Background Barth syndrome is a rare, life-threatening X-linked recessive mitochondrial disorder of lipid metabolism primarily affecting males. Previous research suggests that bezafibrate may ameliorate cellular lipid abnormalities and reduce cardiac dysfunction in an animal model. Objectives Estimate the effect of bezafibrate on clinical, biochemical, and quality-of-life outcomes. Investigate whether within-participant clinical changes parallel in vitro changes in cardiolipin ratio/profile and mitochondrial morphology when each participant’s cells are cultured with bezafibrate. Investigate as for objective 2, culturing each participant’s cells with resveratrol. Describe the most feasible methods and standardised outcome measures to optimise the conduct of future trials and evaluations in Barth syndrome. Describe features of the research infrastructure which optimised recruitment, retention and communication with families and people with Barth syndrome. Describe the perceptions of participants and their families about the research and any important potential barriers to participation. Design Randomised, placebo-controlled, crossover trial of bezafibrate versus placebo. Setting NHS hospital providing UK-wide Barth Syndrome Service. Participants Males aged ≥ 6 years with a confirmed diagnosis of Barth syndrome with stable cardiac status, able to swallow tablets of bezafibrate/placebo. Exclusions were: hypersensitivity or allergy to bezafibrate or any component of bezafibrate; hepatic, liver or renal dysfunction; gallbladder disease; or recent deterioration in general health. Interventions Fifteen weeks of bezafibrate in one period and placebo in a second period, or vice versa (randomly allocated), with at least a 1-month washout between periods. Main outcome measures The primary outcome was peak VO2; secondary outcomes were cardiac function rest and exercise echocardiography and magnetic resonance imaging, cardiolipin ratio, quality of life, dynamic skeletal muscle P-magnetic resonance spectroscopy, mitochondrial studies and neutrophil counts, and adverse events. Outcomes were measured at baseline and the end of each period. Results Eleven males were studied; all attended all three assessments. There was no difference in peak VO2 between periods (0.66 ml/kg/min lower with bezafibrate than placebo, 95% confidence interval 2.34 to 1.03; p = 0.43). There was a trend towards a higher left ventricular ejection fraction with bezafibrate when measured by echocardiography but not magnetic resonance imaging, and better echocardiography-derived rest longitudinal and circumferential strain with bezafibrate. There was no difference in quality of life or cardiolipin ratio between periods. Skeletal muscle 31P magnetic resonance spectroscopy was performed cross-sectionally and showed a trend to higher Tau and lower Qmax indices in the bazafibrate group. Two participants had serious, expected adverse reactions when taking bezafibrate; otherwise, bezafibrate was well tolerated. Limitations The sample size was very small; the bezafibrate dose may have been too low or 15 weeks too short to observe an effect; measurements of mitochondrial content and membrane potential were highly variable; P-magnetic resonance spectroscopy was available only at the final assessment. Conclusions This study did not show significant improvement in the primary and secondary outcomes with bezafibrate treatment. Future work Elamipretide, studied in a small crossover trial in the USA, is another potential intervention which may be worth evaluating in an international study. Trial registration This trial is registered as ISRCTN58006579. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/205/56) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 13. See the NIHR Funding and Awards website for further award information.

Background The Big Data for Quality of Life (BD4QoL) study investigates quality of life (QoL) in head and neck cancer (HNC) survivors, focusing on survivorship and characterizing survivor demographics.Methods We screened data from 5 studies across Europe (N=7276) and included patients with a diagnosis of squamous cell carcinoma (oral cavity, hypopharynx, larynx, oropharynx, nasal cavity and paranasal sinuses), treated with curative intent, alive after treatment, TNM 7th ed. stages I, II, III, IVa and IVb, with availability of QoL questionnaires.Results The cohort of 4448 HNC survivors primarily includes men (78%) with median age 61 years. Most received radiotherapy (75%) and had a history of smoking (78%). Survivors’ scores on EORTC QLQ-C30 functioning scales indicated high functioning, with prevalent symptoms of fatigue, pain, and insomnia. Lower rates of missing data were observed in older patients, those with higher education and income levels, nonsmokers, married individuals, and patients not treated with radiotherapy. The odds ratios ranged from 0.47 to 0.99, indicating these factors may predict more consistent QoL data reporting in HNC survivors.Conclusions These data support the development and validation of clinical prediction models for QoL in HNC survivors in a multicentre randomized controlled trial.### Competing Interest StatementMarissa LeBlanc reports receiving a speaker fee from MSD unrelated to the content of this work. Susanne Singer reports receiving honoraria for reviewing journal papers for the Quality-of-life-prize of Lilly, outside of this work. Lisa Licitra declares research funds to the institute for clinical studies from Astrazeneca, BMS, Boehringer Ingelheim, Celgene International, Eisai, Exelixis, Debiopharm International SA, Hoffmann-La Roche ltd, IRX Therapeutics, Medpace, Merck-Serono, MSD, Novartis, Pfizer, Roche, Buran, Alentis; occasional fees for participation as a speaker at conferences/congresses or as a scientific consultant for advisory boards from Astrazeneca, Bayer, MSD, Merck-Serono, AccMed, Neutron Therapeutics, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. ### Funding StatementThe BD4QoL project, in the frame of which this work is being conducted, has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 875192. MM-S received funding from the European Union's Horizon 2020 Research and Innovation program under the Marie Sklodowska-Curie Actions Grant, agreement No. 80113 (Scientia fellowship). This Publication presents data from the Head and Neck 5000 study. The study was a component of independent research funded by the National Institute for Health and Care Research (NIHR) under its programme Grands for applied Research scheme (RP-PG-070-10034). The views expressed in this publication are those of the author(s) and are not necessarily those of the NHS, the NIHR or the department of health and Social Care. Core funding was also provided through awards from Above and Beyond, University Hospitals Bristol and Weston Research Capability Funding and the NIHR Senior Investigator award to Professor Andy Ness. The UMM1 study was funded by the German Federal Ministry of Education and Science (Grant Number: 7DZAIQTX), the UMM1 and UMM2 study by the German Cancer Aid (Grant Numbers #106654, #107440, #108758, #109604), the UMM3 study by the European Organisation for Research and Treatment of Cancer (Grant Number: 001/2014).### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Our study was conducted in full accordance with ethical principles, including the World Medical Association's Declaration of Helsinki (2002 version). The study protocol received ethical approval by the Norwegian Regional Committee for Medical and Health Research Ethics (REK) South-East D under application number 154191. The data is stored in compliance with GDPR legislation in the secure server for sensitive data at the University of Oslo (TSD/USIT) and access is granted to authorised collaborators included in the ethical approval. Each individual study that provided data received ethical approval from local authorities in Italy, Germany, the UK, and all further countries involved. The data providers submitted copies of these ethical approvals to the principal investigator. BD2Decide study was approved by institutional research ethics board with identifier N. INT 65/16. The HN5000 study was approved by the National Research Ethics Committee (South West Frenchay Ethics Committee, reference number 10/H0107/57, 5 November 2010) and the Research and Development departments of participating NHS Trusts. Informed consent was obtained from all patients recruited to HN5000. UMM1 and UMM2 received ethical approval from the Leipzig University Ethics Committee. UMM3 was approved by Landesaerztekammer Rheinland-Pfalz ethics committee under approval number 837.281.14 (9520). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.Yes

Background: Conditional outcomes are outcomes defined only under specific circumstances. For example, future quality of life can only be ascertained when subjects are alive. In prognostic models involving conditional outcomes, a choice must be made on the precise target of prediction: one could target future quality of life, given that the individual is still alive (conditional) or target future quality of life jointly with the event of being alive (unconditional).We aim to (1) introduce a probabilistic framework for prognostic models for conditional outcomes, and (2) apply this framework to develop a prognostic model for quality of life 3 years after diagnosis in head and neck cancer patients. Methods: A joint probability framework was proposed for prognostic model development for a conditional outcome dependent on a post-baseline variable. Joint probability was estimated with conformal estimators. We included head and neck cancer patients alive with no evidence of disease 12 months after diagnosis from the UK-based Head & Neck 5000 cohort (N=3572) and made predictions 3 years after diagnosis. Predictors included clinical and demographic characteristics and longitudinal measurements of quality of life. External validation was performed in studies from Italy and Germany. Findings: Of 3572 subjects, 400 (11.2%) were deceased by the time of prediction. Model performance was assessed for prediction of quality of life, both conditionally and jointly with survival. C-statistics ranged from 0.66 to 0.80 in internal and external validation, and the calibration curves showed reasonable calibration in external validation. An API and dashboard were developed. Interpretation: Our probabilistic framework for conditional outcomes provides both joint and conditional predictions and thus the flexibility needed to answer different clinical questions. Our model had reasonable performance in external validation and has potential as a tool in long-term follow-up of quality of life in head and neck cancer patients. Funding: The EU. ### Competing Interest Statement Marissa LeBlanc reports receiving a speaker fee from MSD unrelated to the content of this work. Susanne Singer reports receiving honoraria for reviewing journal papers for the Quality-of-life-prize of Lilly, outside of this work. Lisa Licitra declares research funds to the institute for clinical studies from Astrazeneca, BMS, Boehringer Ingelheim, Celgene International, Eisai, Exelixis, Debiopharm International SA, Hoffmann-La Roche ltd, IRX Therapeutics, Medpace, Merck-Serono, MSD, Novartis, Pfizer, Roche, Buran, Alentis; occasional fees for participation as a speaker at conferences/congresses or as a scientific consultant for advisory boards from Astrazeneca, Bayer, MSD, Merck-Serono, AccMed, Neutron Therapeutics, Inc. Stefano Cavalieri declares occasional fees for participation as a speaker at conferences/congresses from AccMed; support for attending meetings and/or travel from AccMed, MultiMed Engineers srl, Care Insight sas. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. ### Funding Statement MM-S received funding from the European Union's Horizon 2020 Research and Innovation program under the Marie Skłodowska-Curie Actions Grant, agreement No. 80113 (Scientia fellowship). The BD2Decide project was funded by the European Union Horizon 2020 Framework Programme, Grant/Award Number: 689715. This publication presents data from the Head and Neck 5000 study. The study was a component of independent research funded by the National Institute for Health and Care Research (NIHR under its programme Grands for applied Research scheme (RP-PG-070-10034). The views expressed in this publication are those of the author(s) and are not necessarily those of the NHS, the NIHR or the department of health and Social Care. Core funding was also provided through awards from Above and Beyond, University Hospitals Bristol and Weston Research Capability Funding and the NIHR Senior Investigator award to Professor Andy Ness. The 3-years follow up was supported with a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169). The UMM1 study was funded by the German Federal Ministry of Education and Science (grant number: 7DZAIQTX), the UMM1 and UMM2 study by the German Cancer Aid (grant numbers #106654, #107440, #108758, #109604), the UMM3 study by the European Organisation for Research and Treatment of Cancer (grant number: 001/2014). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol received ethical approval by the Norwegian Regional Committee for Medical and Health Research Ethics (REK) South-East D under application number 154191. The data is stored in compliance with GDPR legislation in the secure server for sensitive data at the University of Oslo (TSD/USIT) and access is granted to authorised collaborators included in the ethical approval. The HN5000 study was approved by the National Research Ethics Committee (South West Frenchay Ethics Committee, reference number 10/H0107/57, 5 November 2010) and the Research and Development departments of participating NHS Trusts. Informed consent was obtained from all patients recruited to HN5000. BD2Decide study was approved by institutional research ethics board with identifier N. INT 65/16. UMM1 and UMM2 received ethical approval from the Leipzig University Ethics Committee. UMM3 was approved by Landesaerztekammer Rheinland-Pfalz ethics committee under approval number 367 837.281.14 (9520). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Non-sensitive data generated during model development is shared in this manuscript and the respective supplementary material. The BD4QoL historical cohort dataset is hosted by the Services for Sensitive Data (TSD) at the University of Oslo. Access to the data may be granted by the data owners upon application. The data that support the findings of this study are available from head and neck 5000. Further information may be found on the Head and Neck 5000 website: https://www.headand neck5000.org.uk/information-for-researchers.

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. Head and neck squamous cell carcinoma can occur with and without the presence of HPV infection. Here, the authors utilise Mendelian randomization to assess the causal effects of smoking and alcohol on HPV-positive and HPV-negative head and neck cancer development.

A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV-driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk-factor analysis based on serology was conducted, comparing HPV-driven to non-HPV-driven OPC. Overall, HPV serology had a sensitivity of 86.8% (95% CI 85.1-88.3) and specificity of 91.2% (95% CI 88.6-93.4) for HPV-driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7%), OPC without lymph node involvement (74.4%) and the ARCAGE study (66.7%), while specificity decreased for cases with <10 pack-years (72.1%). The risk-factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack-years, TNM-T and TNM-N stage. HPV serology is a robust biomarker for HPV-driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels.

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/m 2 ]) 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.

Objectives To estimate both the association of surgical variables in complete unilateral cleft lip and palate (cUCLP) in the UK with outcomes at age 5 years, and the association of secondary speech surgery, volume of surgery, and surgeon with the same outcomes. Setting and Sample Population The Cleft Care UK study, a cross-sectional study of 268 5-year-olds, born from 2005 to 2007, with cUCLP. Materials and Methods Information on surgical variables was extracted from a standardized questionnaire. Dento-facial outcomes were derived from dental study casts of dental arch relationships. Three speech outcomes - intelligibility, structure and articulation - were derived using the Cleft Audit Protocol for Speech-Augmented tool. Results Surgical and outcome data were available for 211 (79%) children from all cleft centres in the UK. Later soft palate surgery was associated with a 17% increased chance of a poor intelligibility score (P = .02), and high volume surgery with a 249% increased chance of a good articulation score (P = .01). There were no between surgeon effects identified. No association between the surgical variables examined and dento-facial outcome, or secondary speech surgery by the age of 5 years were found. Conclusion This study found associations between surgical variables and speech outcomes at 5 years of age, but not between surgical variables and dento-facial outcome, nor between surgical variables and secondary speech surgery. High surgical volume should be maintained, and any changes towards later surgery monitored for changes in speech outcome.

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.

In the UK, the incidence of oral cavity cancer continues to rise, with an increase of around 60% over the past 10 years. Many patients still present with advanced disease, often resulting in locoregional recurrence and poor outcomes, which has not changed significantly for over four decades. Changes in aetiology may also be emerging, given the decline of smoking in developed countries. Therefore, new methods to better target prevention, improve screening and detect recurrence are needed. High-throughput 'omics' technologies appear promising for future individual-level diagnosis and prognosis. However, given this is a relatively rare cancer with significant intra-tumour heterogeneity and variation in patient response, reliable biomarkers have been difficult to elucidate. From a public health perspective, implementing these novel technologies into current services would require substantial practical, financial and ethical considerations. This may be difficult to justify and implement at present, therefore focus remains on early detection using new patient-led follow-up strategies. This paper reviews the latest evidence on epidemiological trends in oral cavity cancer to help identify at risk groups, population-based approaches for prevention, in addition to potential cutting-edge approaches in the diagnosis and prognosis of this disease.

Background Barth syndrome is a rare, life-threatening, X-linked recessive genetic disease that predominantly affects young males and is caused by abnormal mitochondrial lipid metabolism. Currently, there is no definitive treatment for Barth syndrome other than interventions to ameliorate acute symptoms, such as heart failure, cardiac arrhythmias, neutropenia, and severe muscle fatigue. Previous mechanistic studies have identified the lipid-lowering drug bezafibrate as a promising potential treatment; however, to date, no human trials have been performed in this population. Objective The aim of this study is to determine whether bezafibrate (and resveratrol in vitro) will increase mitochondrial biogenesis and potentially modify the cellular ratio of monolysocardiolipin (MLCL) to tetralinoleoyl-cardiolipin (L4-CL), ameliorating the disease phenotype in those living with the disease. Methods The CARDIOMAN (Cardiolipin Manipulation) study is a UK single-center, double-blinded, randomized, placebo-controlled crossover study investigating the efficacy of bezafibrate in participants with Barth syndrome. Treatment was administered in two 15-week phases with a minimum washout period of 1 month between the phases where no treatment was administered. The primary outcome is peak oxygen consumption (VO2 peak). Secondary outcomes include MLCL/L4-CL ratio and CL profile in blood cells, amino acid expression, phosphocreatine to adenosine triphosphate ratio in cardiac muscle and skeletal muscle oxidative function on phosphorus-31 magnetic resonance spectroscopy, quality of life using the Pediatric Quality of Life Inventory questionnaire, absolute neutrophil count, cardiac function and rhythm profiles at rest and during exercise, and mitochondrial organization and function assessments. Outcomes were assessed at baseline and during the final week of each treatment phase. Results A total of 12 patients were scheduled to participate across three consecutive research clinics between March and April 2019. In total, 11 participants were recruited, and the follow-up was completed in January 2020. Data analysis is ongoing, with publication expected in 2021. Conclusions This trial was approved by the United Kingdom National Research Ethics Service Committee and the Medicines and Healthcare products Regulatory Agency. The feasibility of the CARDIOMAN study will help to inform the future conduct of randomized controlled trials in rare disease populations as well as testing the efficacy of bezafibrate as a potential treatment for the disease and advancing the mechanistic understanding of Barth syndrome. Trial Registration International Standard Randomized Controlled Trial Number (ISRCTN): 58006579; https://www.isrctn.com/ISRCTN58006579 International Registered Report Identifier (IRRID) DERR1-10.2196/22533

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 inHMGCR,NPC1L1,CETP,PCSK9andLDLRwere 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.

The independent effects of smoking and alcohol in head and neck cancer are not clear, given the strong association between these risk factors. Their apparent synergistic effect reported in previous observational studies may also underestimate independent effects. Here we report multivariable Mendelian randomization performed in a two-sample approach using summary data on 6,034 oral/oropharyngeal cases and 6,585 controls from a recent genome-wide association study. Our results demonstrate strong evidence for an independent causal effect of smoking on oral/oropharyngeal cancer (IVW OR 2.6, 95% CI = 1.7, 3.9 per standard deviation increase in lifetime smoking behaviour) and an independent causal effect of alcohol consumption when controlling for smoking (IVW OR 2.1, 95% CI = 1.1, 3.8 per standard deviation increase in drinks consumed per week). This suggests the possibility that the causal effect of alcohol may have been underestimated. However, the extent to which alcohol is modified by smoking requires further investigation.

OBJECTIVES The objective of this study was to explore potential relationships between neonatal line (NNL) width and early life history variables such as maternal health, gestation, the birth process, and perinatal health. MATERIALS AND METHODS Histological thin sections of deciduous canines were studied from 71 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). The width of the NNL was measured in three locations on the tooth crown using spatial mapping techniques (ArcGIS) from digital images from an Olympus VS-120 microscope. Life history variables were collected prospectively through a combination of clinical observations and questionnaires. RESULTS Infants born late term or post term had narrower neonatal lines than those born prematurely or at full term. Infants born in Autumn (September to November) had narrower NNLs than those born at other times of year. NNLs in infants born to mothers with hypertension were wider than those without. Infants resuscitated at birth or born to obese mothers had narrower NNLs than those that were not. There was no association between NNL width and either the type or duration of delivery. DISCUSSION The NNL in enamel is an irregular accentuated line, but the factors underlying its formation and width remain unclear. In contrast to some previous studies, we found no association between wider NNLs and long or difficult births. Instead, we found that the width of the neonatal line NNL varied in relation to parameters that reflected the prenatal environment and length of gestation.

BackgroundEvidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses.MethodsWe developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects.ResultsThe multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk.ConclusionsOur findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.

BACKGROUND:This is an update of the review last published in 2011. It focuses on early postoperative enteral nutrition after lower gastrointestinal surgery. Traditional management consisted of 'nil by mouth', where patients receive fluids followed by solids after bowel function has returned. Although several trials have reported lower incidence of infectious complications and faster wound healing upon early feeding, other trials have shown no effect. The immediate advantage of energy intake (carbohydrates, protein or fat) could enhance recovery with fewer complications, and this warrants a systematic evaluation.OBJECTIVES:To evaluate whether early commencement of postoperative enteral nutrition (within 24 hours), oral intake and any kind of tube feeding (gastric, duodenal or jejunal), compared with traditional management (delayed nutritional supply) is associated with a shorter length of hospital stay (LoS), fewer complications, mortality and adverse events in patients undergoing lower gastrointestinal surgery (distal to the ligament of Treitz).SEARCH METHODS:We searched the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library 2017, issue 10), Ovid MEDLINE (1950 to 15 November 2017), Ovid Embase (1974 to 15 November 2017). We also searched for ongoing trials in ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform (15 November 2017). We handsearched reference lists of identified studies and previous systematic reviews.SELECTION CRITERIA:We included randomised controlled trials (RCT) comparing early commencement of enteral nutrition (within 24 hours) with no feeding in adult participants undergoing lower gastrointestinal surgery.DATA COLLECTION AND ANALYSIS:Two review authors independently assessed study quality using the Cochrane 'Risk of bias' tool tailored to this review and extracted data. Data analyses were conducted according to the Cochrane recommendations.We rated the quality of evidence according to GRADE.Primary outcomes were LoS and postoperative complications (wound infections, intraabdominal abscesses, anastomotic dehiscence, pneumonia).Secondary outcomes were: mortality, adverse events (nausea, vomiting), and quality of life (QoL).LoS was estimated using mean difference (MD (presented as mean +/- SD). For other outcomes we estimated the common risk ratio (RR) and calculated the associated 95% confidence intervals. For analysis, we used an inverse-variance random-effects model for the primary outcome (LoS) and Mantel-Haenszel random-effects models for the secondary outcomes. We also performed Trial Sequential Analyses (TSA).MAIN RESULTS:We identified 17 RCTs with 1437 participants undergoing lower gastrointestinal surgery. Most studies were at high or unclear risk of bias in two or more domains. Six studies were judged as having low risk of selection bias for random sequence generation and insufficient details were provided for judgement on allocation concealment in all 17 studies. With regards to performance and deception bias; 14 studies reported no attempt to blind participants and blinding of personnel was not discussed either. Only one study was judged as low risk of bias for blinding of outcome assessor. With regards to incomplete outcome data, three studies were judged to be at high risk because they had more than 10% difference in missing data between groups. For selective reporting, nine studies were judged as unclear as protocols were not provided and eight studies had issues with either missing data or incomplete reporting of results.LOS was reported in 16 studies (1346 participants). The mean LoS ranged from four days to 16 days in the early feeding groups and from 6.6 days to 23.5 days in the control groups. Mean difference (MD) in LoS was 1.95 (95% CI, -2.99 to -0.91, P < 0.001) days shorter in the early feeding group. However, there was substantial heterogeneity between included studies (I2 = 81, %, Chi2 = 78.98, P < 0.00001), thus the overall quality of evidence for LoS is low. These results were confirmed by the TSA showing that the cumulative Z-curve crossed the trial sequential monitoring boundary for benefit.We found no differences in the incidence of postoperative complications: wound infection (12 studies, 1181 participants, RR 0.99, 95%CI 0.64 to 1.52, very low-quality evidence), intraabdominal abscesses (6 studies, 554 participants, RR 1.00, 95%CI 0.26 to 3.80, low-quality evidence), anastomotic leakage/dehiscence (13 studies, 1232 participants, RR 0.78, 95%CI 0.38 to 1.61, low-quality evidence; number needed to treat for an additional beneficial outcome (NNTB) = 100), and pneumonia (10 studies, 954 participants, RR 0.88, 95%CI 0.32 to 2.42, low-quality evidence; NNTB = 333).Mortality was reported in 12 studies (1179 participants), and showed no between-group differences (RR = 0.56, 95%CI, 0.21 to 1.52, P = 0.26, I2 = 0%, Chi2 = 3.08, P = 0.96, low-quality evidence). The most commonly reported cause of death was anastomotic leakage, sepsis and acute myocardial infarction.Seven studies (613 participants) reported vomiting (RR 1.23, 95%CI, 0.96 to 1.58, P = 0.10, I2 = 0%, Chi2 = 4.98, P = 0.55, low-quality evidence; number needed to treat for an additional harmful outcome (NNTH) = 19), and two studies (118 participants) reported nausea (RR 0.95, 0.71 to 1.26, low-quality evidence). Four studies reported combined nausea and vomiting (RR 0.94, 95%CI 0.51 to 1.74, very low-quality evidence). One study reported QoL assessment; the scores did not differ between groups at 30 days after discharge on either QoL scale EORTC QLQ-C30 or EORTC QlQ-OV28 (very low-quality evidence).AUTHORS' CONCLUSIONS:This review suggests that early enteral feeding may lead to a reduced postoperative LoS, however cautious interpretation must be taken due to substantial heterogeneity and low-quality evidence. For all other outcomes (postoperative complications, mortality, adverse events, and QoL) the findings are inconclusive, and further trials are justified to enhance the understanding of early feeding for these. In this updated review, only a few additional studies have been included, and these were small and of poor quality.To improve the evidence, future trials should address quality issues and focus on clearly defining and measuring postoperative complications to allow for better comparison between studies. However due to the introduction of fast track protocols which already include an early feeding component, future trials may be challenging. A more feasible trial may be to investigate the effect of differing postoperative energy intake regimens on relevant outcomes.

Background The association between diet and head and neck cancer (HNC) survival is unclear. Methods Cox proportional hazard models measured the association between fruit, vegetable, and deep-fried food intake and HNC overall survival adjusting for clinical, social and lifestyle variables including smoking, alcohol, and HPV status. Results Fruit and vegetable intake and improved survival were associated in minimally adjusted analyses. Following adjustment for smoking and alcohol consumption (fully adjusted analyses), the association with survival disappeared for fruit (HR 0.91, 95% CI 0.67, 1.23; P for trend = .55) and attenuated for vegetables (HR 0.79, 95% CI 0.61, 1.03; P for trend = .04). We observed no association between survival and deep-fried food intake in minimally adjusted or fully adjusted analyses (HR 0.88 95% CI 0.72, 1.07; P for trend = .13). Conclusions Vegetable intake and HNC survival are modestly associated. There is some confounding by tobacco and alcohol consumption.

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Lycopene and green tea consumption have been observationally associated with reduced prostate cancer risk, but the underlying mechanisms have not been fully elucidated. We investigated the effect of factorial randomisation to a 6‐month lycopene and green tea dietary advice or supplementation intervention on 159 serum metabolite measures in 128 men with raised PSA levels (but prostate cancer‐free), analysed by intention‐to‐treat. The causal effects of metabolites modified by the intervention on prostate cancer risk were then assessed by Mendelian randomisation, using summary statistics from 44,825 prostate cancer cases and 27,904 controls. The systemic effects of lycopene and green tea supplementation on serum metabolic profile were comparable to the effects of the respective dietary advice interventions (R2 = 0.65 and 0.76 for lycopene and green tea respectively). Metabolites which were altered in response to lycopene supplementation were acetate [β (standard deviation difference vs. placebo): 0.69; 95% CI = 0.24, 1.15; p = 0.003], valine (β: −0.62; −1.03, −0.02; p = 0.004), pyruvate (β: −0.56; −0.95, −0.16; p = 0.006) and docosahexaenoic acid (β: −0.50; −085, −0.14; p = 0.006). Valine and diacylglycerol were lower in the lycopene dietary advice group (β: −0.65; −1.04, −0.26; p = 0.001 and β: −0.59; −1.01, −0.18; p = 0.006). A genetically instrumented SD increase in pyruvate increased the odds of prostate cancer by 1.29 (1.03, 1.62; p = 0.027). An intervention to increase lycopene intake altered the serum metabolome of men at risk of prostate cancer. Lycopene lowered levels of pyruvate, which our Mendelian randomisation analysis suggests may be causally related to reduced prostate cancer risk.

BACKGROUND:Recently, an alcohol predictor was developed using DNA methylation at 144 CpG sites (DNAm-Alc) as a biomarker for improved clinical or epidemiologic assessment of alcohol-related ill health. We validate the performance and characterise the drivers of this DNAm-Alc for the first time in independent populations. RESULTS:In N = 1049 parents from the Avon Longitudinal Study of Parents and Children (ALSPAC) Accessible Resource for Integrated Epigenomic Studies (ARIES) at midlife, we found DNAm-Alc explained 7.6% of the variation in alcohol intake, roughly half of what had been reported previously, and interestingly explained a larger 9.8% of Alcohol Use Disorders Identification Test (AUDIT) score, a scale of alcohol use disorder. Explanatory capacity in participants from the offspring generation of ARIES measured during adolescence was much lower. However, DNAm-Alc explained 14.3% of the variation in replication using the Head and Neck 5000 (HN5000) clinical cohort that had higher average alcohol consumption. To investigate whether this relationship was being driven by genetic and/or earlier environment confounding, we examined how earlier versus concurrent DNAm-Alc measures predicted AUDIT scores. In both ARIES parental and offspring generations, we observed associations between AUDIT and concurrent, but not earlier DNAm-Alc, suggesting independence from genetic and stable environmental contributions. CONCLUSIONS:The stronger relationship between DNAm-Alcs and AUDIT in parents at midlife compared to adolescents despite similar levels of consumption suggests that DNAm-Alc likely reflects long-term patterns of alcohol abuse. Such biomarkers may have potential applications for biomonitoring and risk prediction, especially in cases where reporting bias is a concern.