A retrospective longitudinal assessment of artificial intelligence-assisted radiographic prediction of lower third molar eruption.

Prediction of lower third molar eruption is crucial for its timely extraction. Therefore, the primary aim of this study was to investigate the prediction of lower third molar eruption and its uprighting with the assistance of an artificial intelligence (AI) tool. The secondary aim was identifying the incidence of fully erupted lower third molars with hygienic cleansability. In total, 771 patients having two panoramic radiographs were recruited, where the first radiograph was acquired at 8-15 years of age (T1) and the second acquisition was between 16 and 23 years (T2). The predictive model for third molar eruption could not be obtained as few teeth reached full eruption. However, uprighting model at T2 showed that in cases with sufficient retromolar space, an initial angulation of < 32° predicted uprighting. Full eruption was observed for 13.9% of the teeth, and only 1.7% showed hygienic cleansability. The predictions model of third molar uprighting could act as a valuable aid for guiding a clinician with the decision-making process of extracting third molars which fail to erupt in an upright fashion. In addition, a low incidence of fully erupted molars with hygienic cleansability suggest that a clinician might opt for prophylactic extraction.

Modulation of thromboinflammation in hospitalized COVID-19 patients with aprotinin, low molecular weight heparin, and anakinra: The DAWn-Antico study.

Background: Thromboinflammation plays a central role in severe COVID-19. The kallikrein pathway activates both inflammatory pathways and contact-mediated coagulation. We investigated if modulation of the thromboinflammatory response improves outcomes in hospitalized COVID-19 patients. Methods: In this multicenter open-label randomized clinical trial (EudraCT 2020-001739-28), patients hospitalized with COVID-19 were 1:2 randomized to receive standard of care (SOC) or SOC plus study intervention. The intervention consisted of aprotinin (2,000,000 IE IV four times daily) combined with low molecular weight heparin (LMWH; SC 50 IU/kg twice daily on the ward, 75 IU/kg twice daily in intensive care). Additionally, patients with predefined hyperinflammation received the interleukin-1 receptor antagonist anakinra (100 mg IV four times daily). The primary outcome was time to a sustained 2-point improvement on the 7-point World Health Organization ordinal scale for clinical status, or discharge. Findings: Between 24 June 2020 and 1 February 2021, 105 patients were randomized, and 102 patients were included in the full analysis set (intervention N = 67 vs. SOC N = 35). Twenty-five patients from the intervention group (37%) received anakinra. The intervention did not affect the primary outcome (HR 0.77 [CI 0.50-1.19], p = 0.24) or mortality (intervention n = 3 [4.6%] vs. SOC n = 2 [5.7%], HR 0.82 [CI 0.14-4.94], p = 0.83). There was one treatment-related adverse event in the intervention group (hematuria, 1.49%). There was one thrombotic event in the intervention group (1.49%) and one in the SOC group (2.86%), but no major bleeding. Conclusions: In hospitalized COVID-19 patients, modulation of thromboinflammation with high-dose aprotinin and LMWH with or without anakinra did not improve outcome in patients with moderate to severe COVID-19.

Dysregulation of the kallikrein-kinin system in bronchoalveolar lavage fluid of patients with severe COVID-19.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the angiotensin-converting enzyme 2 (ACE2) receptor, a critical component of the kallikrein-kinin system. Its dysregulation may lead to increased vascular permeability and release of inflammatory chemokines. Interactions between the kallikrein-kinin and the coagulation system might further contribute to thromboembolic complications in COVID-19. METHODS: In this observational study, we measured plasma and tissue kallikrein hydrolytic activity, levels of kinin peptides, and myeloperoxidase (MPO)-DNA complexes as a biomarker for neutrophil extracellular traps (NETs), in bronchoalveolar lavage (BAL) fluid from patients with and without COVID-19. FINDINGS: In BAL fluid from patients with severe COVID-19 (n = 21, of which 19 were mechanically ventilated), we observed higher tissue kallikrein activity (18·2 pM [1·2-1535·0], median [range], n = 9 vs 3·8 [0·0-22·0], n = 11; p = 0·030), higher levels of the kinin peptide bradykinin-(1-5) (89·6 [0·0-2425·0], n = 21 vs 0·0 [0·0-374·0], n = 19, p = 0·001), and higher levels of MPO-DNA complexes (699·0 ng/mL [66·0-142621·0], n = 21 vs 70·5 [9·9-960·0], n = 19, p < 0·001) compared to patients without COVID-19. INTERPRETATION: Our observations support the hypothesis that dysregulation of the kallikrein-kinin system might occur in mechanically ventilated patients with severe pulmonary disease, which might help to explain the clinical presentation of patients with severe COVID-19 developing pulmonary oedema and thromboembolic complications. Therefore, targeting the kallikrein-kinin system should be further explored as a potential treatment option for patients with severe COVID-19. FUNDING: Research Foundation-Flanders (G0G4720N, 1843418N), KU Leuven COVID research fund.

Mechanical properties and cellular content of leukocyte- and platelet-rich fibrin membranes of patients on antithrombotic drugs.

INTRODUCTION: The aim of this study was to examine the potential influence of antithrombotics on leukocyte- and platelet-rich fibrin (L-PRF) membranes. METHODS: Tensile tests and cell counts were performed with L-PRF membranes originating from patients on anticoagulants and antiplatelets versus patients not taking antithrombotics. RESULTS: For the tensile tests, 13 control patients, 12 on anticoagulants, and 10 on antiplatelets donated blood. Compared to controls, membranes from anticoagulated donors were weaker (strength 0.57 ± 0.24 MPa vs. 0.80 ± 0.27 MPa, p = .03) and could not be stretched as far (1.8 ± 0.3 vs. 2.1 ± 0.3 times the initial length, p = .01). For the cell counting, 23 control patients, 16 on anticoagulants, and 16 on antiplatelets donated blood. The percentage of platelets was ±50% in the three groups. The percentage of leukocytes was lower in the anticoagulant group compared with controls (69 ± 10% vs. 78 ± 8%, p = .04). However, because of the unknown error of method, it is questionable whether the statistical significance is meaningful. There was no difference between membranes from the control group and the group on antiplatelets. CONCLUSION: Our results indicate that L-PRF membranes originating from patients on anticoagulants are weaker, stretch less far, and contain less leukocytes than L-PRF membranes of patients not taking these drugs.

Tranexamic acid for the prevention and treatment of bleeding in surgery, trauma and bleeding disorders: a narrative review.

OBJECTIVES: We review the evidence for tranexamic acid (TXA) for the treatment and prevention of bleeding caused by surgery, trauma and bleeding disorders. We highlight therapeutic areas where evidence is lacking and discuss safety issues, particularly the concern regarding thrombotic complications. METHODS: An electronic search was performed in PubMed and the Cochrane Library to identify clinical trials, safety reports and review articles. FINDINGS: TXA reduces bleeding in patients with menorrhagia, and in patients undergoing caesarian section, myomectomy, hysterectomy, orthopedic surgery, cardiac surgery, orthognathic surgery, rhinoplasty, and prostate surgery. For dental extractions in patients with bleeding disorders or taking antithrombotic drugs, as well as in cases of idiopathic epistaxis, tonsillectomy, liver transplantation and resection, nephrolithotomy, skin cancer surgery, burn wounds and skin grafting, there is moderate evidence that TXA is effective for reducing bleeding. TXA was not effective in reducing bleeding in traumatic brain injury and upper and lower gastrointestinal bleeding. TXA reduces mortality in patients suffering from trauma and postpartum hemorrhage. For many of these indications, there is no consensus about the optimal TXA dose. With certain dosages and with certain indications TXA can cause harm, such as an increased risk of seizures after high TXA doses with brain injury and cardiac surgery, and an increased mortality after delayed administration of TXA for trauma events or postpartum hemorrhage. Whereas most trials did not signal an increased risk for thrombotic events, some trials reported an increased rate of thrombotic complications with the use of TXA for gastro-intestinal bleeding and trauma. CONCLUSIONS: TXA has well-documented beneficial effects in many clinical indications. Identifying these indications and the optimal dose and timing to minimize risk of seizures or thromboembolic events is work in progress.

Is third molar development affected by third molar impaction or impaction-related parameters?

OBJECTIVE: To evaluate the effect of third molar impaction and impaction-related parameters on third molar development. MATERIALS AND METHODS: Panoramic radiographs (N=3972) from 473 males and 558 females between 3.2 and 23.5 years old were analysed. Three parameters of impaction were examined: hindering contact between third and adjacent second molar, retromolar space availability (only in lower third molars), and angulation between the third and adjacent second molar. From the separate parameters, a definition for impaction was derived. Third molars' development was staged according to a modified Köhler et al. staging technique. A linear model was used to compare within-stage and overall age, as a function of hindering contact, retromolar space, and impaction. Furthermore, a quadratic function was used to study the correlation between age and angulation. RESULTS: Significant differences were found in mean age as a function of hindering contact and retromolar space, depending on third molar location and stage. There was a significant relation between angulation and age, depending on the stage, with all third molars evolving to a more upright position (closer to 0°). Mean ages of subjects with impacted third molars were significantly lower in certain third molar stages, but the differences were clinically small (absolute differences ≤0.65 years). Moreover, after correction for stage differences, no significant differences in age could be demonstrated. CONCLUSIONS: The development of impacted and non-impacted third molars can be considered clinically equal in our study population. CLINICAL RELEVANCE: There is no distinction required between impacted and non-impacted third molars for dental age estimation.

Tranexamic acid and bleeding in patients treated with non-vitamin K oral anticoagulants undergoing dental extraction: The EXTRACT-NOAC randomized clinical trial.

BACKGROUND: Oral bleeding after dental extraction in patients on non-vitamin K oral anticoagulants (NOACs) is a frequent problem. We investigated whether 10% tranexamic acid (TXA) mouthwash decreases post-extraction bleeding in patients treated with NOACs. METHODS AND FINDINGS: The EXTRACT-NOAC study is a randomized, double-blind, placebo-controlled, multicenter, clinical trial. Patients were randomly assigned to 10% TXA or placebo mouthwash and were instructed to use the mouthwash once prior to dental extraction, and thereafter for 3 times a day for 3 days. The primary outcome was the number of patients with any post-extraction oral bleeding up to day 7. Secondary outcomes included periprocedural, early, and delayed bleeding, and the safety outcomes included all thrombotic events. The first patient was randomized on February 9, 2018 and the last patient on March 12, 2020. Of 222 randomized patients, 218 patients were included in the full analysis set, of which 106 patients were assigned to TXA (74.8 (±8.8) years; 81 men) and 112 to placebo (72.7 (±10.7) years; 64 men). Post-extraction bleeding occurred in 28 (26.4%) patients in the TXA group and in 32 (28.6%) patients in the placebo group (relative risk, 0.92; 95% confidence interval [CI], 0.60 to 1.42; P = 0.72). There were 46 bleeds in the TXA group and 85 bleeds in the placebo group (rate ratio, 0.57; 95% CI, 0.31 to 1.05; P = 0.07). TXA did not reduce the rate of periprocedural bleeding (bleeding score 4 ± 1.78 versus 4 ± 1.82, P = 0.80) and early bleeding (rate ratio, 0.76; 95% CI, 0.42 to 1.37). Delayed bleeding (rate ratio, 0.32; 95% CI, 0.12 to 0.89) and bleeding after multiple extractions (rate ratio, 0.40; 95% CI, 0.20 to 0.78) were lower in the TXA group. One patient in the placebo group had a transient ischemic attack while interrupting the NOAC therapy in preparation for the dental extraction. Two of the study limitations were the premature interruption of the trial following a futility analysis and the assessment of the patients' compliance that was based on self-reported information during follow-up. CONCLUSIONS: In patients on NOACs undergoing dental extraction, TXA does not seem to reduce the rate of periprocedural or early postoperative oral bleeding compared to placebo. TXA appears to reduce delayed bleeds and postoperative oral bleeding if multiple teeth are extracted. TRIAL REGISTRATION: ClinicalTrials.gov NCT03413891 EudraCT; EudraCT number:2017-001426-17; EudraCT Public website: eudract.ema.europa.eu.

Adjuvant therapies for MRONJ: A systematic review.

OBJECTIVE: Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse reaction caused by the use of antiresorptive antiangiogenic medication. Treating MRONJ is difficult and besides standard treatments, which are conservative medical and surgical approaches, there are some adjuvant therapies that might further stimulate healing. The aim of this systematic review is to compare outcome and effectiveness of currently available adjuvant therapies for MRONJ. METHODS: This systematic review was conducted following the PRISMA guidelines. Articles focusing on mucosal healing in patients treated with an adjuvant therapy for MRONJ were selected and analysed. Inclusion was not limited to randomized controlled trials to present a complete review of the current literature. RESULTS: A search was performed in Pubmed, Embase, Web of Science and Cochrane Central Register of Controlled Trials. Thirty articles out of 3297 were included. Laser ablation had a success of 60-95% for complete healing. The controlled trials of leukocyte- and platelet-rich-fibrine (LPRF) showed 60-100% success for the same outcome. Fluorescence guided surgery had a complete healing percentage of 85-90%. CONCLUSIONS: The results suggest that laser ablation, LPRF and fluorescence guided surgery might have a potential in improving the healing process. Interpreting the results should however be done with great care and a critical point of view, as most articles had a medium to high risk of bias. More randomized controlled trials are necessary to define the most beneficial therapy protocols. CLINICAL RELEVANCE: It seems that adjuvant surgical therapies for treating MRONJ are beneficial for mucosal healing, but there is only low scientific evidence.

Mechanical and structural properties of leukocyte- and platelet-rich fibrin membranes: An in vitro study on the impact of anticoagulant therapy.

OBJECTIVE AND BACKGROUND: Little is known about structural and mechanical properties of leukocyte- and platelet-rich fibrin (L-PRF) membranes and even less about the influence of antithrombotic drugs on L-PRF. The aim of this in vitro study is therefore to investigate mechanical properties, fibrin structure and cell content of L-PRF membranes and the impact of anticoagulant therapy on L-PRF. METHODS: Blood samples were obtained from 12 volunteers and supplemented with either no, 1.25 IU, 2.5 IU, 5 IU, or 10 IU enoxaparin. L-PRF membranes were characterized with tensile testing, scanning electron microscopy, and measurement of platelets and leukocytes. Control and enoxaparin-supplemented L-PRF membranes were compared. RESULTS: At 10 IU enoxaparin, no L-PRF membranes could be generated, whereas the low doses of 1.25 and 2.5 IU had no influence on L-PRF properties. The mechanical properties, fibrin networks, and number of platelets and leukocytes of 5 IU supplemented membranes were unlike the control membranes, but were not found to be significantly different because of limited sampling and inter- and intra-variability. CONCLUSION: Low doses of the anticoagulant enoxaparin do not affect mechanical properties, fibrin network, nor cellular content of L-PRF, whereas high doses impair L-PRF generation.

Radiographic prediction of mandibular third molar eruption and mandibular canal involvement based on angulation.

OBJECTIVES: The aim of our study was to identify and predict patients at risk of impeded mandibular third molar eruption and potential relation between the third molar roots and the mandibular canal, based on molar angulations in an early development stage. SETTING AND SAMPLE POPULATION: A total of 1011 adolescent orthodontic patients were included in this longitudinal study. MATERIALS AND METHODS: We analysed pre-eruptive rotational changes and root development of mandibular third molars on 2022 panoramic radiographs (two time-points). Five variables were evaluated: third molar eruption level, development stage, risk of relation between the third molar and the mandibular canal, the molar angulations and orthodontic treatment. The relation between early third molar angulation and mean annual angulation change was assessed using a linear mixed model. Logistic regression was applied to investigate a potential correlation of the radiographic variables with the eruption potential and risk of developing a relation between the third molar and the mandibular canal. RESULTS: Mandibular third molar follicles with an initial angulation exceeding 27.0° relative to the second molar tend to progressively increase their angulation during further development. A significant correlation was found between the hemimandibular molar angulations and the probability of eruption (P < 0.0001). The second to first molar angulation was predictive for potential development of a relation with the mandibular canal (P = 0.005). CONCLUSION: From the present data, it appears that severely angulated mandibular third molars (>27.0°) have a minimal chance of future eruption and a maximal risk of developing a relation with the mandibular canal.

Local haemostatic measures after tooth removal in patients on antithrombotic therapy: a systematic review.

OBJECTIVE: The interruption of antithrombotics prior to tooth removal because of the fear of bleeding or following postoperative bleeding increases the risk of thromboembolic events. The aim of this systematic review was to investigate which local haemostatic measures can effectively prevent postoperative bleeding in patients continuing oral antithrombotics. METHODS: A systematic review was conducted by running a search in PubMed, Embase, Web of Science and Cochrane Library. Clinical randomised trials investigating bleeding and haemostatics after tooth removal in patients on antithrombotics were identified. RESULTS: In total, 15 articles were included. The investigated haemostatics included gauze pressure, tranexamic acid-soaked gauze, sponges, glue, calcium sulfate, plant extract Ankaferd Blood Stopper, epsilon-aminocaproic acid and tranexamic acid. In patients treated with vitamin K antagonists, tranexamic acid mouthwash significantly reduced bleeding compared to placebo. Further, histoacryl glue was proven better than gelatin sponges. Other studies failed to show significant differences between haemostatics, but bleeding events were low. CONCLUSIONS: Tranexamic acid seems to effectively reduce bleeding, although its superiority to other haemostatics was not proven. In view of the rapidly changing landscape of antithrombotics and the lack of standardization of bleeding outcome, adequately powered clinical studies are required to optimise postoperative management in patients on antithrombotics. CLINICAL RELEVANCE: In order to optimise postoperative management, the best haemostatics over different patient groups have to be identified and implemented in guidelines.