What is the future of Periodontal Medicine?

Abstract

In the last five decades, considerable progress has been made towards understanding the etiology and pathogenesis of periodontal diseases and their interactions with the host. The impact of an individual periodontal condition on systemic homeostasis became more evident because of this knowledge and prompted advances in studies that associate periodontitis with systemic diseases and conditions. The term Periodontal Medicine describes how periodontal infection/inflammation can affect extraoral health. This review presents the current scientific evidence on the most investigated associations between periodontitis and systemic diseases and conditions, such as cardiovascular diseases, diabetes, preterm birth and low birth weight, and pneumonia. Additionally, other associations between periodontitis and chronic inflammatory bowel disease, colorectal cancer, and Alzheimer’s disease that were recently published and are still poorly studied were described. Thus, the aim of this review was to answer the following question: What is the future of Periodontal Medicine? Epidemiological evidence and the evidence of biological plausibility between periodontitis and general health reinforce the rationale that the study of Periodontal Medicine should continue to advance, along with improvements in the epidemiological method, highlighting the statistical power of the studies, the method for data analysis, the case definition of periodontitis, and the type of periodontal therapy to be applied in intervention studies.

Periodontitis; Diabetes Mellitus; Cardiovascular Diseases; Pneumonia

Introduction

Periodontal diseases are chronic inflammatory conditions of infectious origin that affect tooth-supporting tissues. They are classified as gingivitis and periodontitis. Although they are initially caused by microbial biofilm, environmental and genetic factors contribute to their development. Gingivitis is an inflammation of the gums originated by the biofilm of bacteria that is formed on the dental surface. However, periodontitis occurs due to untreated gingivitis, which proceeds to the loss of periodontal tissue, manifested by periodontal attachment loss and radiographically assessed alveolar bone loss. Several epidemiological studies from the 1980s and the 1990s have shown that periodontitis can also have an impact on systemic health.¹

The concept of focal infection, that is, the appearance of systemic disease as a result of a dental infection, was accepted until the middle of the 20th century, but due to the lack of scientific evidence at the time, this hypothesis was disregarded. In the late 1980s, some studies resumed interest in the association between periodontal diseases and other systemic diseases. With the evolution of knowledge about the pathogenesis of periodontal diseases, it was possible to identify their role in the rupture of systemic homeostasis.²

Over the past 30 years, many studies have assessed the association between periodontitis and systemic conditions/diseases, such as cardiovascular disease, diabetes, preterm birth and low birthweight, chronic lung diseases, and, more recently, chronic inflammatory bowel disease, colorectal cancer, and Alzheimer’s disease. The term Periodontal Medicine has been defined to describe how periodontal infection/inflammation can affect extraoral health.

This paper describes the current scientific evidence regarding the knowledge about the most investigated associations between periodontitis and the aforementioned systemic conditions/diseases, in addition to presenting associations that have not yet been studied between periodontitis and other health conditions. Finally, this article seeks to answer the following question: What is the future of Periodontal Medicine?

Periodontitis and diabetes mellitus

As it is observed in large population surveys, people with diabetes, especially those who do not have it under control, are at high risk of periodontitis when compared to people who do not have diabetes.³ On the other hand, observational studies have demonstrated the impact of periodontitis on the glycemic control of diabetes mellitus (DM).⁴-⁷ Thus, the relationship between DM and periodontitis works in a two-way manner. As an infectious process, it is biologically plausible that periodontitis influences the metabolic control of people with diabetes.⁸ High levels of inflammatory mediators expressed during the periodontal destruction process can negatively interfere with glycemic control.⁸

However, periodontal treatment can reduce the levels of these mediators, which suggests that the inflammatory state will be reduced, positively interfering in insulin regulation and leading to better glycemic control.⁸,⁹ Although it is of great relevance, there is insufficient evidence about the effect of periodontal therapy in reducing glycemic levels in individuals with type 1 diabetes mellitus due to the lack of studies. However, clinical studies that generate better evidence like randomized clinical trials¹⁰-¹⁷ or their meta-analysis¹⁸have been published to study the impact of periodontal therapy on the glycemic control of type 2 diabetes mellitus (T2DM).

Effect of periodontal therapy on diabetes control

The hypothesis raised by randomized controlled trials (RCTs) would be that periodontal treatment could contribute to better glycemic control in individuals with diabetes. The removal of bacterial deposits would reduce both the inflammation of oral tissues and the systemic inflammation burden caused by periodontitis, thus improving glycemic control. Periodontal treatment may initially play the role of an inflammatory stressor due to bacteremia and the rise of inflammatory markers, but in the long term it has beneficial effects on biochemical parameters related to systemic inflammation and risk factors for chronic diseases.¹⁹

Over time, RCTs have improved their methodological rigor and produced more reliable data and better evidence. A search for randomized clinical trials that were published in English and investigated the effect of periodontal treatment on the control of type 2 diabetes, with follow-up and a control group that did not undergo subgingival intervention in a timeframe of at least six months, identified eight studies (Table).¹⁰-¹⁷ These studies have shown divergent results regarding the reduction of glycated hemoglobin (HbA1c). Two of these studies have shown a significant reduction in the mean level of HbA1c after six months in the group that received periodontal therapy when compared to a control group.¹⁵,¹⁷ Two other studies have shown a reduction in HbA1c in intra-group analyses when comparing the results of the initial period and the results of the follow-up after six months in the treated group;¹¹,¹³however, no differences were observed between the groups of treated and untreated individuals. Conversely, the other four studies¹⁰,¹²,¹⁴,¹⁶did not observe a significant reduction in HbA1c at the follow-up, despite noticing that the periodontal therapy resulted in an improvement in the periodontal clinical condition. These results may be due to the methodological limitations of some of the published RCTs, including sample size problems, inclusion criteria, patients’ clinical characteristics, results of periodontal therapy, and biased criteria for defining the presence of periodontitis.

Table
Randomized clinical trials with at least 6 months of follow-up that evaluated the effect of periodontal treatment in type 2 diabetic patients. Comparison between groups that underwent periodontal treatment (test) or not (control).

Author (Country)	Sample		Periodontal treatment impact on glycemic control (HbA1c)
	n	Age (years)
D’Aiuto et al.17, 2018, UK	264	> 18	No difference at 6 months of follow-up; Significant reduction in HbA1c at 12 months of follow-up (-0.6%; -0.3 to -0.9; p < 0.0001)
Mizuno et al.16,2017, Japan	28	≥ 30	No difference at 6 months of follow-up
Wu et al.15, 2015, China	54	54.7 ± 5.64	Significant difference in HbA1c at 6 months between test group (7.41±0.20 to 7.09±0.12) and control (7.39±0.16 to 7.42±0.18); p < 0,01
Artese et al.14, 2015, Brazil	24	≥ 35	No difference at 6 months of follow-up
Zhang et al.13, 2013, China	71	35–80	No difference at 6 months of follow-up
Engebretson et al.12, 2013, USA	214	≥ 35	No difference at 6 months of follow-up
Chen et al.11, 2012, China	134	38–81	No difference at 6 months of follow-up
Katagiri et al.10, 2009, Japan	49	39–75	No difference at 6 months of follow-up

In 2013, Engebretson et al.¹²published the study with the largest sample size ever carried out. There were no differences between the glycemic levels of individuals who received periodontal treatment and the control group without treatment.¹²This study, however, faced criticism due to the biases it presented.²⁰Included patients had average glycemic levels close to the initial inclusion criterion (7%); 60% had HbA1c below 8% in the initial period; and a large proportion of obese individuals was included, which could mask the possible anti-inflammatory effects of periodontal treatment. Also, changes in periodontal clinical parameters after therapy were below the expectations considering the quality of the treatment performed.²⁰

In the most recent study, D’Aiuto et al.¹⁷have evaluated over a year of observation of the effect of periodontal treatment, both non-surgical and surgical, when necessary, in 264 patients with T2DM and moderate to severe periodontitis. The patients were also subjected to strict hygiene control and supportive periodontal therapy every three months. The inclusion of patients was also more careful, with patients presenting at least 20 periodontal pockets bigger than 4 mm, alveolar bone loss greater than 30%, and at least 15 teeth in the dental arch. Over a year, a difference in glycemic levels was observed between the test group (HbA1c = 7.8%) and the control group (HbA1c = 8.3%), which did not receive treatment over the same period, only supragingival scraping and dental polishing, in the same periods in which the patients in the test group received active therapy. After an adjustment of age, sex, ethnicity, smoking habits, duration of diabetes, body mass index, and initial HbA1c level, the difference between the groups was 0.6% (95% CI: 0.3–0.9%), thus remaining significant. This reduction in HbA1c in individuals of the test group after 12 months was compared to the effect of adding a second antidiabetic drug to the conventional treatment. The active periodontal treatment employed proved to be effective, since after one year patients had an average of 27 periodontal pockets > 4 mm smaller (approximately 70%), as well as lower plaque rates (21%), bleeding rates (26%), and average depth gauge (0.8 mm) compared to the control group.¹⁷ Two important points of this study can be mentioned. It was the study with the longer follow-up period after periodontal treatment, one year, and the therapy provided was based on the individual needs of the patients. Patients with good oral hygiene (dental plaque scores ≤ 20%) and at least one 6 mm or deeper residual periodontal pocket at 2 months had periodontal surgical therapy, while patients who still had suboptimum oral hygiene and patients who did not have residual 6 mm or deeper periodontal pockets received additional scaling and root planing.¹⁷

When evaluated together, it is difficult to reach a solid conclusion by compiling the results of these few studies, as they present high heterogeneity from the patient selection to the presentation of results.¹⁰-¹⁷ A clear source of heterogeneity are the discrepancies in the characteristics of the samples in terms of HbA1c levels and for how long the individual had been diagnosed with diabetes at the beginning of the study. In some studies, glycemic levels that are close to the level of adequate control of diabetes may be attributed to the ineffectiveness of periodontal treatment in reducing glycemic levels, since the periodontal therapy would have little effect in a controlled patient with regular medication and a balanced diet because the low level of HbA1c would already be a non-changeable feature, considering that diabetes is a chronic disease with no cure yet.

Another issue that deserves attention is the different method adopted for case definitions of periodontitis,²¹ since the patients’ periodontal profile differs both in severity and in extension in the different studies. For example, Chen et al.¹¹included patients with at least one site with loss of clinical insertion of 1 mm; in the study by D’Aiuto et al.¹⁷there were ≥ 20 periodontal pockets with probing pocket depths of > 4 mm and marginal alveolar bone loss of > 30%, and at least 15 teeth. For comparison, the second study presents a proportion of periodontal pockets ≥ 4 mm almost twice as big as the first (34% vs. 18%). These differences in the initial profile of the patients included in the studies can mitigate the real dimension of the effect of the treatment. The lack of rigorous inclusion criteria can lead to the inclusion of patients with a milder periodontal clinical condition, that is, a systemic inflammatory load that is also less intense as a result of periodontitis. Thus, the effects of the treatment could also be barely noticeable after periodontal therapy.

A systematic review with meta-analysis carried out by the Cochrane collaboration, updated in 2015,¹⁸pointed out that there was low-quality evidence that periodontal treatment, associated or not with the use of antimicrobials, improves the glycemic control of T2DM. This improvement resulted in an average reduction of 0.29% (95%CI: 0.10%–0.48%) of HbA1c, three to four months after the treatment. This is an important and clinically relevant result since the magnitude of HbA1C reductions in this short term obtained after periodontal interventions is similar to that frequently achieved by adding a second medication to a pharmacological regimen.²²

However, there is insufficient evidence that these results are maintained after six months. Periodontal treatment results in an average percentage reduction of HbA1c of -0.02 (95%CI -0.20–0.16; p = 0.84). The quality of the evidence was low due to the high risk of bias and heterogeneity between studies.¹⁸Another important point is that the concomitant use of antibiotics with mechanical therapy might not be beneficial. It should be noted that at the time of publication of this meta-analysis, four studies previously cited had not yet been published¹⁴-¹⁷ and were, therefore, not included here. Among these studies,¹⁴-¹⁷ one had the greatest methodological robustness and another had the best results after one year of periodontal therapy follow-up.¹⁷The inclusion of those studies could modify the magnitude of the observed treatment, as well as the statistical significance of the results.

Identification of patients at risk for diabetes

A population-based study found that individuals with a self-reported family history of diabetes, hypertension, high cholesterol levels, and clinical evidence of periodontitis have a 27-53% probability of having undiagnosed diabetes.²³The study by Lalla et al.²⁴ was able to identify 92% of patients with diabetes or pre-diabetes due to the presence of periodontal pockets greater than five mm associated with tooth loss and the presence of HbA1c ≥ 5.7%. A recently published systematic review has shown that the prevalence of overall clinical assessment of diabetes in patients with periodontitis was 17.3 ± 4%, while in patients without periodontitis it was 11.0 ± 3.1%.²⁵ The odds ratio for individuals with periodontitis to be diagnosed with diabetes was 2.27 (95%CI 1.90–2.72).²⁵

Therefore, it is possible that in addition to the treatment that may be important to improve glycemic control, the dentist may also contribute to the early diagnosis of the diabetic patient, thus contributing to the prevention of possible complications of the disease.

Tooth loss in diabetic patients

Because of the destruction of the tooth support apparatus, severe periodontitis can lead to tooth loss. Total or partial tooth loss is associated with poor DM glycemic control.²⁶,²⁷On average, adults with diabetes lose approximately twice as many teeth as those without DM, and one in five cases of edentulism in the United States is related to this disease,²⁷resulting in significant effects on the oral and general health of people with diabetes. The loss of masticatory function as a result of tooth loss due to severe periodontitis can impact the nutrition of individuals and indirectly influence the glycemic control of those with diabetes.²⁸ Oral rehabilitation should be suggested to restore masticatory function.²²

Future prospects

Periodontal treatment is suggested for the glycemic control of T2DM because of its benefits. If such reductions after periodontal therapy can be maintained over the long term, this can contribute to the reduction of morbidity and mortality associated with diabetes.²⁹Studies that can generate better evidence (RCTs), with a better design, and that can correct biases of previous studies are still needed to better define the patient profile that can be most benefited and the magnitude of this benefit.

Despite limited evidence, it can be interpreted that periodontal treatment can contribute to better glycemic control of T2DM. It is a relevant and effective treatment to interrupt the process of destruction of the gingival tissues, control the present infection, keep the teeth in proper function, and prevent tooth loss. Patients with diabetes must be alerted to the possibility of developing periodontitis and also greater tooth loss. Likewise, patients with periodontitis should be warned that they are at a higher risk for diabetes. Thus, patients should be instructed to seek a periodontist for the correct diagnosis and appropriate treatment. Moreover, periodontists can play a very important role in the early identification of patients with diabetes.

Periodontitis and adverse pregnancy outcomes

In this section on the relationship between periodontitis and adverse pregnancy outcomes, three “landmark periods” will be addressed to present the evolution of this topic in the literature.

In the first period, the 1990s, the first studies on the subject emerged and, despite the methodological limitations at that time, investigations fulfilled their role as pioneers. During this period, Offenbacher et al.³⁰developed the first epidemiological case-control study with women in the postpartum period, of which 93 had had premature children and/or children with low birthweight and 31 were controls, confirming the hypothesis that maternal periodontal disease is associated with this pregnancy outcome.³⁰Other studies on the theme were also carried out, with highlights to Dasanayake,³¹ who outlined an investigation with greater attention to confounding factors, developing a paired case-control study in 110 women, also in the postpartum period. Even then, Davenport et al.³² advanced in terms of the statistical power of the study when they estimated a sample of 800 London women to test the hypothesis.³²During this period, researchers faced challenges related to the epidemiological method, since there was no specific definition of periodontal disease for population-based studies. Despite this, these results contributed to strengthening Periodontal Medicine.

The second period, the 2000s, stands out for the high number of observational studies of different designs, such as cross-sectional, case-control, and cohort, with samples of different sizes, and definitions of periodontitis both dichotomously (presence or absence of the disease) and continuously (with the use of periodontal parameters). In addition to that, there was an evaluation of numerous gestational outcomes that included low birthweight (< 2,500 g) or very low birthweight (< 1,500 g), premature birth (< 37 weeks, or extremely premature < 32 weeks), pre-eclampsia, and miscarriage and/or stillbirth. Although the method of these investigations has been diversified, in general, the findings of these studies have shown that there is a positive/moderate association between periodontitis and gestational outcomes. Scientific evidence from this period, composed of observational studies reviewed until May 2012 and summarized in the annals of a workshop held jointly by the European Federation of Periodontology and the American Academy of Periodontics, published in 2013, strengthened the biological plausibility of the association between periodontitis and gestational outcomes.³³

Since then, findings have supported the theory that periodontitis promotes the hematogenous dissemination of the oral microbiota and its products, which directly reach the fetoplacental unit and induce immune-inflammatory responses. Indirectly, these inflammatory mediators produced in periodontal tissues, such as prostaglandin E₂ and tumor necrosis factor, reach the bloodstream and will impact the fetoplacental unit. They can also reach the liver and induce greater production of cytokines, including interleukin-6, and acute-phase proteins, such as C-reactive protein.³⁴

Thus, according to the gestational period and the severity of the disease, periodontitis promotes undesirable pregnancy outcomes. Premature birth could be caused by exposure of the pregnant woman to less severe forms of periodontitis. Growth restriction and extreme prematurity would be due to exposure to more severe periodontitis and in an early gestational period. Even more serious exposures of periodontitis could induce spontaneous abortion, late abortion, and stillbirth.³⁴

Still in the 2000s, in the annals of the aforementioned event, a review identified 13 randomized clinical trials on periodontal interventions and their effect on the occurrence of premature birth and low birthweight until July 2012.³⁵The findings, obtained based on the quality and power of the investigations, suggested that non-surgical periodontal treatment in pregnant women did not reduce the risk of these outcomes.

In the third period, which concerns knowledge from the decade of 2010, studies reaffirm theories regarding biological plausibility between exposure to periodontitis and adverse pregnancy outcomes through direct and indirect pathways triggered by periodontopathogens, previously described, reinforcing that the direct route, that is, hematogenous transmission due to dental bacteremia, has remained the most accepted and the most investigated route in recent years. Also, exposure to oral infection is confirmed by the presence of microorganisms and their products in the fetoplacental unit, as well as serum and placental inflammatory biomarkers of the pregnant woman. This set of mechanisms would promote a metastatic infection, of a different extent, resulting in adverse pregnancy effects.³⁶

As for the most recent epidemiological investigations on the subject, it appears that observational studies need improvement in methodological quality, by increasing the size of the samples evaluated, the appropriate definition of periodontitis for a younger population group, and an improved method of statistical analysis. Furthermore, it is also important to advance in a more comprehensive conceptual and theoretical model, with effective treatment of confounding covariables and evaluation of interaction factors, also called effect modifiers.

The relevance of modifiers in the association between periodontitis and adverse pregnancy outcomes was highlighted by Beck et al.²¹ and encouraged methods of subgroup analysis to attribute greater validity and precision to the association measurements. The authors drew attention to the findings of Gomes-Filho et al.,³⁷ who studied the association between exposure to periodontitis and newborns with low weight in women with a normal level of HbA1c. In women with a high level of HbA1c, the association disappeared, with a possible influence of the maternal glycemic level on birthweight. Thus, specific woman-related factors that are not measured may account, in part, for the contradiction of the findings related to the hypothesis.

Regarding periodontal therapy, according to a Cochrane systematic review,³⁸non-surgical interventions during the second quarter of pregnancy are safe. Furthermore, there is poor-quality evidence that periodontal treatment can reduce low birthweight and there are not enough findings to determine which type of periodontal treatment is best. Despite the findings of better quality, randomized controlled trials point to the lack of effect of the treatment on the prevention of adverse pregnancy outcomes.³⁵,³⁸,³⁹

These results show that only one type of intervention applied at a specific time during the gestational period of approximately 37 weeks is not able to change the outcome of the pregnancy. Nevertheless, it can be considered, at the level of biological plausibility, that, in the existence of periodontitis even before and during the gestational period, the pathogens would already be present in the fetoplacental unit and the effects of periodontal therapy during pregnancy to reduce bacteremia would not be enough to prevent the clinical condition that was already installed.

These findings by themselves do not demonstrate the inexistence of a causal relationship between infection/periodontal inflammation and adverse pregnancy outcomes. The period between the first clinical trial and the most recent is still short and many scientific advances need to be achieved for methodological improvement on this topic.

In this sense, the need for improvement in data analysis procedures must be highlighted. For example, Merchant et al.⁴⁰reanalyzed data from the Obstetrics and Periodontal Therapy (OPT) randomized controlled trial,⁴¹which had not reported the effect of periodontal treatment on premature births. In this reanalysis, when considering miscarriages or stillbirths, which were more frequent in the control group, the therapy seemed to be beneficial to the participants. For this purpose, new epidemiological methods were employed, such as the survivor average causal effect (SACE), which corrected the potential bias resulting from unequal fetal survival in the treatment and control groups. Thus, the periodontal treatment provided to mothers with mild to moderate periodontitis, when done before the 21st week of gestation, prevented premature births.⁴⁰

Thus, it seems plausible to consider the inclusion of periodontal treatment in a group of recommended procedures for preparing for pregnancy. In summary, the future of investigations related to periodontitis and adverse pregnancy outcomes must follow a path of incorporating the improvement of conceptual and methodological elements on the topic (Figure).

Figure
Possible future timeline for investigations into periodontitis and adverse pregnancy outcomes.

Cardiovascular diseases

The relationship between periodontitis and cardiovascular diseases (CVD) has been verified by epidemiological studies. A meta-analysis based on 22 case-control and cross-sectional studies presented an odds ratio of 2.35 (95%CI 1.87–2.96) for the existence of CVDs in patients with periodontitis.⁴²This same meta-analysis, while evaluating solely longitudinal studies, concluded that the risk of developing CVDs was significantly higher in patients with periodontitis. And the relative risk observed was 1.34 (95%CI 1.27–1.42). More recently, after adjustments for potential confounding factors, severe periodontitis has been associated as an agent responsible for causing myocardial infarction exclusively in women, especially those under the age of 65.⁴³ A prospective study indicated an association between periodontitis and mortality in a homogeneous population of men aged between 60 and 70 years in Western Europe. The risk of death in men with greater loss of periodontal insertion was 1.57 (1.04–2.36) after adjustments for confounding factors (age, smoking, hypertension, BMI, cholesterol level, and previous history of cardiovascular events).⁴⁴Sharma et al.⁴⁵verified in a longitudinal study an association between periodontitis and increased mortality in individuals with chronic kidney disease.

Figuero et al.³⁶ identified bacterial DNA associated with periodontitis in atheromatous carotid plaques. These findings may offer additional evidence to support the association between periodontitis and CVDs. However, the mere presence of bacterial DNA does not imply that live bacteria would be present on atheromatous plaques. Moreover, additional studies should evaluate microbiological data on the atheromatous plaque and on the dental biofilm of these patients to confirm this direct relationship between periodontitis and CVDs. On the other hand, edentulism was associated with an increased risk of CVDs and mortality in postmenopausal women, whereas the presence of self-reported periodontitis was associated with an increase in the mortality rate of such subjects.⁴⁶ Poor oral health, calculated by the number of remaining teeth, was related to the incidence of myocardial infarction and heart failure over an average length of time of 15.8 years. However, such association was not related to stroke occurrence, which suggests that oral health is not related in the same manner to the main cardiovascular disorders.⁴⁷

While several studies have pointed out an association between periodontitis and CVDs, others have not shown such an association. Several factors have contributed to these conflicting results, like different study designs, great variety in the size of the samples, and more, which results in substantial differences concerning their statistical powers and in difficulties in establishing a consensus on the definition of periodontitis as an exposure. The use of numerous diagnostic criteria makes comparing and interpreting the results of different studies a difficult task. Clinical parameters such as bleeding on probing, depth of pocket on probing, clinical level of insertion, bone loss, and tooth loss were used as markers of periodontitis. Periodontal evaluation often included the use of partial indices. Partial indices (CPITN) and questionnaires underestimate the true extent and severity of the periodontal disease and can lead to misdiagnosis. In addition to these factors, the control of confounding factors may vary, with different parameters being used in each study. Additionally, most longitudinal studies evaluated only the prevalence of periodontitis and its relationship with future cardiovascular outcomes.

The incidence of periodontitis was significantly associated with an increased risk of cardiovascular events.⁴⁸The association between the prevalence of periodontitis and the incidence of CVDs can be mitigated by performing periodontal treatment over the years of follow-up. However, despite all the differences mentioned above, meta-analysis demonstrated a mild to moderate association between periodontitis and CVDs.⁴²,⁴⁹

Studies evaluating the effect of periodontal treatment are key to determine the causal relationship between periodontitis and CVDs. The idea is that randomized clinical studies demonstrate a decrease in the “effect” (cardiovascular events) by eliminating the “cause” (periodontitis). Such evidence, so far, does not exist. Conducting this type of study is difficult, since many challenges must be overcome, like sample size, follow-up time (with all associated ethical problems), presence of comorbidities, concomitant medications, effective periodontal treatment, and periodontal maintenance. A sample calculation simulation for this type of study illustrates the magnitude of the issue. Approximately 9,600 patients per group would be required to demonstrate a 20% relative risk reduction of a second heart attack in patients who received periodontal treatment after the first heart attack when compared to patients who did not receive periodontal treatment, with α = 0.05 and β = 0.10.⁵⁰

Studies investigating the effects of periodontal treatment have mainly focused on two aspects: evaluations of soluble biomarkers, such as C-reactive protein (CRP) and LDL cholesterol, and the use of imaging technologies, such as the thickness of the intima-media of the carotid artery and ultrasound of the brachial artery. Additionally, some studies have evaluated the relationship between dental treatment and reduced risk of cardiovascular events.

Several studies have evaluated the impact of periodontal treatment in reducing blood levels of inflammatory substances, which are considered to be risk markers for CVDs. Patients with periodontitis have higher levels of CRP when compared to healthy controls.⁵¹The magnitude of this difference is clinically significant, since it is high enough to place them at levels of greater risk for CVD. D’Aiuto et al.¹⁹conducted one of the first studies evaluating the effect of periodontal treatment on systemic inflammation and exposed that periodontal therapy resulted in a dose-dependent decrease in serum CRP levels. A meta-analysis has shown that periodontal treatment decreased serum levels of CRP by about 0.5 mg/l.⁵² In a 6-month randomized clinical study, Caúla et al.⁵³ demonstrated that periodontal treatment reduced serum levels of CRP by 50%. Other studies have indicated that periodontal treatment significantly decreased serum CRP levels in patients suffering solely from periodontitis and other associated diseases, such as chronic kidney disease and refractory arterial hypertension.⁵⁴,⁵⁵ Thus, periodontal treatment can reduce CRP levels for the low cardiovascular risk category. These findings are important since high levels of CRP are excellent predictors of the development of atherosclerosis, AMI, and death. Another strong risk marker for CVDs is fibrinogen, which is associated with the development or presence of atherothrombosis. Its levels are also significantly reduced after periodontal treatment. A study carried out by our group demonstrated a significant reduction in fibrinogen levels in patients with periodontitis and refractory arterial hypertension after periodontal therapy.⁵⁶,⁵⁷

Circulating levels of proinflammatory cytokines are also higher in patients with periodontitis when compared to healthy patients. The same is also true when comparing patients with CVDs and periodontitis and those who suffer solely from CVDs. Although several studies point to significant effects of periodontal treatment in reducing the levels of pro-inflammatory cytokines, the results are still very controversial. The difficulty in accurately measuring the levels of cytokines in the blood may contribute to this condition. Cytokines in the blood are linked to other proteins and only a small portion of the total can be detected, since commonly used tests detect only their unbound fractions.⁵⁸ However, significant reductions in IL-6 and TNF-α occur after periodontal treatment.⁵⁹

Dyslipidemia is one of the main modifiable risk factors for CVDs. Several lipid markers have been identified as traditional biomarkers associated with CVDs, including LDL and HLD cholesterol, total cholesterol, and triglycerides. Numerous studies have shown that reductions in LDL levels are associated with decreases in cardiovascular risk. The magnitude of the reduction in cardiovascular events is related to the extent of LDL reduction, with each decrease of 40 mg/dl (1 mmol/l) corresponding to a 24% reduction in cardiovascular events.⁶⁰ Likewise, the increase in HDL has been associated with a decrease in cardiovascular risk. Each increase of 1 mg/dl (0.03 mmol/l) in HDL is associated with a 2 to 3% reduction in the risk of future coronary heart disease.⁶¹ A meta-analysis has discovered significant improvements in total cholesterol and HDL levels after periodontal therapy. Interestingly, patients with periodontitis and comorbidities are those who benefit the most from improvements resulting from periodontal treatment.⁵⁹

Hypertension is widely recognized as a risk factor for cardiovascular events. Periodontitis is associated with a higher risk of high blood pressure. In addition, the management of periodontitis can influence the management of hypertension. The outcomes of CVDs may be better if the poor oral health of the general population is taken into account.⁶² On the other hand, a reduction of 7 mmHg in systolic blood pressure was observed two months after intensive periodontal treatment. This reduction was more pronounced in smoking patients.⁶³ Reductions of 12.5 mmHg and 10 mmHg in systolic and diastolic pressures, respectively, have been reported after periodontal therapy in patients with refractory arterial hypertension, in addition to a reduction in left ventricular mass.⁵⁷This reduction is equivalent to the introduction of another medication for the control of hypertension. A meta-analysis has shown that a reduction of 10 mmHg in systolic pressure and 5 mmHg in diastolic pressure, with the use of any of the main classes of antihypertensive drugs, reduces cardiovascular events (fatal and non-fatal) by about 25%, stroke by about 33%, and heart failure by about 25% as well.⁶⁴ Czesnikiewicz-Guzik et al.⁶⁵evaluated the effect of periodontal treatment in patients with arterial hypertension through a 2-month randomized clinical study. The group that received periodontal treatment had a significant reduction in systolic blood pressure (mean difference of -11.1 mmHg; 95%CI 6.5–15.8; p < 0.001), correlating with an improvement in periodontal status. Diastolic pressure and endothelial function also improved after periodontal treatment. These cardiovascular improvements were accompanied by reduced levels of IFN-c and IL-6.⁶⁵

Patients with chronic kidney disease present an increased risk of death originated by problems associated with atherosclerosis. The increase in CRP levels is a risk indicator for the progression of atherosclerosis in this group of patients, especially patients on pre-dialysis and hemodialysis. Brito et al.⁶⁶ have shown that periodontitis was associated with high levels of CRP in pre-dialysis and hemodialysis patients. On the other hand, periodontal treatment in pre-dialysis patients improved the glomerular filtration rate, indicating an improvement in renal function.⁶⁷

Another common target of periodontal pathogens and circulating cytokines is the endothelium, which plays a central role in the regulation of vascular homeostasis. The reduction in endothelium-dependent vascular reactivity characterizes the condition of endothelial dysfunction, which is currently considered the initial stage for the development of atherosclerosis.⁶⁸ Studies have shown that periodontitis was associated with endothelial and microvascular dysfunction.⁶⁹,⁷⁰Tonetti et al.⁷¹ evaluated the effect of periodontal therapy on endothelial dysfunction. Systemically healthy patients with severe generalized periodontitis were randomized into two treatment groups: control (supra-gingival scraping), and test (periodontal therapy). Six months later, the group that received periodontal therapy showed a significant improvement in endothelial function. In the control group, there was no change in endothelial function. The treatment effect was dose-dependent, with a significant correlation between the reduction in the number of periodontal pockets and bleeding on probing and improvement in endothelial function. Similar results were found in patients with hypertension and CVD.⁵⁶,⁷⁰,⁷²

The first signs of carotid atherosclerosis are usually measured by the thickness of the intima layer of the carotid arteries. This measure receives considerable attention, since it is highly correlated with diseases in the carotid arteries and is considered a good predictor of cerebral and ischemic cardiovascular events. An increase in this thickness occurs in patients with periodontitis, even in early stages, without clinical evidence of atherosclerosis. Patients with refractory arterial hypertension who received periodontal therapy significantly reduced the values of intima-media thickness after six months.⁵⁶A recent randomized clinical trial has also shown a significant reduction in the thickness of the intima-media after periodontal treatment.⁷³

So far, concrete data on the effects of treatment on cardiovascular morbidity and mortality do not exist. Paju et al.⁷⁴ evaluated 141 patients with acute infarction or unstable angina who participated in a controlled clinical trial using clarithromycin for three months. According to the authors, antibiotic therapy would have an impact on the progression of chronic infections, including periodontitis, and could result in a reduction in cardiovascular events. After an average follow-up of 519 days, the authors noted that the use of clarithromycin was not beneficial in preventing recurrent cardiovascular events in patients with periodontitis compared to healthy patients. A pilot study with 303 participants was conducted to assess the feasibility of a secondary prevention clinical trial to investigate whether periodontal treatment reduces the risk of CVD. After 25 months of follow-up, the frequency of adverse cardiovascular events was similar between the group that received periodontal treatment (oral hygiene instruction and scaling, and root planing using a piezoelectric ultrasonic scraper) and the group that received community care (oral hygiene instruction and referral letter to seek periodontal treatment).⁷⁵ It is worth mentioning that all patients had their teeth with poor prognosis extracted before randomization. Of the patients assigned to the community care group, 48% received periodontal or preventive treatments.⁷⁶

On the other hand, Lee et al.⁷⁷demonstrated that patients with periodontitis who received treatment had a lower risk of stroke. Regular use of dental services (dental care at least once a year) was also associated with a reduced risk of stroke over 15 years of follow-up.⁷⁸Holmlund et al.⁷⁹reported that patients who did not respond satisfactorily to periodontal treatment, which means they presented > 10% of periodontal pockets > 4 mm and ≥ 20% of sites with bleeding on probing one year after active treatment, had an increased risk of CVDs during a median follow-up of 16.8 years.⁷⁹Interestingly, hemodialysis patients who received intensive periodontal treatment had a 22% reduction in the risk of CVD.⁸⁰

A recent study based on data from an insurance company retrospectively tested the hypothesis that periodontal treatment would reduce medical costs and hospitalizations for five years after treatment in patients with some systemic conditions. Significant reductions in medical costs and hospitalizations were observed in patients with coronary artery diseases and cerebrovascular diseases.⁸¹ According to a systematic review, no study investigating the primary prevention of CVDs in patients with periodontitis has been found. The only secondary prevention study found had a high risk of bias. Therefore, the evidence found was insufficient and of low quality to support or refute the role of periodontal therapy in preventing CVD recurrence in patients with periodontitis.⁸²

Oral health status and pneumonia

It has been known for some time that poor oral health and the oral microbiome and oral inflammation it entails play an important role in the pathogenesis of several respiratory diseases, particularly pneumonia, but also chronic obstructive pulmonary disease and asthma.⁸³ Based on this knowledge, multiple oral interventions have been explored to prevent respiratory infections in high risk patients. This section of this article, which will review the role of poor oral health in lower respiratory infections, is a synopsis of a recently published article that summarized the role of the oral cavity in lower airway infection.⁸⁴

Pneumonia, the inflammatory condition of the lung parenchyma initiated by aspirated microorganisms into the lower airways from proximal sites like the oral and nasal cavities, is a common disease causing significant morbidity and mortality. Pneumonia is classified according to the location of the origin of the etiologic infectious agents (i.e., from the community vs. from within a healthcare institution, the so called nosocomial pneumonia). Pneumonia and influenza together are major causes of death⁸⁵ and are associated with substantial morbidity and economic cost.⁸⁶ Hospital acquired infections (HAP) are those that occur > 48 hours after admission to a hospital or other residential healthcare facility (such as a nursing home). Most patients who contract HAP are infants, young children, and persons > 65 years of age; persons with severe underlying disease, immunosuppression, neurological deficit; and patients undergoing abdominal surgery. HAP can be further divided into two subtypes: ventilator-associated pneumonia (VAP) and non-ventilator-associated pneumonia (NV-HAP).⁸⁷,⁸⁸ Pneumonia is the most common infection in the intensive care unit (ICU) setting, accounting for 10% of infections in ICUs.⁸⁹

Poor oral health status has been associated with the pneumonia etiology. As a result, there has been considerable interest to determine whether oral care can interrupt the process of lung infection to prevent the disease, especially in high risk groups such as the elderly and hospitalized patients.⁹⁰

A complex microbial community resides on the surfaces of the lower airways of healthy subjects.⁹¹ The use of sterile bronchoalveolar lavage sampling techniques has allowed examination of the lower airway in healthy subjects, who are now known to harbor small populations of bacteria. The evidence to date suggests that dispersal of microbes from the oral cavity is the primary driver of the healthy lung microbiome.⁹² Pneumonia patients often harbor multiple species of bacteria and microbes that are normally indigenous to the oral cavity.

The oral cavity serves as an important reservoir of lung infection, particularly in high risk subjects like mechanically ventilated and elderly nursing home patients. When a patient is ventilated, an endotracheal tube is placed through the oral cavity into the lower airway to provide oxygen into the lower airway, and the tube often becomes colonized with microbes from the oral cavity, which subsequently form a biofilm and promote VAP. A “microbial shift” occurs in the dental plaque of ventilated patients, with colonization by potential VAP pathogens that seed the lower airways via endotracheal tube biofilms.⁹³ Molecular epidemiology techniques have been used to demonstrate that respiratory pathogens isolated from the lung are genetically indistinguishable from strains of the same species isolated from the oral cavity in hospital patients who receive mechanical ventilation.⁹⁴,⁹⁵ Another study used molecular techniques to assess the impact of oral hygiene status on the composition of the microbiome of the bronchoalveolar lavage fluid (BALF) directly obtained from lungs suspected to have pneumonia. Poor oral hygiene was found to be significantly associated with anaerobes in the lungs of patients with pneumonia.⁹⁶

Metataxonomics, a recently developed approach to assess microbial diversity that uses data from high-throughput sequencing to identify microorganisms and viruses within a complex mixture, found no significant differences in the microbial communities between the microbiome of dental plaque, endotracheal tubes (ETTs), and non-directed bronchial lavages (NBLs) in mechanically ventilated patients’ samples, and most bacteria detected were oral species and respiratory pathogens (Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumoniae, and Haemophilus influenzae).⁹⁷

Poor oral health is also connected to aspiration pneumonia, especially in the case of nursing home residents.⁹⁸-¹⁰⁰ There is also some evidence that periodontal disease may be associated with risk for pneumonia in elderly patients. A study of an elderly Japanese population found that the adjusted mortality due to pneumonia was 3.9 times higher in persons with 10 or more teeth with a probing depth exceeding 4 mm (i.e., with periodontal pockets) than in those without periodontal pockets.¹⁰¹ A case-control study compared 85 cases with nosocomial pneumonia against 230 controls without nosocomial pneumonia, employing a full-mouth periodontal examination of all subjects.¹⁰²Individuals with periodontitis had a three-fold excess risk pneumonia compared to the control group without periodontal disease, following adjustment for a variety of potential confounding variables. It has also been suggested that the number of teeth may also impact the risk for pneumonia, with a direct relationship between number of teeth lost and pneumonia reported.¹⁰³

Taken together, these and other published findings suggest that oral biofilm is an important reservoir for the microbes that are aspirated into the lower airway and attach to the endotracheal tube.

In light of these findings, oral hygiene or periodontal therapy could help prevent the onset or progression of pneumonia in high-risk patients. Several studies have evaluated the effectiveness of oral care to prevent pneumonia in nursing home patients; for example, mechanical oral care, in some cases in combination with povidone iodine, has been shown to have a moderate effect in reducing the risk of pneumonia in nursing home residents.¹⁰⁴-¹⁰⁷A recent study has shown that the loss of oral self-care ability along with gender (male) and malnutrition can increase the risk of pneumonia in elderly patients.¹⁰⁸ In addition, once-a-week professional oral cleaning significantly reduced influenza infections in an elderly population.¹⁰⁹

Implementation of professional oral care programs in nursing facilities, involving the use of dental hygienists to provide direct oral care, including tooth, tongue, and denture brushing, may help reduce the oropharyngeal microbial burden and therefore the number of microbes that can be aspirated into the lower airway.¹¹⁰ Such an approach may also reduce the risk of other respiratory infections, like influenza.¹¹¹ This idea is supported by a recent systematic review that reported evidence that oral care interventions given by dental personnel in elderly adults were more effective on mortality from HAP than oral care interventions given by nursing personnel in hospitals and in nursing homes.¹¹²

Some studies have not supported the effectiveness of oral care to prevent pneumonia in nursing homes.¹¹³ A unique cluster-randomized study of 834 nursing home patients, followed over the course of a year, has shown no benefit of a comprehensive oral care program, which included tooth brushing, topical chlorhexidine, and upright positioning during feeding. The lack of effect could be explained by several possibilities, including less than ideal staff adherence to the intervention protocol, control home usual oral care may have been modified after study initiation to more closely resemble the intervention arm, or changes in the microbial flora over time in response to the implementation of the intervention.

Overall, oral cleansing protocols have been shown to reduce pneumonia in both edentulous and dentate subjects, suggesting that oral colonization of bacteria contributes to nosocomial pneumonia to a greater extent than periodontitis per se. However, intervention studies where periodontitis is treated on the incidence of pneumonia have not been performed due to the complexities imposed by ICU or bed-bound nursing home patients. It has been suggested that dental services are underutilized by nursing home residents. Thus, more effort must be made to improve the frequency and effectiveness of oral care protocols in nursing homes.¹¹⁴

More recent associations between periodontitis and other diseases

Despite the tremendous progress made by periodontal medicine since the early 1990s, new associations and, more importantly, the elucidation of the biological mechanisms for such associations continue to emerge. A systematic review conducted in 2016 revealed that periodontitis has been linked to 57 other systemic diseases.¹¹⁵ Periodontal medicine has been shown to be quite dynamic and in constant evolution, however, a future challenge will be to demonstrate convincingly that the prevention and treatment of periodontitis will bring significant benefits to other diseases.¹¹⁶

Among the associations that have gained more attention recently, we can highlight inflammatory bowel disease, several types of cancer, and Alzheimer’s disease. In this sense, the interrelation between the oral and intestinal ecosystems appears as a new frontier for periodontal medicine. Changes in the oral microbiota concerning oral and systemic diseases have been the focus of constant investigation.¹¹⁷,¹¹⁸ Several reports have shown that microorganisms from the oral cavity can overcome physical and chemical barriers and colonize other sites, potentially contributing to the emergence and/or aggravation of other diseases. Studies have shown the growth of oral bacteria in the intestinal microbiota of patients with several diseases.¹¹⁹,¹²⁰,¹²¹Experimental studies have shown that oral administration of P. gingivalis causes changes in the intestinal microbiota and intestinal epithelial barrier, together with changes in the liver and adipose tissue.¹²²,¹²³In line with these findings, individuals with periodontitis have shown changes in the intestinal microbiome, such as less diversity and an increase in the Firmicutes / Bacteroidetes ratio.¹²⁴

Epidemiological studies have shown that individuals with inflammatory bowel disease were more likely to have periodontitis.¹²⁵On the other hand, the presence of periodontitis increased the risk of developing ulcerative colitis, one of the types of inflammatory bowel disease, over a 13-year follow-up.¹²⁶Despite limited epidemiological evidence pointing to periodontitis as a possible risk factor for inflammatory bowel disease, substantial studies in animal models are beginning to point out the possible biological mechanisms by which periodontal disease and oral pathogens contribute to inflammatory bowel disease. Oral bacteria have been shown to colonize and persist in the intestine, activating the immune system and causing chronic inflammation in a susceptible host. Klebsiella strains isolated from saliva can induce a strong T helper 1 cell response in the intestine in the context of intestinal dysbiosis and induce colitis in genetically susceptible hosts.¹²⁷ More recently, it has been shown that oral pathobionts, including Klebsiella species, increase their number in periodontitis and can trigger an inflammatory response in the intestine through two mechanisms. First, when colonizing the intestine, oral pathobionts activate the local immune system, triggering the production of IL-1β and colitis. Second, T helper 17 cells that appear during periodontitis can migrate to the intestine and be activated by oral pathobionts that colonized the intestine and lead to the development of colitis.¹²⁸ These discoveries reveal new mechanisms of how periodontitis can influence other pathogenic processes in sites far from the oral cavity and open new paths for investigating the clinical and therapeutic impact of periodontitis.

The role of the oral microbiota in the development of cancer, especially Fusobacterium nucleatum and colorectal cancer, has been the focus of research and has recently been reviewed.¹²⁹This relationship is based on the premise that periodontitis facilitates bacterial translocation to other parts of the body, where dysbiosis, chronic inflammation, and breaking of the epithelial barrier synergize to favor carcinogenesis.¹²⁹ Recent evidence that analyzed paired samples of saliva and colorectal cancer suggested that the origin of F. nucleatum in cancerous tissue is the oral cavity and that the hematogenic pathway may be the preferred one for its dissemination and colonization of the tumor.¹³⁰Also, an increase in Fusobacterium spp. has been observed in colon adenoma compared to healthy adjacent tissue, as well as in the feces of patients with adenoma and colorectal cancer compared to healthy controls,¹³¹ and the amount of F. nucleatum DNA in cancerous tissue is positively associated with the specific mortality from colorectal cancer.¹³² As for the mechanisms for such an association, F. nucleatum inhibits the cytotoxicity of NK (natural killer) cells and the activities of lymphocytes that infiltrate the tumor tissue through the interaction of bacterial protein Fap2 with the TIGIT receptor.¹³³ Similarly, associations with other types of cancer have also been proposed, for example, with lung and pancreatic cancer.¹²⁹,¹³⁴It is noteworthy that the existing epidemiological evidence points mainly to a positive association between periodontal disease and cancer risk, however, it still lacks more robust analyses.¹³⁴

Another aspect of periodontal medicine that has gained a lot of attention in the last decade is the relationship with neurodegenerative diseases, particularly Alzheimer’s disease, in which evidence indicates that periodontal disease can induce systemic inflammation, disruption of the blood-brain barrier, degeneration, and cognitive impairment.¹³⁵ Epidemiological studies show an association between periodontitis and Alzheimer’s disease.¹³⁶,¹³⁷ A post-mortem analysis of brain tissue has shown that Treponema species were detected more frequently and in greater proportions in Alzheimer’s patients than in controls.¹³⁸Furthermore, a positive association has been demonstrated between loss of clinical insertion and accumulation of amyloid in the brain of cognitively normal elderly people.¹³⁹Studies in vitro and in animal models have provided biological plausibility for such a relationship. For example, DNA from P. gingivalis and gingipains was found in the brain affected by Alzheimer’s disease, and oral administration of gingipain inhibitors in an animal model was able to reduce the load of P. gingivalis in the brain, the production of β amyloid, and neuroinflammation.¹⁴⁰However, the clinical impact of such inhibitors on the management of neurodegeneration deserves careful investigation.

Final considerations

According to the most recent scientific evidence, Periodontal Medicine is a significant topic in dental and craniofacial research and should continue to advance, since in many areas the time of investigation makes the topic still very incipient and “underexplored”. Therefore, improvement of the epidemiological method is necessary through conceptual and methodological elements.

In this sense, the power of studies can be emphasized. The studies must be presented with sufficient sample sizes so that it is possible to evaluate several confounder and modifier covariables, as well as to allow advances in the methods of data analysis. As for the confounding factors, the importance of incorporating conceptual theoretical models related to the socioeconomic condition of the studied populations is also emphasized. Regarding the modifying covariables, the sample needs to be of a scope that allows it to be divided into subgroups, without losing the power of the studies.

The full-mouth periodontal examination is essential for defining periodontitis cases, since association studies need the diagnosis of the periodontal condition to have greater specificity. That should also help avoid the incorporation of false-positive diagnoses that will influence the magnitude of the association between periodontitis and the outcome under investigation. Also, it is crucial to improve the type of periodontal therapy used in interventional studies, advancing towards the possibility of individualized periodontal treatment.

Thus, the future of Periodontal Medicine must follow paths that are increasingly closer to the continuous advances in the epidemiological method, considering that the individual with periodontitis may present a hyperinflammatory phenotype, a common condition, concomitant with other chronic diseases, and this oral condition is the signal for the diagnosis of the “inflamed individual”.

References

• ¹ Kinane DF, Stathopoulou PG, Papapanou PN. Periodontal diseases. Nat Rev Dis Primers. 2017 Jun;3(1):17038. https://doi.org/10.1038/nrdp.2017.38
  » https://doi.org/10.1038/nrdp.2017.38
• ² Cullinan MP, Seymour GJ. Periodontal disease and systemic illness: will the evidence ever be enough? Periodontol 2000. 2013 Jun;62(1):271-86. https://doi.org/10.1111/prd.12007
  » https://doi.org/10.1111/prd.12007
• ³ Garcia D, Tarima S, Okunseri C. Periodontitis and glycemic control in diabetes: NHANES 2009 to 2012. J Periodontol. 2015 Apr;86(4):499-506. https://doi.org/10.1902/jop.2014.140364
  » https://doi.org/10.1902/jop.2014.140364
• ⁴ Taylor GW, Burt BA, Becker MP, Genco RJ, Shlossman M, Knowler WC, et al. Severe periodontitis and risk for poor glycemic control in patients with non-insulin-dependent diabetes mellitus. J Periodontol. 1996;67(10s Suppl 10S):1085-93. https://doi.org/10.1902/jop.1996.67.10s.1085
  » https://doi.org/10.1902/jop.1996.67.10s.1085
• ⁵ Saremi A, Nelson RG, Tulloch-Reid M, Hanson RL, Sievers ML, Taylor GW, et al. Periodontal disease and mortality in type 2 diabetes. Diabetes Care. 2005 Jan;28(1):27-32. https://doi.org/10.2337/diacare.28.1.27
  » https://doi.org/10.2337/diacare.28.1.27
• ⁶ Costa KL, Taboza ZA, Angelino GB, Silveira VR, Montenegro R Jr, Haas AN, et al. Influence of periodontal disease on changes of glycated hemoglobin levels in patients with type 2 diabetes mellitus: a retrospective cohort study. J Periodontol. 2017 Jan;88(1):17-25. https://doi.org/10.1902/jop.2016.160140
  » https://doi.org/10.1902/jop.2016.160140
• ⁷ Shultis WA, Weil EJ, Looker HC, Curtis JM, Shlossman M, Genco RJ, et al. Effect of periodontitis on overt nephropathy and end-stage renal disease in type 2 diabetes. Diabetes Care. 2007 Feb;30(2):306-11. https://doi.org/10.2337/dc06-1184
  » https://doi.org/10.2337/dc06-1184
• ⁸ Taylor JJ, Preshaw PM, Lalla E. A review of the evidence for pathogenic mechanisms that may link periodontitis and diabetes. J Periodontol. 2013 Apr;84(4 Suppl):S113-34. https://doi.org/10.1111/jcpe.12059
  » https://doi.org/10.1111/jcpe.12059
• ⁹ Artese HP, Foz AM, Rabelo MS, Gomes GH, Orlandi M, Suvan J, et al. Periodontal therapy and systemic inflammation in type 2 diabetes mellitus: a meta-analysis. PLoS One. 2015 May;10(5):e0128344. https://doi.org/10.1371/journal.pone.0128344
  » https://doi.org/10.1371/journal.pone.0128344
• ¹⁰ Katagiri S, Nitta H, Nagasawa T, Uchimura I, Izumiyama H, Inagaki K, et al. Multi-center intervention study on glycohemoglobin (HbA1c) and serum, high-sensitivity CRP (hs-CRP) after local anti-infectious periodontal treatment in type 2 diabetic patients with periodontal disease. Diabetes Res Clin Pract. 2009 Mar;83(3):308-15. https://doi.org/10.1016/j.diabres.2008.10.016
  » https://doi.org/10.1016/j.diabres.2008.10.016
• ¹¹ Chen L, Luo G, Xuan D, Wei B, Liu F, Li J, et al. Effects of non-surgical periodontal treatment on clinical response, serum inflammatory parameters, and metabolic control in patients with type 2 diabetes: a randomized study. J Periodontol. 2012 Apr;83(4):435-43. https://doi.org/10.1902/jop.2011.110327
  » https://doi.org/10.1902/jop.2011.110327
• ¹² Engebretson SP, Hyman LG, Michalowicz BS, Schoenfeld ER, Gelato MC, Hou W, et al. The effect of nonsurgical periodontal therapy on hemoglobin A1c levels in persons with type 2 diabetes and chronic periodontitis: a randomized clinical trial. JAMA. 2013 Dec;310(23):2523-32. https://doi.org/10.1001/jama.2013.282431
  » https://doi.org/10.1001/jama.2013.282431
• ¹³ Zhang H, Li C, Shang S, Luo Z. Scaling and root planing with enhanced root planing on healthcare for type 2 diabetes mellitus: a randomized controlled clinical trial. J Dent Sci. 2013;8(3):272-80. https://doi.org/10.1016/j.jds.2012.10.009
  » https://doi.org/10.1016/j.jds.2012.10.009
• ¹⁴ Artese HP, Longo PL, Gomes GH, Mayer MP, Romito GA. Supragingival biofilm control and systemic inflammation in patients with type 2 diabetes mellitus. Braz Oral Res. 2015;29(1):29. https://doi.org/10.1590/1807-3107BOR-2015.vol29.0071
  » https://doi.org/10.1590/1807-3107BOR-2015.vol29.0071
• ¹⁵ Wu Y, Chen L, Wei B, Luo K, Yan F. Effect of non-surgical periodontal treatment on visfatin concentrations in serum and gingival crevicular fluid of patients with chronic periodontitis and type 2 diabetes mellitus. J Periodontol. 2015 Jun;86(6):795-800. https://doi.org/10.1902/jop.2015.140476
  » https://doi.org/10.1902/jop.2015.140476
• ¹⁶ Mizuno H, Ekuni D, Maruyama T, Kataoka K, Yoneda T, Fukuhara D, et al. The effects of non-surgical periodontal treatment on glycemic control, oxidative stress balance and quality of life in patients with type 2 diabetes: A randomized clinical trial. PLoS One. 2017 Nov;12(11):e0188171. https://doi.org/10.1371/journal.pone.0188171
  » https://doi.org/10.1371/journal.pone.0188171
• ¹⁷ D’Aiuto F, Gkranias N, Bhowruth D, Khan T, Orlandi M, Suvan J, et al. Systemic effects of periodontitis treatment in patients with type 2 diabetes: a 12 month, single-centre, investigator-masked, randomised trial. Lancet Diabetes Endocrinol. 2018 Dec;6(12):954-65. https://doi.org/10.1016/S2213-8587(18)30038-X
  » https://doi.org/10.1016/S2213-8587(18)30038-X
• ¹⁸ Simpson TC, Weldon JC, Worthington HV, Needleman I, Wild SH, Moles DR, et al. Treatment of periodontal disease for glycaemic control in people with diabetes mellitus. Cochrane Database Syst Rev. 2015 Nov;11(11):CD004714. https://doi.org/10.1002/14651858.CD004714.pub3
  » https://doi.org/10.1002/14651858.CD004714.pub3
• ¹⁹ D’Aiuto F, Parkar M, Andreou G, Suvan J, Brett PM, Ready D, et al. Periodontitis and systemic inflammation: control of the local infection is associated with a reduction in serum inflammatory markers. J Dent Res. 2004 Feb;83(2):156-60. https://doi.org/10.1177/154405910408300214
  » https://doi.org/10.1177/154405910408300214
• ²⁰ Borgnakke WS, Chapple IL, Genco RJ, Armitage G, Bartold PM, D’Aiuto F, et al. The multi-center randomized controlled trial (RCT) published by the journal of the American Medical Association (JAMA) on the effect of periodontal therapy on glycated hemoglobin (HbA1c) has fundamental problems. J Evid Based Dent Pract. 2014 Sep;14(3):127-32. https://doi.org/10.1016/j.jebdp.2014.04.017
  » https://doi.org/10.1016/j.jebdp.2014.04.017
• ²¹ Beck JD, Papapanou PN, Philips KH, Offenbacher S. Periodontal medicine: 100 years of progress. J Dent Res. 2019 Sep;98(10):1053-62. https://doi.org/10.1177/0022034519846113
  » https://doi.org/10.1177/0022034519846113
• ²² Genco RJ, Graziani F, Hasturk H. Effects of periodontal disease on glycemic control, complications, and incidence of diabetes mellitus. Periodontol 2000. 2020 Jun;83(1):59-65. https://doi.org/10.1111/prd.12271
  » https://doi.org/10.1111/prd.12271
• ²³ Borrell LN, Kunzel C, Lamster I, Lalla E. Diabetes in the dental office: using NHANES III to estimate the probability of undiagnosed disease. J Periodontal Res. 2007 Dec;42(6):559-65. https://doi.org/10.1111/j.1600-0765.2007.00983.x
  » https://doi.org/10.1111/j.1600-0765.2007.00983.x
• ²⁴ Lalla E, Kunzel C, Burkett S, Cheng B, Lamster IB. Identification of unrecognized diabetes and pre-diabetes in a dental setting. J Dent Res. 2011 Jul;90(7):855-60. https://doi.org/10.1177/0022034511407069
  » https://doi.org/10.1177/0022034511407069
• ²⁵ Ziukaite L, Slot DE, Van der Weijden FA. Prevalence of diabetes mellitus in people clinically diagnosed with periodontitis: A systematic review and meta-analysis of epidemiologic studies. J Clin Periodontol. 2018 Jun;45(6):650-62. https://doi.org/10.1111/jcpe.12839
  » https://doi.org/10.1111/jcpe.12839
• ²⁶ Taboza ZA, Costa KL, Silveira VR, Furlaneto FA, Montenegro R Jr, Russell S, et al. Periodontitis, edentulism and glycemic control in patients with type 2 diabetes: a cross-sectional study. BMJ Open Diabetes Res Care. 2018 Mar;6(1):e000453. https://doi.org/10.1136/bmjdrc-2017-000453
  » https://doi.org/10.1136/bmjdrc-2017-000453
• ²⁷ Luo H, Pan W, Sloan F, Feinglos M, Wu B. Forty-year trends in tooth loss among american adults with and without diabetes mellitus: an age-period-cohort analysis. Prev Chronic Dis. 2015 Dec;12:E211. https://doi.org/10.5888/pcd12.150309
  » https://doi.org/10.5888/pcd12.150309
• ²⁸ Tonetti MS, Jepsen S, Jin L, Otomo-Corgel J. Impact of the global burden of periodontal diseases on health, nutrition and wellbeing of mankind: A call for global action. J Clin Periodontol. 2017 May;44(5):456-62. https://doi.org/10.1111/jcpe.12732
  » https://doi.org/10.1111/jcpe.12732
• ²⁹ Sanz M, Ceriello A, Buysschaert M, Chapple I, Demmer RT, Graziani F, et al. Scientific evidence on the links between periodontal diseases and diabetes: consensus report and guidelines of the joint workshop on periodontal diseases and diabetes by the International Diabetes Federation and the European Federation of Periodontology. J Clin Periodontol. 2018 Feb;45(2):138-49. https://doi.org/10.1111/jcpe.12808
  » https://doi.org/10.1111/jcpe.12808
• ³⁰ Offenbacher S, Katz V, Fertik G, Collins J, Boyd D, Maynor G, et al. Periodontal infection as a possible risk factor for preterm low birth weight. J Periodontol. 1996;67(10s Suppl 10S):1103-13. https://doi.org/10.1902/jop.1996.67.10s.1103
  » https://doi.org/10.1902/jop.1996.67.10s.1103
• ³¹ Dasanayake AP. Poor periodontal health of the pregnant woman as a risk factor for low birth weight. Ann Periodontol. 1998 Jul;3(1):206-12. https://doi.org/10.1902/annals.1998.3.1.206
  » https://doi.org/10.1902/annals.1998.3.1.206
• ³² Davenport ES, Williams CE, Sterne JA, Murad S, Sivapathasundram V, Curtis MA. Maternal periodontal disease and preterm low birthweight: case-control study. J Dent Res. 2002 May;81(5):313-8. https://doi.org/10.1177/154405910208100505
  » https://doi.org/10.1177/154405910208100505
• ³³ Ide M, Papapanou PN. Epidemiology of association between maternal periodontal disease and adverse pregnancy outcomes—systematic review. J Periodontol. 2013 Apr;84(4 Suppl):S181-94.
• ³⁴ Madianos PN, Bobetsis YA, Offenbacher S. Adverse pregnancy outcomes (APOs) and periodontal disease: pathogenic mechanisms. J Clin Periodontol. 2013 Apr;40 Suppl 14:S170-80. https://doi.org/10.1111/jcpe.12082
  » https://doi.org/10.1111/jcpe.12082
• ³⁵ Michalowicz BS, Gustafsson A, Thumbigere-Math V, Buhlin K. The effects of periodontal treatment on pregnancy outcomes. J Periodontol. 2013 Apr;84(4 Suppl):S195-208.
• ³⁶ Figuero E, Sánchez-Beltrán M, Cuesta-Frechoso S, Tejerina JM, Castro JA, Gutiérrez JM, et al. Detection of periodontal bacteria in atheromatous plaque by nested polymerase chain reaction. J Periodontol. 2011 Oct;82(10):1469-77. https://doi.org/10.1902/jop.2011.100719
  » https://doi.org/10.1902/jop.2011.100719
• ³⁷ Gomes-Filho IS, Pereira EC, Cruz SS, Adan LF, Vianna MI, Passos-Soares JS, et al. Relationship Among Mothers’ Glycemic Level, Periodontitis, and Birth Weight. J Periodontol. 2016 Mar;87(3):238-47. https://doi.org/10.1902/jop.2015.150423
  » https://doi.org/10.1902/jop.2015.150423
• ³⁸ Iheozor-Ejiofor Z, Middleton P, Esposito M, Glenny AM. Treating periodontal disease for preventing adverse birth outcomes in pregnant women. Cochrane Database Syst Rev. 2017 Jun;6:CD005297. https://doi.org/10.1002/14651858.CD005297.pub3
  » https://doi.org/10.1002/14651858.CD005297.pub3
• ³⁹ Bobetsis YA, Graziani F, Gürsoy M, Madianos PN. Periodontal disease and adverse pregnancy outcomes. Periodontol 2000. 2020 Jun;83(1):154-74. https://doi.org/10.1111/prd.12294
  » https://doi.org/10.1111/prd.12294
• ⁴⁰ Merchant AT, Sutherland MW, Liu J, Pitiphat W, Dasanayake A. Periodontal treatment among mothers with mild to moderate periodontal disease and preterm birth: reanalysis of OPT trial data accounting for selective survival. Int J Epidemiol. 2018 Oct;47(5):1670-8. https://doi.org/10.1093/ije/dyy089
  » https://doi.org/10.1093/ije/dyy089
• ⁴¹ Michalowicz BS, Hodges JS, DiAngelis AJ, Lupo VR, Novak MJ, Ferguson JE, et al.; OPT Study. Treatment of periodontal disease and the risk of preterm birth. N Engl J Med. 2006 Nov;355(18):1885-94. https://doi.org/10.1056/NEJMoa062249
  » https://doi.org/10.1056/NEJMoa062249
• ⁴² Blaizot A, Vergnes JN, Nuwwareh S, Amar J, Sixou M. Periodontal diseases and cardiovascular events: meta-analysis of observational studies. Int Dent J. 2009 Aug;59(4):197-209.
• ⁴³ Nordendahl E, Gustafsson A, Norhammar A, Näsman P, Rydén L, Kjellström B; PAROKRANK Steering Committee. Severe Periodontitis Is Associated with Myocardial Infarction in Females. J Dent Res. 2018 Sep;97(10):1114-21. https://doi.org/10.1177/0022034518765735
  » https://doi.org/10.1177/0022034518765735
• ⁴⁴ Linden GJ, Linden K, Yarnell J, Evans A, Kee F, Patterson CC. All-cause mortality and periodontitis in 60-70-year-old men: a prospective cohort study. J Clin Periodontol. 2012 Oct;39(10):940-6. https://doi.org/10.1111/j.1600-051X.2012.01923.x
  » https://doi.org/10.1111/j.1600-051X.2012.01923.x
• ⁴⁵ Sharma P, Dietrich T, Ferro CJ, Cockwell P, Chapple IL. Association between periodontitis and mortality in stages 3-5 chronic kidney disease: NHANES III and linked mortality study. J Clin Periodontol. 2016 Feb;43(2):104-13. https://doi.org/10.1111/jcpe.12502
  » https://doi.org/10.1111/jcpe.12502
• ⁴⁶ LaMonte MJ, Genco RJ, Hovey KM, Wallace RB, Freudenheim JL, Michaud DS, et al. History of Periodontitis Diagnosis and Edentulism as Predictors of Cardiovascular Disease, Stroke, and Mortality in Postmenopausal Women. J Am Heart Assoc. 2017 Mar;6(4):6. https://doi.org/10.1161/JAHA.116.004518
  » https://doi.org/10.1161/JAHA.116.004518
• ⁴⁷ Holmlund A, Lampa E, Lind L. Oral health and cardiovascular disease risk in a cohort of periodontitis patients. Atherosclerosis. 2017 Jul;262:101-6. https://doi.org/10.1016/j.atherosclerosis.2017.05.009
  » https://doi.org/10.1016/j.atherosclerosis.2017.05.009
• ⁴⁸ Yu YH, Chasman DI, Buring JE, Rose L, Ridker PM. Cardiovascular risks associated with incident and prevalent periodontal disease. J Clin Periodontol. 2015 Jan;42(1):21-8. https://doi.org/10.1111/jcpe.12335
  » https://doi.org/10.1111/jcpe.12335
• ⁴⁹ Kebschull M, Demmer RT, Papapanou PN. “Gum bug, leave my heart alone!”—epidemiologic and mechanistic evidence linking periodontal infections and atherosclerosis. J Dent Res. 2010 Sep;89(9):879-902. https://doi.org/10.1177/0022034510375281
  » https://doi.org/10.1177/0022034510375281
• ⁵⁰ Pihlstrom BL, Barnett ML. Design, operation, and interpretation of clinical trials. J Dent Res. 2010 Aug;89(8):759-72. https://doi.org/10.1177/0022034510374737
  » https://doi.org/10.1177/0022034510374737
• ⁵¹ Piconi S, Trabattoni D, Luraghi C, Perilli E, Borelli M, Pacei M, et al. Treatment of periodontal disease results in improvements in endothelial dysfunction and reduction of the carotid intima-media thickness. FASEB J. 2009 Apr;23(4):1196-204. https://doi.org/10.1096/fj.08-119578
  » https://doi.org/10.1096/fj.08-119578
• ⁵² Paraskevas S, Huizinga JD, Loos BG. A systematic review and meta-analyses on C-reactive protein in relation to periodontitis. J Clin Periodontol. 2008 Apr;35(4):277-90. https://doi.org/10.1111/j.1600-051X.2007.01173.x
  » https://doi.org/10.1111/j.1600-051X.2007.01173.x
• ⁵³ Caúla AL, Lira-Junior R, Tinoco EM, Fischer RG. The effect of periodontal therapy on cardiovascular risk markers: a 6-month randomized clinical trial. J Clin Periodontol. 2014 Sep;41(9):875-82. https://doi.org/10.1111/jcpe.12290
  » https://doi.org/10.1111/jcpe.12290
• ⁵⁴ Amar S, Gokce N, Morgan S, Loukideli M, Van Dyke TE, Vita JA. Periodontal disease is associated with brachial artery endothelial dysfunction and systemic inflammation. Arterioscler Thromb Vasc Biol. 2003 Jul;23(7):1245-9. https://doi.org/10.1161/01.ATV.0000078603.90302.4A
  » https://doi.org/10.1161/01.ATV.0000078603.90302.4A
• ⁵⁵ Longo PL, Artese HP, Rabelo MS, Kawamoto D, Foz AM, Romito GA, et al. Serum levels of inflammatory markers in type 2 diabetes patients with chronic periodontitis. J Appl Oral Sci. 2014 Apr;22(2):103-8. https://doi.org/10.1590/1678-775720130540
  » https://doi.org/10.1590/1678-775720130540
• ⁵⁶ Vidal F, Cordovil I, Figueredo CM, Fischer RG. Non-surgical periodontal treatment reduces cardiovascular risk in refractory hypertensive patients: a pilot study. J Clin Periodontol. 2013 Jul;40(7):681-7. https://doi.org/10.1111/jcpe.12110
  » https://doi.org/10.1111/jcpe.12110
• ⁵⁷ Vidal F, Figueredo CM, Cordovil I, Fischer RG. Periodontal therapy reduces plasma levels of interleukin-6, C-reactive protein, and fibrinogen in patients with severe periodontitis and refractory arterial hypertension. J Periodontol. 2009 May;80(5):786-91. https://doi.org/10.1902/jop.2009.080471
  » https://doi.org/10.1902/jop.2009.080471
• ⁵⁸ D’Aiuto F, Orlandi M, Gunsolley JC. Evidence that periodontal treatment improves biomarkers and CVD outcomes. J Clin Periodontol. 2013 Apr;40 Suppl 14:S85-105. https://doi.org/10.1111/jcpe.12061
  » https://doi.org/10.1111/jcpe.12061
• ⁵⁹ Teeuw WJ, Slot DE, Susanto H, Gerdes VE, Abbas F, D’Aiuto F, et al. Treatment of periodontitis improves the atherosclerotic profile: a systematic review and meta-analysis. J Clin Periodontol. 2014 Jan;41(1):70-9. https://doi.org/10.1111/jcpe.12171
  » https://doi.org/10.1111/jcpe.12171
• ⁶⁰ Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005 Oct;366(9493):1267-78. https://doi.org/10.1016/S0140-6736(05)67394-1
  » https://doi.org/10.1016/S0140-6736(05)67394-1
• ⁶¹ Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989 Jan;79(1):8-15. https://doi.org/10.1161/01.CIR.79.1.8
  » https://doi.org/10.1161/01.CIR.79.1.8
• ⁶² Muñoz Aguilera E, Suvan J, Buti J, Czesnikiewicz-Guzik M, Ribeiro AB, Orlandi M, et al. Periodontitis is associated with hypertension: a systematic review and meta-analysis. Cardiovasc Res. 2020 Jan;116(1):28-39. https://doi.org/10.1093/cvr/cvz201
  » https://doi.org/10.1093/cvr/cvz201
• ⁶³ D’Aiuto F, Parkar M, Nibali L, Suvan J, Lessem J, Tonetti MS. Periodontal infections cause changes in traditional and novel cardiovascular risk factors: results from a randomized controlled clinical trial. Am Heart J. 2006 May;151(5):977-84. https://doi.org/10.1016/j.ahj.2005.06.018
  » https://doi.org/10.1016/j.ahj.2005.06.018
• ⁶⁴ Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009 May;338(may19 1):b1665. https://doi.org/10.1136/bmj.b1665
  » https://doi.org/10.1136/bmj.b1665
• ⁶⁵ Czesnikiewicz-Guzik M, Osmenda G, Siedlinski M, Nosalski R, Pelka P, Nowakowski D, et al. Causal association between periodontitis and hypertension: evidence from Mendelian randomization and a randomized controlled trial of non-surgical periodontal therapy. Eur Heart J. 2019 Nov;40(42):3459-70. https://doi.org/10.1093/eurheartj/ehz646
  » https://doi.org/10.1093/eurheartj/ehz646
• ⁶⁶ Brito F, Almeida S, Figueredo CM, Bregman R, Suassuna JH, Fischer RG. Extent and severity of chronic periodontitis in chronic kidney disease patients. J Periodontal Res. 2012 Aug;47(4):426-30. https://doi.org/10.1111/j.1600-0765.2011.01449.x
  » https://doi.org/10.1111/j.1600-0765.2011.01449.x
• ⁶⁷ Almeida S, Figueredo CM, Lemos C, Bregman R, Fischer RG. Periodontal treatment in patients with chronic kidney disease: a pilot study. J Periodontal Res. 2017 Apr;52(2):262-7. https://doi.org/10.1111/jre.12390 PMID:27135778
  » https://doi.org/10.1111/jre.12390
• ⁶⁸ Sitia S, Tomasoni L, Atzeni F, Ambrosio G, Cordiano C, Catapano A, et al. From endothelial dysfunction to atherosclerosis. Autoimmun Rev. 2010 Oct;9(12):830-4. https://doi.org/10.1016/j.autrev.2010.07.016
  » https://doi.org/10.1016/j.autrev.2010.07.016
• ⁶⁹ Amar S, Han X. The impact of periodontal infection on systemic diseases. Med Sci Monit. 2003 Dec;9(12):RA291-9.
• ⁷⁰ Higashi Y, Goto C, Hidaka T, Soga J, Nakamura S, Fujii Y, et al. Oral infection-inflammatory pathway, periodontitis, is a risk factor for endothelial dysfunction in patients with coronary artery disease. Atherosclerosis. 2009 Oct;206(2):604-10. https://doi.org/10.1016/j.atherosclerosis.2009.03.037
  » https://doi.org/10.1016/j.atherosclerosis.2009.03.037
• ⁷¹ Tonetti MS, D’Aiuto F, Nibali L, Donald A, Storry C, Parkar M, et al. Treatment of periodontitis and endothelial function. N Engl J Med. 2007 Mar;356(9):911-20. https://doi.org/10.1056/NEJMoa063186
  » https://doi.org/10.1056/NEJMoa063186
• ⁷² Lira-Junior R, Figueredo CM, Bouskela E, Fischer RG. Severe chronic periodontitis is associated with endothelial and microvascular dysfunctions: a pilot study. J Periodontol. 2014 Dec;85(12):1648-57. https://doi.org/10.1902/jop.2014.140189
  » https://doi.org/10.1902/jop.2014.140189
• ⁷³ Kapellas K, Maple-Brown LJ, Jamieson LM, Do LG, O’Dea K, Brown A, et al. Effect of periodontal therapy on arterial structure and function among aboriginal australians: a randomized, controlled trial. Hypertension. 2014 Oct;64(4):702-8. https://doi.org/10.1161/HYPERTENSIONAHA.114.03359
  » https://doi.org/10.1161/HYPERTENSIONAHA.114.03359
• ⁷⁴ Paju S, Pussinen PJ, Sinisalo J, Mattila K, Doğan B, Ahlberg J, et al. Clarithromycin reduces recurrent cardiovascular events in subjects without periodontitis. Atherosclerosis. 2006 Oct;188(2):412-9. https://doi.org/10.1016/j.atherosclerosis.2005.11.019
  » https://doi.org/10.1016/j.atherosclerosis.2005.11.019
• ⁷⁵ Beck JD, Couper DJ, Falkner KL, Graham SP, Grossi SG, Gunsolley JC, et al. The Periodontitis and Vascular Events (PAVE) pilot study: adverse events. J Periodontol. 2008 Jan;79(1):90-6. https://doi.org/10.1902/jop.2008.070223
  » https://doi.org/10.1902/jop.2008.070223
• ⁷⁶ Offenbacher S, Beck JD, Moss K, Mendoza L, Paquette DW, Barrow DA, et al. Results from the Periodontitis and Vascular Events (PAVE) study: a pilot multicentered, randomized, controlled trial to study effects of periodontal therapy in a secondary prevention model of cardiovascular disease. J Periodontol. 2009 Feb;80(2):190-201. https://doi.org/10.1902/jop.2009.080007
  » https://doi.org/10.1902/jop.2009.080007
• ⁷⁷ Lee YL, Hu HY, Huang N, Hwang DK, Chou P, Chu D. Dental prophylaxis and periodontal treatment are protective factors to ischemic stroke. Stroke. 2013 Apr;44(4):1026-30. https://doi.org/10.1161/STROKEAHA.111.000076
  » https://doi.org/10.1161/STROKEAHA.111.000076
• ⁷⁸ Sen S, Giamberardino LD, Moss K, Morelli T, Rosamond WD, Gottesman RF, et al. Periodontal Disease, Regular Dental Care Use, and Incident Ischemic Stroke. Stroke. 2018 Feb;49(2):355-62. https://doi.org/10.1161/STROKEAHA.117.018990
  » https://doi.org/10.1161/STROKEAHA.117.018990
• ⁷⁹ Holmlund A, Lampa E, Lind L. Poor response to periodontal treatment may predict future cardiovascular disease. J Dent Res. 2017 Jul;96(7):768-73. https://doi.org/10.1177/0022034517701901
  » https://doi.org/10.1177/0022034517701901
• ⁸⁰ Huang ST, Yu TM, Ke TY, Wu MJ, Chuang YW, Li CY, et al. Intensive periodontal treatment reduces risks of hospitalization for cardiovascular disease and all-cause mortality in the hemodialysis population. J Clin Med. 2018 Oct;7(10):344. https://doi.org/10.3390/jcm7100344
  » https://doi.org/10.3390/jcm7100344
• ⁸¹ Jeffcoat MK, Jeffcoat RL, Gladowski PA, Bramson JB, Blum JJ. Impact of periodontal therapy on general health: evidence from insurance data for five systemic conditions. Am J Prev Med. 2014 Aug;47(2):166-74. https://doi.org/10.1016/j.amepre.2014.04.001
  » https://doi.org/10.1016/j.amepre.2014.04.001
• ⁸² Li C, Lv Z, Shi Z, Zhu Y, Wu Y, Li L, et al. Periodontal therapy for the management of cardiovascular disease in patients with chronic periodontitis. Cochrane Database Syst Rev. 2014 Aug;(8):CD009197. https://doi.org/10.1002/14651858.CD009197.pub2
  » https://doi.org/10.1002/14651858.CD009197.pub2
• ⁸³ Scannapieco FA. Role of oral bacteria in respiratory infection. J Periodontol. 1999 Jul;70(7):793-802. https://doi.org/10.1902/jop.1999.70.7.793 PMID:10440642
  » https://doi.org/10.1902/jop.1999.70.7.793
• ⁸⁴ Mammen MJ, Scannapieco FA, Sethi S. Oral-lung microbiome interactions in lung diseases. Periodontol 2000. 2020 Jun;83(1):234-41. https://doi.org/10.1111/prd.12301
  » https://doi.org/10.1111/prd.12301
• ⁸⁵ Kochanek KD, Murphy SL, Xu J, Arias E. Deaths: final Data for 2017. Natl Vital Stat Rep. 2019 Jun;68(9):1-77.
• ⁸⁶ Flanders SA, Collard HR, Saint S. Nosocomial pneumonia: state of the science. Am J Infect Control. 2006 Mar;34(2):84-93. https://doi.org/10.1016/j.ajic.2005.07.003
  » https://doi.org/10.1016/j.ajic.2005.07.003
• ⁸⁷ Baker D, Quinn B. Hospital acquired pneumonia prevention initiative-2: incidence of nonventilator hospital-acquired pneumonia in the United States. Am J Infect Control. 2018 Jan;46(1):2-7. https://doi.org/10.1016/j.ajic.2017.08.036
  » https://doi.org/10.1016/j.ajic.2017.08.036
• ⁸⁸ Giuliano KK, Baker D, Quinn B. The epidemiology of nonventilator hospital-acquired pneumonia in the United States. Am J Infect Control. 2018 Mar;46(3):322-7. https://doi.org/10.1016/j.ajic.2017.09.005
  » https://doi.org/10.1016/j.ajic.2017.09.005
• ⁸⁹ Vincent JL, Bihari DJ, Suter PM, Bruining HA, White J, Nicolas-Chanoin MH, et al. The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. JAMA. 1995 Aug;274(8):639-44. https://doi.org/10.1001/jama.1995.03530080055041
  » https://doi.org/10.1001/jama.1995.03530080055041
• ⁹⁰ Raghavendran K, Mylotte JM, Scannapieco FA. Nursing home-associated pneumonia, hospital-acquired pneumonia and ventilator-associated pneumonia: the contribution of dental biofilms and periodontal inflammation. Periodontol 2000. 2007;44(1):164-77. https://doi.org/10.1111/j.1600-0757.2006.00206.x
  » https://doi.org/10.1111/j.1600-0757.2006.00206.x
• ⁹¹ Segal LN, Rom WN, Weiden MD. Lung microbiome for clinicians. New discoveries about bugs in healthy and diseased lungs. Ann Am Thorac Soc. 2014 Jan;11(1):108-16. https://doi.org/10.1513/AnnalsATS.201310-339FR
  » https://doi.org/10.1513/AnnalsATS.201310-339FR
• ⁹² Venkataraman A, Bassis CM, Beck JM, Young VB, Curtis JL, Huffnagle GB, et al. Application of a neutral community model to assess structuring of the human lung microbiome. MBio. 2015 Jan;6(1):6. https://doi.org/10.1128/mBio.02284-14
  » https://doi.org/10.1128/mBio.02284-14
• ⁹³ Sands KM, Wilson MJ, Lewis MA, Wise MP, Palmer N, Hayes AJ, et al. Respiratory pathogen colonization of dental plaque, the lower airways, and endotracheal tube biofilms during mechanical ventilation. J Crit Care. 2017 Feb;37:30-7. https://doi.org/10.1016/j.jcrc.2016.07.019
  » https://doi.org/10.1016/j.jcrc.2016.07.019
• ⁹⁴ El-Solh AA, Pietrantoni C, Bhat A, Okada M, Zambon J, Aquilina A, et al. Colonization of dental plaques: a reservoir of respiratory pathogens for hospital-acquired pneumonia in institutionalized elders. Chest. 2004 Nov;126(5):1575-82. https://doi.org/10.1016/S0012-3692(15)31374-X
  » https://doi.org/10.1016/S0012-3692(15)31374-X
• ⁹⁵ Heo SM, Haase EM, Lesse AJ, Gill SR, Scannapieco FA. Genetic relationships between respiratory pathogens isolated from dental plaque and bronchoalveolar lavage fluid from patients in the intensive care unit undergoing mechanical ventilation. Clin Infect Dis. 2008 Dec;47(12):1562-70. https://doi.org/10.1086/593193
  » https://doi.org/10.1086/593193
• ⁹⁶ Hata R, Noguchi S, Kawanami T, Yamasaki K, Akata K, Ikegami H, et al. Poor oral hygiene is associated with the detection of obligate anaerobes in pneumonia. J Periodontol. 2020 Jan;91(1):65-73. https://doi.org/10.1002/JPER.19-0043
  » https://doi.org/10.1002/JPER.19-0043
• ⁹⁷ Marino PJ, Wise MP, Smith A, Marchesi JR, Riggio MP, Lewis MA, et al. Community analysis of dental plaque and endotracheal tube biofilms from mechanically ventilated patients. J Crit Care. 2017 Jun;39:149-55. https://doi.org/10.1016/j.jcrc.2017.02.020
  » https://doi.org/10.1016/j.jcrc.2017.02.020
• ⁹⁸ Russell SL, Boylan RJ, Kaslick RS, Scannapieco FA, Katz RV. Respiratory pathogen colonization of the dental plaque of institutionalized elders. Spec Care Dentist. 1999 May-Jun;19(3):128-34. https://doi.org/10.1111/j.1754-4505.1999.tb01413.x
  » https://doi.org/10.1111/j.1754-4505.1999.tb01413.x
• ⁹⁹ Sumi Y, Miura H, Michiwaki Y, Nagaosa S, Nagaya M. Colonization of dental plaque by respiratory pathogens in dependent elderly. Arch Gerontol Geriatr. 2007 Mar-Apr;44(2):119-24. https://doi.org/10.1016/j.archger.2006.04.004
  » https://doi.org/10.1016/j.archger.2006.04.004
• ¹⁰⁰ Didilescu AC, Skaug N, Marica C, Didilescu C. Respiratory pathogens in dental plaque of hospitalized patients with chronic lung diseases. Clin Oral Investig. 2005 Sep;9(3):141-7. https://doi.org/10.1007/s00784-005-0315-6
  » https://doi.org/10.1007/s00784-005-0315-6
• ¹⁰¹ Awano S, Ansai T, Takata Y, Soh I, Akifusa S, Hamasaki T, et al. Oral health and mortality risk from pneumonia in the elderly. J Dent Res. 2008 Apr;87(4):334-9. https://doi.org/10.1177/154405910808700418
  » https://doi.org/10.1177/154405910808700418
• ¹⁰² Gomes-Filho IS, Oliveira TF, Cruz SS, Passos-Soares JS, Trindade SC, Oliveira MT, et al. Influence of periodontitis in the development of nosocomial pneumonia: a case control study. J Periodontol. 2014 May;85(5):e82-90. https://doi.org/10.1902/jop.2013.130369
  » https://doi.org/10.1902/jop.2013.130369
• ¹⁰³ Suma S, Naito M, Wakai K, Naito T, Kojima M, Umemura O, et al. Tooth loss and pneumonia mortality: A cohort study of Japanese dentists. PLoS One. 2018 Apr;13(4):e0195813. https://doi.org/10.1371/journal.pone.0195813
  » https://doi.org/10.1371/journal.pone.0195813
• ¹⁰⁴ Yoneyama T, Hashimoto K, Fukuda H, Ishida M, Arai H, Sekizawa K, et al. Oral hygiene reduces respiratory infections in elderly bed-bound nursing home patients. Arch Gerontol Geriatr. 1996 Jan-Feb;22(1):11-9. https://doi.org/10.1016/0167-4943(95)00672-9
  » https://doi.org/10.1016/0167-4943(95)00672-9
• ¹⁰⁵ Yoneyama T, Yoshida M, Ohrui T, Mukaiyama H, Okamoto H, Hoshiba K, et al.; Oral Care Working Group. Oral care reduces pneumonia in older patients in nursing homes. J Am Geriatr Soc. 2002 Mar;50(3):430-3. https://doi.org/10.1046/j.1532-5415.2002.50106.x
  » https://doi.org/10.1046/j.1532-5415.2002.50106.x
• ¹⁰⁶ Adachi M, Ishihara K, Abe S, Okuda K, Ishikawa T. Effect of professional oral health care on the elderly living in nursing homes. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002 Aug;94(2):191-5. https://doi.org/10.1067/moe.2002.123493
  » https://doi.org/10.1067/moe.2002.123493
• ¹⁰⁷ Liu C, Cao Y, Lin J, Ng L, Needleman I, Walsh T, et al. Oral care measures for preventing nursing home-acquired pneumonia. Cochrane Database Syst Rev. 2018 Sep;9:CD012416. https://doi.org/10.1002/14651858.CD012416.pub2
  » https://doi.org/10.1002/14651858.CD012416.pub2
• ¹⁰⁸ Fujiwara A, Minakuchi H, Uehara J, Miki H, Inoue-Minakuchi M, Kimura-Ono A, et al. Loss of oral self-care ability results in a higher risk of pneumonia in older inpatients: A prospective cohort study in a Japanese rural hospital. Gerodontology. 2019 Sep;36(3):236-43. https://doi.org/10.1111/ger.12402
  » https://doi.org/10.1111/ger.12402
• ¹⁰⁹ Molloy J, Wolff LF, Lopez-Guzman A, Hodges JS. The association of periodontal disease parameters with systemic medical conditions and tobacco use. J Clin Periodontol. 2004 Aug;31(8):625-32. https://doi.org/10.1111/j.1600-051X.2004.00539.x
  » https://doi.org/10.1111/j.1600-051X.2004.00539.x
• ¹¹⁰ Ishikawa A, Yoneyama T, Hirota K, Miyake Y, Miyatake K. Professional oral health care reduces the number of oropharyngeal bacteria. J Dent Res. 2008 Jun;87(6):594-8. https://doi.org/10.1177/154405910808700602
  » https://doi.org/10.1177/154405910808700602
• ¹¹¹ Abe S, Ishihara K, Adachi M, Okuda K. Oral hygiene evaluation for effective oral care in preventing pneumonia in dentate elderly. Arch Gerontol Geriatr. 2006 Jul-Aug;43(1):53-64. https://doi.org/10.1016/j.archger.2005.09.002
  » https://doi.org/10.1016/j.archger.2005.09.002
• ¹¹² Sjögren P, Wårdh I, Zimmerman M, Almståhl A, Wikström M. Oral Care and Mortality in Older Adults with Pneumonia in Hospitals or Nursing Homes: Systematic Review and Meta-Analysis. J Am Geriatr Soc. 2016 Oct;64(10):2109-15. https://doi.org/10.1111/jgs.14260
  » https://doi.org/10.1111/jgs.14260
• ¹¹³ Juthani-Mehta M, Van Ness PH, McGloin J, Argraves S, Chen S, Charpentier P, et al. A cluster-randomized controlled trial of a multicomponent intervention protocol for pneumonia prevention among nursing home elders. Clin Infect Dis. 2015 Mar;60(6):849-57. https://doi.org/10.1093/cid/ciu935
  » https://doi.org/10.1093/cid/ciu935
• ¹¹⁴ Scannapieco FA, Amin S, Salme M, Tezal M. Factors associated with utilization of dental services in a long-term care facility: a descriptive cross-sectional study. Spec Care Dentist. 2017 Mar;37(2):78-84. https://doi.org/10.1111/scd.12208
  » https://doi.org/10.1111/scd.12208
• ¹¹⁵ Monsarrat P, Blaizot A, Kémoun P, Ravaud P, Nabet C, Sixou M, et al. Clinical research activity in periodontal medicine: a systematic mapping of trial registers. J Clin Periodontol. 2016 May;43(5):390-400. https://doi.org/10.1111/jcpe.12534
  » https://doi.org/10.1111/jcpe.12534
• ¹¹⁶ Genco RJ, Sanz M. Clinical and public health implications of periodontal and systemic diseases: an overview. Periodontol 2000. 2020 Jun;83(1):7-13. https://doi.org/10.1111/prd.12344
  » https://doi.org/10.1111/prd.12344
• ¹¹⁷ Lira-Junior R, Åkerman S, Klinge B, Boström EA, Gustafsson A. Salivary microbial profiles in relation to age, periodontal, and systemic diseases. PLoS One. 2018 Mar;13(3):e0189374. https://doi.org/10.1371/journal.pone.0189374
  » https://doi.org/10.1371/journal.pone.0189374
• ¹¹⁸ Bajaj JS, Betrapally NS, Hylemon PB, Heuman DM, Daita K, White MB, et al. Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy. Hepatology. 2015 Oct;62(4):1260-71. https://doi.org/10.1002/hep.27819
  » https://doi.org/10.1002/hep.27819
• ¹¹⁹ Gevers D, Kugathasan S, Denson LA, Vázquez-Baeza Y, Van Treuren W, Ren B, et al. The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe. 2014 Mar;15(3):382-92. https://doi.org/10.1016/j.chom.2014.02.005
  » https://doi.org/10.1016/j.chom.2014.02.005
• ¹²⁰ Bajaj JS, Cox IJ, Betrapally NS, Heuman DM, Schubert ML, Ratneswaran M, et al. Systems biology analysis of omeprazole therapy in cirrhosis demonstrates significant shifts in gut microbiota composition and function. Am J Physiol Gastrointest Liver Physiol. 2014 Nov;307(10):G951-7. https://doi.org/10.1152/ajpgi.00268.2014
  » https://doi.org/10.1152/ajpgi.00268.2014
• ¹²¹ Kostic AD, Gevers D, Pedamallu CS, Michaud M, Duke F, Earl AM, et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res. 2012 Feb;22(2):292-8. https://doi.org/10.1101/gr.126573.111
  » https://doi.org/10.1101/gr.126573.111
• ¹²² Nakajima M, Arimatsu K, Kato T, Matsuda Y, Minagawa T, Takahashi N, et al. Oral Administration of P. gingivalis Induces Dysbiosis of Gut Microbiota and Impaired Barrier Function Leading to Dissemination of Enterobacteria to the Liver. PLoS One. 2015 Jul;10(7):e0134234. https://doi.org/10.1371/journal.pone.0134234
  » https://doi.org/10.1371/journal.pone.0134234
• ¹²³ Arimatsu K, Yamada H, Miyazawa H, Minagawa T, Nakajima M, Ryder MI, et al. Oral pathobiont induces systemic inflammation and metabolic changes associated with alteration of gut microbiota. Sci Rep. 2014 May;4(1):4828. https://doi.org/10.1038/srep04828
  » https://doi.org/10.1038/srep04828
• ¹²⁴ Lourenço TG, Spencer SJ, Alm EJ, Colombo AP. Defining the gut microbiota in individuals with periodontal diseases: an exploratory study. J Oral Microbiol. 2018 Jul;10(1):1487741. https://doi.org/10.1080/20002297.2018.1487741
  » https://doi.org/10.1080/20002297.2018.1487741
• ¹²⁵ Papageorgiou SN, Hagner M, Nogueira AV, Franke A, Jäger A, Deschner J. Inflammatory bowel disease and oral health: systematic review and a meta-analysis. J Clin Periodontol. 2017 Apr;44(4):382-93. https://doi.org/10.1111/jcpe.12698
  » https://doi.org/10.1111/jcpe.12698
• ¹²⁶ Lin CY, Tseng KS, Liu JM, Chuang HC, Lien CH, Chen YC, et al. Increased risk of ulcerative colitis in patients with periodontal disease: a nationwide population-based cohort study. Int J Environ Res Public Health. 2018 Nov;15(11):15. https://doi.org/10.3390/ijerph15112602
  » https://doi.org/10.3390/ijerph15112602
• ¹²⁷ Atarashi K, Suda W, Luo C, Kawaguchi T, Motoo I, Narushima S, et al. Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation. Science. 2017 Oct;358(6361):359-65. https://doi.org/10.1126/science.aan4526
  » https://doi.org/10.1126/science.aan4526
• ¹²⁸ Kitamoto S, Nagao-Kitamoto H, Jiao Y, Gillilland MG 3rd, Hayashi A, Imai J, et al. The Intermucosal connection between the mouth and gut in commensal pathobiont-driven colitis. Cell. 2020 Jul;182(2):447-462.e14. https://doi.org/10.1016/j.cell.2020.05.048
  » https://doi.org/10.1016/j.cell.2020.05.048
• ¹²⁹ Teles FR, Alawi F, Castilho RM, Wang Y. Association or causation? Exploring the oral microbiome and cancer links. J Dent Res. 2020 Dec;99(13):1411-24. https://doi.org/10.1177/0022034520945242 PMID:32811287
  » https://doi.org/10.1177/0022034520945242
• ¹³⁰ Abed J, Maalouf N, Manson AL, Earl AM, Parhi L, Emgård JE, et al. Colon cancer-associated Fusobacterium nucleatum may originate from the oral cavity and reach colon tumors via the circulatory system. Front Cell Infect Microbiol. 2020 Aug;10:400. https://doi.org/10.3389/fcimb.2020.00400
  » https://doi.org/10.3389/fcimb.2020.00400
• ¹³¹ Kostic AD, Chun E, Robertson L, Glickman JN, Gallini CA, Michaud M, et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe. 2013 Aug;14(2):207-15. https://doi.org/10.1016/j.chom.2013.07.007
  » https://doi.org/10.1016/j.chom.2013.07.007
• ¹³² Mima K, Nishihara R, Qian ZR, Cao Y, Sukawa Y, Nowak JA, et al. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut. 2016 Dec;65(12):1973-80. https://doi.org/10.1136/gutjnl-2015-310101
  » https://doi.org/10.1136/gutjnl-2015-310101
• ¹³³ Gur C, Ibrahim Y, Isaacson B, Yamin R, Abed J, Gamliel M, et al. Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity. 2015 Feb;42(2):344-55. https://doi.org/10.1016/j.immuni.2015.01.010
  » https://doi.org/10.1016/j.immuni.2015.01.010
• ¹³⁴ Nwizu N, Wactawski-Wende J, Genco RJ. Periodontal disease and cancer: epidemiologic studies and possible mechanisms. Periodontol 2000. 2020 Jun;83(1):213-33. https://doi.org/10.1111/prd.12329
  » https://doi.org/10.1111/prd.12329
• ¹³⁵ Kamer AR, Craig RG, Niederman R, Fortea J, Leon MJ. Periodontal disease as a possible cause for Alzheimer’s disease. Periodontol 2000. 2020 Jun;83(1):242-71. https://doi.org/10.1111/prd.12327
  » https://doi.org/10.1111/prd.12327
• ¹³⁶ Holmer J, Eriksdotter M, Schultzberg M, Pussinen PJ, Buhlin K. Association between periodontitis and risk of Alzheimer’s disease, mild cognitive impairment and subjective cognitive decline: A case-control study. J Clin Periodontol. 2018 Nov;45(11):1287-98. https://doi.org/10.1111/jcpe.13016
  » https://doi.org/10.1111/jcpe.13016
• ¹³⁷ Chen CK, Wu YT, Chang YC. Association between chronic periodontitis and the risk of Alzheimer’s disease: a retrospective, population-based, matched-cohort study. Alzheimers Res Ther. 2017 Aug;9(1):56. https://doi.org/10.1186/s13195-017-0282-6
  » https://doi.org/10.1186/s13195-017-0282-6
• ¹³⁸ Riviere GR, Riviere KH, Smith KS. Molecular and immunological evidence of oral Treponema in the human brain and their association with Alzheimer’s disease. Oral Microbiol Immunol. 2002 Apr;17(2):113-8. https://doi.org/10.1046/j.0902-0055.2001.00100.x
  » https://doi.org/10.1046/j.0902-0055.2001.00100.x
• ¹³⁹ Kamer AR, Pirraglia E, Tsui W, Rusinek H, Vallabhajosula S, Mosconi L, et al. Periodontal disease associates with higher brain amyloid load in normal elderly. Neurobiol Aging. 2015 Feb;36(2):627-33. https://doi.org/10.1016/j.neurobiolaging.2014.10.038
  » https://doi.org/10.1016/j.neurobiolaging.2014.10.038
• ¹⁴⁰ Dominy SS, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A, et al. Porphyromonas gingivalis in Alzheimer’s disease brains: evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv. 2019 Jan;5(1):eaau3333. https://doi.org/10.1126/sciadv.aau3333
  » https://doi.org/10.1126/sciadv.aau3333

Publication Dates

• Publication in this collection
  24 Sept 2021
• Date of issue
  2021

History

• Received
  27 Apr 2021
• Accepted
  3 May 2021
• Reviewed
  8 June 2021