemporaneous understanding of what it means to be an oral health care professional at a time of social and health care upheaval. Dental educators can use this insight to work towards being more understanding of and responsive to dental student professional development.

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.

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.

Case series of medication-related osteonecrosis of the jaw (MRONJ) patients prescribed a drug holiday.

The role of a drug holiday in the management of medication-related osteonecrosis of the jaw (MRONJ) remains controversial. Current UK guidance does not recommend this practice given the lack of conclusive evidence, and potential risk of skeletal-related events or cancer metastasis. This paper aims to describe a series of fifty patients with confirmed MRONJ who were prescribed a drug holiday as part of their management. Data were collected on exposures including: anti-resorptive and/or anti-angiogenic drug history, duration of drug, method of administration, concurrent therapy, MRONJ stage, management of MRONJ and duration of drug holiday. The primary outcome was complete healing as documented in the clinical notes. Multivariate Cox regression analysis was performed to evaluate the association between exposures and primary MRONJ outcome. Models were adjusted for age, sex, and index of multiple deprivation. Survival analysis was performed using a log-rank test, censoring any patients with no primary outcome recorded (p < 0.05). A total of 44% of patients stopped their medication for >36 months. Over half of all MRONJ cases presented in the posterior mandible and dental extraction was the most common precipitating factor (76%). Almost three-quarters (72%) of patients achieved complete healing. MRONJ recurrence (new site) was reported at 30%, mainly in those with incomplete healing of the initial area. There was a lack of evidence for an association between all recorded exposures and the primary MRONJ outcome using multivariate Cox regression. Similarly, we did not demonstrate evidence for an association between the duration of the drug holiday and MRONJ outcome. Our results support published guidelines, which do not recommend the discontinuation of bone modifying drugs for the prevention of MRONJ, or as part of treatment for established MRONJ.

Treatment of pediatric spasticity, including children with cerebral palsy, with Botox (onabotulinumtoxinA): Development, insights, and impact.

Spasticity is a velocity-dependent increase in muscle tone that has a negative effect on quality of life and hinders the ability of others to provide care. In children, most cases are caused by cerebral palsy. Traditionally, many children are treated with surgery, sometimes performed before their limbs had grown sufficiently to permit long-term success. Nonsurgical treatment comprises oral pharmacological options, but their efficacy is limited and side effects such as drowsiness and decreased short-term memory are common; nerve block procedures can cause painful dysesthesias and muscle scarring. OnabotulinumtoxinA was first approved for the treatment of pediatric lower limb spasticity in Europe in the 1990s and is now licensed for use in pediatric patients in over 80 countries worldwide, based on a large body of clinical evidence demonstrating its efficacy and safety. In 2019 the U.S. Food and Drug Administration approved onabotulinumtoxinA for the treatment of pediatric patients with upper or lower limb spasticity. This approval represents 3 decades of work to refine the dose, measurements, patient selection, and muscle selection. The availability of onabotulinumtoxinA as a treatment for pediatric spasticity can have a substantial impact on a patient's quality of life. The use of onabotulinumtoxinA in combination with orthoses and occupational/physical therapy can postpone corrective surgery until growth is nearly complete and minimize the number of corrective surgeries.

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.

Acquired amputations in patients with spina bifida.

PURPOSE: The purpose of this study was to assess if the incidence of lower extremity (LE) pressure injuries resulting in amputations was more frequent in ambulatory versus non-ambulatory patients with spina bifida. METHODS: The medical records of all patients at a large pediatric rehabilitation hospital who had spina bifida and a history of a pressure injury between 1997-2018 were retrospectively reviewed. RESULTS: In this study, 112 patients with spina bifida developed LE pressure injuries, 53 patients walked with braces and/or an assistive device, and 59 patients used a wheelchair for mobility. Of the 11 patients who had amputations, 10 walked and 1 did not walk prior to their amputation. Ambulatory patients with LE pressure injuries had a 19% chance (10 out of 53 patients) of requiring an amputation. Non-ambulatory patients with a LE pressure injury had only a 2% chance (1 out of 59 patients) of requiring an amputation. Ambulatory patients with LE pressure injuries were at a much higher risk of requiring an amputation than patients who did not walk (p-value of < 0.005). CONCLUSION: Patients with spina bifida who are ambulatory and develop a pressure injury have a high risk of ultimately needing an amputation and should be monitored and treated aggressively.

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.

Reviewing the epidemiology of head and neck cancer: definitions, trends and risk factors.

Introduction Head and neck cancer appears to be increasing in incidence, with potential changes in aetiology proposed. This paper aims to provide a narrative overview of the epidemiological literature to describe the disease burden and trends in terms of incidence and mortality both in the UK and globally and to review the evidence on current risk factors.Methods A search was performed on multiple databases (PubMed and Epistemonikos), applying filters to identify systematic reviews and meta-analyses which investigated head and neck cancer incidence, mortality and risk factors. International and UK cancer registries and sources were searched for incidence and mortality data.Results Multiple definitions of head and neck cancer are employed in epidemiology. Globally, incidence rates have increased in recent decades, largely driven by oropharyngeal cancer. Mortality rates over the last decade have also started to rise, reflecting the disease incidence and static survival rates. Major risk factors include tobacco smoking alone and in combination with alcohol consumption, betel chewing (particularly in Southeast Asian populations) and the human papillomavirus in oropharyngeal cancer.Conclusions These epidemiological data can inform clinical and preventive service planning for head and neck cancer.