Oral diseases are among the most prevalent diseases globally and have serious health and economic burdens, depriving people of health, wellbeing, and the ability to achieve their full potential. By virtue of their high prevalence, the most consequential oral diseases affecting global health are: dental caries, periodontal disease, tooth loss, and cancers of the lips and oral cavity. In this first of two papers, we describe the scope of the global oral disease epidemic, describe its origins in social and commercial determinants, and its costs in terms of human suffering and societal impact. Even though oral diseases are largely preventable, they persist with high prevalence as a reflection of pervasive social and economic inequalities, along with inadequate funding for prevention and treatment, particularly in low and middleincome countries (LMIC). As with most non-communicable diseases (NCDs), oral conditions are chronic and strongly socially patterned. Poor children, socially marginalised groups, and older people suffer the most from oral diseases and have more limited access to dental care. In many LMIC oral diseases remain largely untreated as the treatment costs exceed available resources. The personal consequences of chronic untreated oral diseases are often severe and include unremitting pain, sepsis, reduced quality of life, lost school days, family disruption, and decreased work productivity. The societal costs of treating oral diseases are a very high economic burden to families and the health care system. Oral diseases are truly a global public health problem with particular concern over rising prevalence in many LMIC linked to wider social, economic and commercial changes. By describing the extent and consequences of oral diseases, their roots in social and commercial determinants, and their ongoing neglect in global health policy, we aim to highlight the urgency of addressing oral diseases as a global health and NCD priority. 4 Key messages  Oral health is an integral element of overall health and wellbeing enabling individuals to perform essential daily functions.  Oral diseases include a range of chronic clinical conditions that affect the teeth and mouth including dental caries (tooth decay), periodontal (gum) disease and oral cancers.  Despite being largely preventable, oral diseases are highly prevalent conditions affecting over 3.5 billion people around the world, with dental caries being the most common disease globally with increasing prevalence in many low and middle-income countries (LMIC)  Oral diseases disproportionally affect poorer and marginalised groups in society being very closely linked to socioeconomic status and the broader social determinants of health.  Oral diseases have a significant impact causing pain, sepsis, reduced quality of life, lost school days, family disruption, decreased work productivity, and the costs of dental treatment can be considerable for both individuals, and the wider health care system.  Oral conditions share common risks with other non-communicabl...

75Oral diseases are a major global public health problem affecting over 3.5 billion people. 76Dentistry however has failed to tackle this problem. A fundamentally different approach is 77 now needed. In this second paper on oral health, we present a critique of dentistry 78 highlighting its key limitations and the urgent need for system reform. In high-income 79 countries (HIC) the current treatment-dominated, increasingly high-tech, interventionist and 80 specialised approach, is failing to tackle the underlying causes of disease and is not 81 addressing oral health inequalities. In low-and middle-income countries (LMIC) the 82 limitations of "westernised" dentistry are most acutedentistry is often unavailable, 83 unaffordable and inappropriate to the majority of these populations, but particularly the rural 84 poor. Rather than being isolated and separated from the mainstream health care system, 85 dentistry needs to be more integrated with primary care services in particular. The global 86 drive for universal health coverage (UHC) provides an ideal opportunity for this. Dental care 87 systems should focus more on promoting and maintaining oral health and achieving greater 88 oral health equity, rather than the interventionist treatment approach that currently dominates. 89Sugar, alcohol and tobacco use and their driving social and commercial determinants are the 90 underlying causes of oral diseases, common risks shared with a range of other non-91 communicable diseases (NCDs). Coherent and comprehensive regulation and legislation is 92 needed to tackle these shared risk factors. In this paper we focus on the need to reduce sugars 93 consumption through the adoption of a range of upstream policies designed to combat the 94 corporate strategies used by the global sugar industry to promote sugar consumption and 95 profits. At present the sugar industry is influencing dental research, oral health policy and 96 professional organisations through its well-developed corporate strategies. There is a pressing 97 need to develop clearer and more transparent conflict of interest policies and procedures to 98 limit and clarify the influence of the sugar industry on research, policy and practice. 99

The disposition of paclitaxel in humans is nonlinear. Paclitaxel metabolism to 6 alpha-hydroxylpaclitaxel is likely an important detoxification pathway. Myelosuppression is related to the duration that plasma paclitaxel concentrations are > or = 0.05 mumol/L. Trials of new doses and schedules of paclitaxel should take into account its nonlinear disposition to rule out adverse clinical consequences, especially if the drug is administered by short infusion. Our pharmacokinetic model should prove to be a powerful tool in predicting paclitaxel disposition, regardless of dose and schedule, and should facilitate further pharmacodynamic investigations.

BackgroundArtificially sweetened beverage consumption has steadily increased in the last 40 years. Several reviews examining the effects of artificially sweetened beverages on weight outcomes have discrepancies in their results and conclusions.ObjectivesTo determine whether risk of bias, results, and conclusions of reviews of effects of artificially sweetened beverage consumption on weight outcomes differ depending on review sponsorship and authors’ financial conflicts of interest.MethodsWe performed a systematic review of reviews of the effects of artificially sweetened beverages on weight. Two assessors independently screened articles for inclusion, extracted data, and assessed risks of bias. We compared risk of bias, results and conclusions of reviews by different industry sponsors, authors’ financial conflict of interest and journal sponsor. We also report the concordance between review results and conclusions.ResultsArtificial sweetener industry sponsored reviews were more likely to have favorable results (3/4) than non-industry sponsored reviews (1/23), RR: 17.25 (95% CI: 2.34 to 127.29), as well as favorable conclusions (4/4 vs. 15/23), RR: 1.52 (95% CI: 1.14 to 2.06). All reviews funded by competitor industries reported unfavorable conclusions (4/4). In 42% of the reviews (13/31), authors’ financial conflicts of interest were not disclosed. Reviews performed by authors that had a financial conflict of interest with the food industry (disclosed in the article or not) were more likely to have favorable conclusions (18/22) than reviews performed by authors without conflicts of interest (4/9), RR: 7.36 (95% CI: 1.15 to 47.22). Risk of bias was similar and high in most of the reviews.ConclusionsReview sponsorship and authors’ financial conflicts of interest introduced bias affecting the outcomes of reviews of artificially sweetened beverage effects on weight that could not be explained by other sources of bias.

BackgroundIn 1966, the National Institute of Dental Research (NIDR) began planning a targeted research program to identify interventions for widespread application to eradicate dental caries (tooth decay) within a decade. In 1971, the NIDR launched the National Caries Program (NCP). The objective of this paper is to explore the sugar industry’s interaction with the NIDR to alter the research priorities of the NIDR NCP.Methods and FindingsWe used internal cane and beet sugar industry documents from 1959 to 1971 to analyze industry actions related to setting research priorities for the NCP. The sugar industry could not deny the role of sucrose in dental caries given the scientific evidence. They therefore adopted a strategy to deflect attention to public health interventions that would reduce the harms of sugar consumption rather than restricting intake. Industry tactics included the following: funding research in collaboration with allied food industries on enzymes to break up dental plaque and a vaccine against tooth decay with questionable potential for widespread application, cultivation of relationships with the NIDR leadership, consulting of members on an NIDR expert panel, and submission of a report to the NIDR that became the foundation of the first request for proposals issued for the NCP. Seventy-eight percent of the sugar industry submission was incorporated into the NIDR’s call for research applications. Research that could have been harmful to sugar industry interests was omitted from priorities identified at the launch of the NCP. Limitations are that this analysis relies on one source of sugar industry documents and that we could not interview key actors.ConclusionsThe NCP was a missed opportunity to develop a scientific understanding of how to restrict sugar consumption to prevent tooth decay. A key factor was the alignment of research agendas between the NIDR and the sugar industry. This historical example illustrates how industry protects itself from potentially damaging research, which can inform policy makers today. Industry opposition to current policy proposals—including a World Health Organization guideline on sugars proposed in 2014 and changes to the nutrition facts panel on packaged food in the US proposed in 2014 by the US Food and Drug Administration—should be carefully scrutinized to ensure that industry interests do not supersede public health goals.

Author Contributions: Drs Kearns and Glantz had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of data analysis.

2-CDA given by prolonged continuous infusion has clinically significant activity against AML and merits further testing in multidrug regimens for this disease.

The utility of combining paclitaxel with radiation therapy to treat CNS malignancies should be considered in light of the documented limited access of paclitaxel to the CNS.