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4.8. Statistical Analysis of Clinical Data | IBM SPSS Statistics for Windows version 23.0 was used to perform statistical analyses (IBM Corp., Armonk, NY, USA). Mann–Whitney U tests were used to test for statistical significance. The study results were accepted as statistically significant if | PMC10454735 | ||
Supplementary Materials | The supporting information can be downloaded at: Click here for additional data file. | PMC10454735 | ||
Author Contributions | J.K.: Investigation, formal analysis, resources. E.J.: Investigation, formal analysis. W.Y.: Investigation, formal analysis. C.-K.K.: Investigation, formal analysis. S.D.: Formal analysis, writing original draft, writing, review, and editing. I.-R.O.: Formal analysis, resources. C.-W.K.: Validation, supervision. A.J.S.: Conceptualization, validation, supervision. M.C.M.J.: Conceptualization, validation, supervision. J.H.L.: Resources, validation, supervision. All authors have read and agreed to the published version of the manuscript. | PMC10454735 | ||
Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Yonsei University Severance Hospital (IRB protocol no. 4-2018-0124). | PMC10454735 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10454735 | ||
Data Availability Statement | Not applicable. | PMC10454735 | ||
Conflicts of Interest | E.J., W.Y., C.-K.K., S.D. and I.-R.O. are current employees of Biocoz Global Korea. C.-W.K. holds patents for SPM. A.J.S., M.C.M. and J.H.L. are medical and scientific advisors of the company. J.K. reports no conflict of interest. | PMC10454735 | ||
References | chronic atopic dermatitis, eczema | INFILTRATION, SKIN LESIONS | SPM reverses LPS-induced damage. (SPM suppresses the expression of LPS-induced IL-1β in HaCaT cells. (SPM suppresses the expression of poly(I:C)/TNFα-induced cytokines in HaCaT cells. (SPM suppresses cytokine secretion in UV-damaged cells in a 3D human epidermis model. (The topical agent containing SPM alleviates mild chronic atopic dermatitis and eczema symptoms. (Corneum stratum and lymphocyte infiltration at the dermis–epidermis interface in skin lesions of one subject before and after topical application of SPM. (Demographic data for the subjects. | PMC10454735 |
Materials and Methods | HEAT, ACUTE RESPIRATORY DISTRESS SYNDROME, GROUP B | This was a single-center randomized controlled pilot trial (NCT04494867), and we have previously published the study protocol (Bonfanti et al., Once the randomization form was entered into the system and saved, the back-end algorithm ran and participants were assigned an arm corresponding to either study device (Group A—Core warming) or standard of care (Group B—Control). Patients underwent randomization after being enrolled into the study and before the placement of the core warming device. Randomization was performed in a 1:1 manner and maintained on the limited access, encrypted, Redcap database. All procedures followed were in accordance with the ethical standards of the Sharp Memorial Hospital IRB (IRB No. 2007901; approved August 17, 2020) and with the Helsinki Declaration of 1975.The primary outcome was the severity of acute respiratory distress syndrome as measured by the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) ratio. Secondary outcomes included the change in viral load measured in lower respiratory tract samples, the duration of mechanical ventilation, and mortality. Patient core warming was provided by a commercially available esophageal heat exchange system (ensoETM; Attune Medical). The device was set to 42°C after initiation and maintained at 42°C for the duration of 72 hours of treatment unless patient temperature exceeded 39.8°C, at which point the device setpoint was reduced to 40°C. Control patients were provided standard temperature management. | PMC10698775 | |
Results | A total of 19 patients were randomized (10 patients to control, 9 to core warming). The patients had a mean age of 60.5 (±12.5) years, 37% were female, with a mean weight of 95.1 (±18.6) kg, and a mean body mass index 34.5 (±5.9) kg/mBaseline DemographicsSOFA, Sequential Organ Failure Assessment score.Temperature curves for each patient group are shown in Patient temperature curves over 72 hours of treatment.Measured outcomes are shown in OutcomesICU, intensive care unit; PaO2/FiO2, the ratio of arterial oxygen partial pressure to fractional inspired oxygen. | PMC10698775 | ||
Discussion | gastrointestinal symptoms, tumor necrosis, abdominal pain, infections, hyperthermia, nausea, vomiting | TUMOR NECROSIS, EVENT, INFECTIONS, ADVERSE EVENT, BLIND, HEAT | Growing data support beneficial effects from warming patients with severe infections, and there are increasing research efforts being undertaken to better understand the mechanistic underpinnings for the clinical effects reported. Challenges in warming patients to febrile-range hyperthermia will need to be adequately addressed to fully explore hyperthermia as a treatment. This pilot study suggests that core warming provided by a commercially available esophageal heat transfer system appears safe and can provide febrile-range temperatures to patients with COVID-19 undergoing mechanical ventilation.Core body temperature is far more tightly regulated than other physiological parameters (including blood pressure and heart rate), and because of the existence of robust thermal defense mechanisms, warming patients to above normal temperatures can be difficult (Sessler, A single adverse event attributed to the use of the device was reported as an episode of nausea, vomiting, and abdominal pain. No differences in sedation level were noted between cohorts in this study, and all patients received sedation levels sufficient to maintain mechanical ventilation, making this event unlikely to be related to sedation level, but a clear etiology or definitive attribution to the device remains uncertain. COVID-19 is known to have gastrointestinal symptoms, which makes it difficult to rule out as a factor (Kwei-Nsoro et al., Further studies are in development, which aim to investigate further mechanistic underpinnings behind the effects of elevated temperature in severe infections. Given the known challenges in warming patients to above-normal body temperature, a multimodal temperature management strategy may be required, and is being anticipated, in subsequent investigations.Limitations of this study include the small sample size, the inability to blind health care providers treating enrolled patients, and the lack of measurement of specific immune factors such as interleukin (IL)-1, IL-6, tumor necrosis factor, and interferon. | PMC10698775 |
Conclusions | Core warming of patients with COVID-19 undergoing mechanical ventilation is feasible and appears safe. To optimize time to achieve febrile-range temperature in subsequent studies, a multimodal temperature management strategy may be necessary. | PMC10698775 | ||
Acknowledgments | The investigators thank DeAnn S. Cary, PhD, MacKenzie Habib, BS, Kyra Rashid, BS, MCR, Kathryn Hong, Cary Murphy, RN, Christine Kappel, RN, the Sharp Memorial Hospital, and the Sharp Center for Research. An earlier draft of this article was posted as a preprint at medRxiv (DOI: 10.1101/2023.04.12.23287815). | PMC10698775 | ||
Authors' Contributions | Writing—original draft, review, and editing by N.P.B. Methodology, data curation, and formal analysis by N.M.M. Project administration, resources, and investigation by D.C.W. Conceptualization and methodology by R.J.B. and A.M.D. Conceptualization by E.G. and K.L.G. Conceptualization, methodology, project administration, and writing—review and editing by E.B.K. | PMC10698775 | ||
Author Disclosure Statement | MOHR | Drs. Bonfanti, Mohr, Gundert, Goff, and Drewry, no disclosures. Dr. Willms, disclosures limited to: Speaker Bureau, La Jolla Pharmaceutical Company, Board of Directors & Investor, Octet Medical, Inc., Investor and Medical Advisor, InVent Respiratory and Connected Rock Ventures. Dr. Bedimo, disclosures limited to: Research support from Merck & Co., Scientific advisory board for Merck & Co., Shionogi, Gilead, and Theratechnologies. Dr. Kulstad, disclosure limited to equity and employment in Attune Medical. | PMC10698775 | |
Funding Information | No funding was received for this article. | PMC10698775 | ||
References | PMC10698775 | |||
Background | AMS | HYPOXIC, ACUTE MOUNTAIN SICKNESS | Cardiorespiratory fitness plays an important role in coping with hypoxic stress at high altitudes. However, the association of cardiorespiratory fitness with the development of acute mountain sickness (AMS) has not yet been evaluated. Wearable technology devices provide a feasible assessment of cardiorespiratory fitness, which is quantifiable as maximum oxygen consumption (VO | PMC10360014 |
Objective | We aimed to determine the validity of VO | PMC10360014 | ||
Methods | SWT and cardiopulmonary exercise | Both SWT and cardiopulmonary exercise test (CPET) were performed for VO | PMC10360014 | |
Results | VO | PMC10360014 | ||
Conclusions | Our study demonstrates that the smartwatch device can be a feasible approach for estimating VO | PMC10360014 | ||
Trial Registration | Chinese Clinical Trial Registry ChiCTR2200059900; https://www.chictr.org.cn/showproj.html?proj=170253 | PMC10360014 | ||
Introduction | AMS, hypobaric hypoxia | ACUTE MOUNTAIN SICKNESS, HYPOBARIC HYPOXIA | In recent years, mountain climbing has become a popular activity for pleasure, work, and athletic competitions. However, inadequate acclimatization to hypobaric hypoxia results in a series of symptoms known as acute mountain sickness (AMS). AMS is relatively common among new travelers, affecting >30% of individuals ascending to 3500 m and >70% of those ascending above 6000 m [Maximum oxygen consumption (VOVO | PMC10360014 |
Methods | PMC10360014 | |||
Participant Recruitment | respiratory and cardiovascular diseases, liver and kidney dysfunctions, neuroses, psychiatric disorders | MALIGNANT TUMORS | We recruited 46 healthy adults (27 women and 19 men, age range 22-54 years) from Chongqing, China, based on the inclusion and exclusion criteria. All participants had lived at low altitudes (<500 m) for at least 10 years and had no recent history of high-altitude (>2500 m) exposure (in the last 6 months). Participants with any one of the following conditions were excluded: respiratory and cardiovascular diseases, malignant tumors, liver and kidney dysfunctions, and psychiatric disorders or neuroses that would not allow them to complete the questionnaires. | PMC10360014 |
Ethics Approval | The study protocol (ChiCTR2200059900) complied with the Declaration of Helsinki and was approved by the ethics committee of Xinqiao Hospital of Army Medical University (approval: 2022-研第-060-01). Written informed consent was obtained from all the participants after the study details, procedures, benefits, and risks were explained. | PMC10360014 | ||
Procedures | AMS | ACUTE MOUNTAIN SICKNESS | This study consisted of 2 exercise tests at low and high altitudes (Cohort development diagram for this study. AMS, acute mountain sickness; CPET, cardiopulmonary exercise test; SWT, smartwatch test. | PMC10360014 |
Blood Routine Examination | BLOOD | The participants were required to avoid eating or drinking anything (fasting) apart from water for up to 12 hours. Approximately 5 mL of intravenous blood was collected from the inside of the elbow and mixed with 1 mL of dipotassium ethylenediaminetetraacetic acid anticoagulant by using a tight band (tourniquet). Blood samples were analyzed using a BC-3000 plus automated hematology corpuscle analyzer (Mindray). The details of the 19 different parameters are presented in | PMC10360014 | |
CPET Analysis | The CPET was performed on an electronically braked cycle ergometer (EC3000e, Customed) in an erect position with breath-by-breath measurements through a tightly fitted face mask of minute ventilation, O | PMC10360014 | ||
SWT Analysis | We provided participants with a smartwatch (Huawei Watch GT Runner) and instructed them to wear it correctly on the left wrist, which enables reliable and persistent measurement of running speed, distance, and heart rate. Therefore, these measurements could be monitored continuously and automatically during each running activity, stored on the participant’s mobile device (Huawei MatePad 11 DBY-W09), and regularly transmitted to a secure cloud server, which was later transferred to the Huawei Health Center software through Bluetooth. Specifically, VOThe signal processing by Huawei Watch GT Runner is licensed by the Firstbeat Technology’s Fitness Test, which is based on intelligent detection for both data reliability and exercise pattern during successive recording [ | PMC10360014 | ||
Lake Louise Consensus Scoring System and AMS | AMS | The presence of AMS at high altitude was assessed using the Lake Louise consensus scoring system 2018 version [ | PMC10360014 | |
Statistical Analyses | AMS | REGRESSION | Categorical variables were described as numbers and percentages. Descriptive statistics were presented as mean (SD) for variables with skewed distribution and median (IQR) for variables with normal distribution. The Mann–Wilcoxon rank-sum, independent-sample The relationship between the variables and AMS was examined by binomial logistic regression analysis with univariate analyses. The relationship between VO | PMC10360014 |
Results | PMC10360014 | |||
Distribution of VO | ACUTE MOUNTAIN SICKNESS | There was a significant difference in the VO(A) Distribution of the estimated maximum oxygen consumption measured by smartwatch test and cardiopulmonary exercise test based on the diagnosis of acute mountain sickness. (B) Diagram of the probability of acute mountain sickness occurrence for different ranges of the maximum oxygen consumption value at low altitude (blue: maximum oxygen consumption measured by cardiopulmonary exercise test; orange: maximum oxygen consumption measured by smartwatch test). **Significantly different between acute mountain sickness and non–acute mountain sickness at | PMC10360014 | |
Discussion | PMC10360014 | |||
Principal Results | Our study comparatively evaluated the VOPrevious clinical trials [Similar to that shown in a previous report, VOVOVOIt can be concluded from our results that individuals with a higher VOThe VOTo advance this field, several measures are required. First, there is an urgent need for validation standards for smartwatch devices to enable standardized research. Second, the open disclosure of commercial validation studies can enable better resource usage, as studies will not have to be repeated unnecessarily. Third, further development of smartwatch devices will allow new possibilities in the field of VO | PMC10360014 | ||
Limitations | This study had some limitations. Notably, the Lake Louise consensus scoring system (2018 version) is subjective; therefore, we described each symptom as clearly as possible and provided necessary instructions before the participants completed the questionnaire to deal with the subjectivity. Second, running exercise instead of cycling should be implemented by CPET to minimize the inconsistencies in VO | PMC10360014 | ||
Conclusions | Our findings demonstrate that VOWe appreciate all the volunteers in this clinical trial and the Shigatse hospital in Tibet. This study was supported by grants from the National Natural Science Foundation of China (81730054) and research project of People's Liberation Army (BLJ18J007).Conflicts of Interest: None declared.Original data of the cardiopulmonary exercise test and smartwatch test in this study. | PMC10360014 | ||
Abbreviations | acute mountain sicknessarea under the curvecardiopulmonary exercise testFirstbeat fitness testmean absolute percentage errorodds ratiored blood cellred blood cell distribution width-coefficient of variationreceiver operating characteristicoxygen saturationsmartwatch testmaximum oxygen consumption | PMC10360014 | ||
Data Availability | The data sets generated and analyzed during this study are available from the corresponding author on reasonable request. | PMC10360014 | ||
Abstract | PTSD, posttraumatic stress disorder, Trauma | SEPARATION, EVENTS | The authors declare no competing financial interests.Author contributions: J.M.W., Y.X., B.K., and D.R.B. designed research; J.M.W., Y.X., B.O., D.M., and D.R.B. performed research; J.M.W. and Y.X. analyzed data; J.M.W. and D.R.B. wrote the paper.This work was supported by the Clinical Research Priority Program of the University of Zurich for the CRPP “Synapse & Trauma.” D.R.B. is supported by funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (Grant Agreement No. ERC-2018 CoG-816564 ActionContraThreat). The Wellcome Centre for Human Neuroimaging is funded by core funding from the Wellcome (203147/Z/16/Z).J.M.W. and Y.X. contributed equally to this work.Learning to predict threat is of adaptive importance, but aversive memory can also become disadvantageous and burdensome in clinical conditions such as posttraumatic stress disorder (PTSD). Pavlovian fear conditioning is a laboratory model of aversive memory and thought to rely on structural synaptic reconfiguration involving matrix metalloproteinase (MMP)9 signaling. It has recently been suggested that the MMP9-inhibiting antibiotic doxycycline, applied before acquisition training in humans, reduces fear memory retention after one week. This previous study used cued delay fear conditioning, in which predictors and outcomes overlap in time. However, temporal separation of predictors and outcomes is common in clinical conditions. Learning the association of temporally separated events requires a partly different neural circuitry, for which the role of MMP9 signaling is not yet known. Here, we investigate the impact of doxycycline on long-interval (15 s) trace fear conditioning in a randomized controlled trial with 101 (50 females) human participants. We find no impact of the drug in our preregistered analyses. Exploratory | PMC9961363 |
Significance Statement | The inhibition of matrix metalloproteinase (MMP)9 attenuates memory consolidation and subsequent recall in a delay cue conditioning paradigm. However, it is currently unclear whether this is also the case for other learning scenarios that rely on a different neurocircuitry. We test this hypothesis in human trace fear conditioning which employs remote cues and is additionally dependent on hippocampus involvement. We find that doxycycline does not reduce fear retention in our preregistered analyses. Exploratory analyze might potentially suggest a weak effect of doxycycline on trace fear memory retention. | PMC9961363 | ||
Introduction | traumatic, trauma | EVENTS, EVENT | The ability to predict threat is fundamental for survival and requires remembering predictive cues. However, when threat is absent, lingering aversive memory can contribute to trauma-related clinical conditions (The molecular processes supporting fear memory acquisition and consolidation in the amygdala (This previous study used cued delay fear conditioning as an experimental model, in which threat predictor and aversive outcome are simultaneously presented. Yet, intrusive memory and physiological arousal after psychological trauma cannot only be triggered by stimuli present during trauma, but also by those that occurred at some interval before the traumatic event (In the laboratory, prediction by temporally preceding events is modelled in trace fear conditioning, where CS and US are separated in time ( | PMC9961363 |
Materials and Methods | PMC9961363 | |||
Overview | We tested the impact of doxycycline versus placebo on human trace fear conditioning in a randomized, placebo-controlled, double-blind trial. We used a trace interval of 15 s, which is long enough to require hippocampus involvement in rodents ( | PMC9961363 | ||
Participants | Anxiety, anxiety, pain | RECRUITMENT | We recruited 101 participants from the general population between November 5, 2019 and December 22, 2020 and randomly assigned them to placebo (Sample characteristicsUS intensity: electric current used in experiment; pain ratings pre vs post: difference in average pain ratings of 14 stimuli before and after the acquisition test; accuracy: % of correct responses in identification task, average of acquisition (visit 2) and recall (visit 3); performance: % of responses in identification task, average of acquisition (visit 2) and recall (visit 3); arousal: difference in arousal ratings between CS+/CS− after the acquisition session (visit 2), and after the recall session (visit 3); valence: difference in valence ratings between CS+/CS− after the acquisition session (visit 2), and after the recall session (visit 3); state anxiety: measured with State-Trait Anxiety Inventory (STAI; The study was conducted in accordance with the Declaration of Helsinki and approved by the governmental research ethics committee (Kantonale Ethikkomission Zürich KEK-ZH-2018–01973) and the Swiss Agency for Therapeutic Products (Swissmedic; 2019DR1026). All participants gave written informed consent before the experiment using a form approved by the ethics committee. The study was preregistered with a WHO-approved primary registry (German Clinical Trials Register, DRKS00017037) and at the Swiss Federal Complementary Database (Kofam: SNCTP000003485). During recruitment, the analysis protocol was adapted based on ongoing methodological work ( | PMC9961363 |
Power analysis | To determine required sample size, we conducted a power analysis (using G*power) based on a methodological study in which the effect size for differential SEBR in an untreated control group was (Cohen’s) | PMC9961363 | ||
Study medication | OSF | The study medication was the tetracycline antibiotic doxycycline, brand name Vibramycin (Pfizer). Study dose (200 mg) was based on a previous study using delay fear conditioning (According to the manufacturer’s information, the drug’s half-life is ∼16 h. Hence, the drug was cleared >99.9% before the recall session 7 d after ingestion. The drug was manufactured, blinded, and randomized separately for males and females, by a GMP-licensed pharmacy (Kantonsapotheke Zurich). Mannitol was used as placebo. Randomization was broken after the last participant completed the study, data were checked for consistency, and the study analysis plan was preregistered on OSF. | PMC9961363 | |
Experimental design | PMC9961363 | |||
Screening visit 1 (day −14 to day −2) | The study procedure is illustrated in Experimental protocol. | PMC9961363 | ||
Acquisition visit 2 (day 0) | Acquisition visit 2 started in the morning hours between 7:30 to 11:00 A.M. Before ingestion of the study medication, participants were asked about their health status, medication intake and psychotropic substance consumption since the screening visit. Then they were administered the study medication. Participants were asked not to eat, or drink beverages containing milk, in the hour before and after drug ingestion, as this can influence the absorption of doxycycline ( | PMC9961363 | ||
Recall visit 3 (day +7) | In recall visit 3, participants filled in the state part of the STAI ( | PMC9961363 | ||
Task and stimuli | pain | Fear acquisition training comprised 40 trials (20 CS+, 20 CS−), and the fear recall test 30 trials (15 CS+, 15 CS−). Each CS was followed by a 15-s trace interval. During acquisition training, US was presented after the trace interval (15 s after CS offset) in all CS+ trials (100% reinforcement; CS were two differently colored [yellow (RGB: 225, 224, 177) and purple (RGB: 238, 194, 244)] isoluminant triangles, presented for 2 s at the center of an isoluminant gray (RGB: 175, 175, 175) computer screen at a visual angle of ∼4.1°. Association of CS+/CS− to CS color was counterbalanced across participants. As an identification task, participants were asked to indicate the color of the CS by pressing the left/right cursor keys during CS presentation on a standard computer keyboard. If participants gave the wrong or no response, the words “wrong key” and “no response,” respectively, were presented immediately after CS offset. During the 15-s trace interval, a white (RGB: 255, 255, 255) fixation cross was presented at the center of the gray background screen at a visual angle of ∼0.8°.US consisted of a sequence of 83 square electric pulses of 0.2-ms duration with a duty cycle of 1.67%, summing up to a total duration of 1000-ms. US were delivered to the participants’ dominant forearm via a pin-cathode/ring anode configuration. Electric pulses were generated by a constant current stimulator (Digitimer DS7A, Digitimer). Intensity of the US was set to a perceived intensity between 80–90% of the lowest clearly painful stimulus. US intensity was estimated in three phases. In the first phase, US intensity was increased until a painful level was firmly reached, marking the upper limit for the second phase, during which 14 US with random intensities were delivered. Participants were asked to rate their subjective pain perception for each of them from 0 to 100. These ratings were then linearly interpolated to estimate a US intensity corresponding to 90% of a clearly painful stimulus. Stimuli with this intensity were once more presented to the participants and adjusted if necessary.During the ITI, a simple visual detection task was presented to keep participants attentive, because previous studies showed that participants become drowsy even with shorter ITIs (15 s; In the recall session, white noise startle probes of 20 ms duration, instantaneous rise time, and 102-dB loudness, were delivered binaurally via headphones (HD 202, Sennheiser). The experiment was conducted in a dark, soundproof chamber. The experimental task was presented on a Dell P2014h 20-inch screen, set to an aspect ratio of 4:3 at 60 Hz, with a resolution of 1152 × 864 pixels. Participants’ heads were positioned with a chin rest at 70 cm distance from the monitor and 47 cm from the eye tracker. | PMC9961363 | |
Psychophysiological recordings | SKIN | Electromyogram (EMG) was recorded from the orbicularis oculi muscle of the participants’ left eye, with two 4 mm Ag/AgCl cup electrodes filled with high-conductance gel. The electrodes were positioned below the lower eyelid on the muscle, in a vertical line with the pupil in forward gaze, and below the lateral canthus. Electromyogram was amplified with a gain of 2000, low-pass filtered at 1 Hz and high-pass filtered at 500 Hz (EMG100C, Biopac Systems). Skin conductance was recorded with a 0.5-V constant voltage (EDA100C, Biopac Systems) from the thenar/hypothenar of the nondominant hand, with disposable Ag/AgCl snap electrodes (EL507, Biopac Systems), filled with 0.5% NaCl electrolyte gel ( | PMC9961363 | |
Preparation and storage of blood samples | Within an hour of withdrawal, two serum tubes (8 ml each) of blood samples were centrifuged in a Universal 320 R (Hettich) for 10 min at 2800 × | PMC9961363 | ||
Data analysis | PMC9961363 | |||
Overview | OSF | For the recall test, an updated data analysis plan was preregistered on OSF (Acquisition paired t test CS+/CS−, not corrected for multiple comparisons. Download Acquisition independent t test between CS+/CS− difference for placebo and doxycycline group, not corrected for multiple comparisons. P = Placebo, D = Doxycycline Download SCR to CS LME (estimated with “nlme” package) in fear acquisition. Download Psychophysiological data were preprocessed and analyzed using MATLAB (version R2018b, MathWorks) with procedures implemented in PsPM 4.1.1 (Psychophysiological modeling, legacy version available at | PMC9961363 | |
Data preprocessing and conditioned response scoring | PMC9961363 | |||
Startle eye-blink responses | Preprocessing followed a peak-scoring procedure developed by | PMC9961363 | ||
Skin conductance responses | To remove artefacts related to US presentation, all data points in the period from 0.2 s before US onset to 1.6 s after US onset were treated as missing values in all SCR analyses. Data were then visually inspected for remaining artefacts. One participant (doxycycline group) was excluded from all SCR analyses because of inadequate quality of the SCR signal but retained in all other analyses. SCR analysis was adapted from the procedure benchmarked in | PMC9961363 | ||
Pupil size response | For conversion of EyeLink 1000 system’s arbitrary units to true diameter, we used the transformation derived in Trial-by-trial pupil response was then estimated using the general linear convolution models (GLMs) approach implemented in PsPM ( | PMC9961363 | ||
Statistical analysis | PMC9961363 | |||
Preregistered analysis | LME, nonconvergence | SECONDARY | Statistical Analysis was performed in R (Acquisition data for SCR and PSR were analyzed with a preregistered 2 (group) × 2 (condition, i.e., CS+/CS−) × 40 (trial) linear mixed effects (LME) model using the R package “lmerTest” (version 3.1.2) function lmer() with trial number as a linear predictor across conditions. The trial numbers are represented as across trials to reflect that CS presentation is randomized and SCR estimates habituate over time (rather than just within conditions). This leads to an unbalanced model which is amenable to the LME approach. For consistency with previous work, we also averaged response estimates from placebo participants across all CS+ and CS− trials separately and computed a paired Our preregistered primary outcome was SEBR data from the recall session, averaged across CS+ and CS− trials separately, and compared in a two-sample Our preregistered secondary outcome was SCR from the recall session. To account for time effects, these were analyzed in a 2 (group) × 2 (condition) × 30 (trial) LME model. Again, using the function lmer() of the R package “lmerTest” (version 3.1.2) with trial number as a function of time across conditions. Significant results were Holm–Bonferroni corrected for three comparisons (i.e., SCR CS time point, SCR trace interval and SCR US time point).For all LMEs, we tested different random effect structures and retained the model with lowest Akaike’s information criterion (AIC) using the “stats” package (version 4.0.2) function AIC(). In case of nonconvergence with the default optimizer, we tested convergence with all available optimizers using the allFit() function of the “lme4” package (version 1.1.23). If models did not converge with alternate optimizers, the respective random effect structure was not considered further. Following this procedure, for all data from the acquisition session and for SCR to the time point of expected US presentation in the recall session, we retained a model with a random intercept per subject. For the remaining analyses, models with random effects accounting for subject and trial were retained. For effect size estimation we used the function eta_squared() of the “effect size” package 0.6.0.1. | PMC9961363 |
Robustness analyses | Primary analyses used different statistical models for the different measures. To make them comparable and check the robustness of findings, we conducted additional (not preregistered) analyses. For SEBR, we computed a 2 (group) × 2 (condition, i.e., CS+/CS−) × 20 (trial) LME model with trial number as a function of time across conditions. Additionally, for SCR to CS onset during acquisition, LME revealed a main effect group that was not apparent in the descriptive statistics. Hence, this analysis was repeated using the “nlme” package version 3.1.149 function lme(). | PMC9961363 | ||
Exploratory analysis | LME, anxiety | Because individuals might differ in their metabolization of doxycycline, we investigated the relation of doxycycline serum levels with SEBR and SCR within the doxycycline group. To this end, we replaced the drug factor in the ANOVA (SEBR) and LME (SCR) analysis with doxycycline level as a linear predictor.Furthermore, during data analysis, we found differences in fear retention between the sexes. For this reason, we separately investigated fear retention in men and women for SEBR and SCR in a Finally, when comparing state anxiety scores ( | PMC9961363 | |
Code and data accessibility | OSF | Analysis code is available on OSF ( | PMC9961363 | |
Results | PMC9961363 | |||
Placebo group analysis | LME | To control the effectiveness of the paradigm, we verified trace fear acquisition and retention within the placebo group. Averaged across the entire acquisition session, we found CS+/CS− differentiation for SCR to CS presentation (CS+/CS− differences in skin conductance responses (SCR) and pupil size responses (PSR) during acquisition training. CS+/CS− differences in startle-eye blink responses (SEBR) and skin conductance responses (SCR) during recall visit 3 and their correlation with doxycycline level in serum. Relation of doxycycline levels with SEBRANOVA for the relation of doxycycline levels with SEBR, dependent on condition and trial number, only for the doxycycline group. Significant effects are marked with ‘*’.Extinction paired t test CS+/CS−, not corrected for multiple comparisons. Download Extinction independent t test between CS+/CS− difference for placebo and doxycycline group, not corrected for multiple comparisons. P = Placebo, D = Doxycycline Download Extinction paired t test CS+/CS− per gender, not corrected for multiple comparisons. Download Extinction independent t test between CS+/CS− difference for placebo and doxycycline group per gender, not corrected for multiple comparisons. P = Placebo, D = Doxycycline Download SEBR ANOVA in fear recall. Download SEBR LME in fear recall. Download SCR and doxycycline level (in doxycycline group) LME in fear recall. Download | PMC9961363 | |
Doxycycline and trace fear acquisition | LME | Next, we investigated drug differences in a preregistered LME model for SCR and PSR. For SCR, we found higher CS+ than CS− responses at all time points (main effect CS), larger SCR to CS presentation in the doxycycline group (main effect group), and faster SCR habituation in the placebo group (group × trial interaction), to CS presentation and during the trace interval (see LME analysis of SCR and PSR during trace fear acquisitionModels are estimated with lme4, lmer(data ∼ (1|subject) + group*condition*trial), significant (In an exploratory analysis, we tested for sex differences and found that both men and women differentiate CS+/CS− successfully, both in the placebo and doxycycline group (see Extended Data Acquisition paired t test CS+/CS− per gender, not corrected for multiple comparisons. Download Acquisition independent t test between CS+/CS− difference for placebo and doxycycline group per gender, not corrected for multiple comparisons. P = Placebo, D = Doxycycline Download | PMC9961363 | |
Trace fear memory recall: preregistered analyses | LME, memory retention | SECONDARY | Our preregistered primary outcome measure for trace fear memory retention was fear-potentiated startle, quantified by SEBR. A direct group comparison, our preregistered primary analysis, revealed no significant difference between doxycycline and placebo (Our preregistered secondary outcome measure of trace fear retention was SCR. In our preregistered LME analysis, we found a significant effect of trial, suggesting habituation. There were no other significant effects after Holm–Bonferroni correction for the three time points (see LME analysis of SCR during trace fear recallModels are estimated with lme4, lmer(data ∼ (1+trial|subject) + group*condition*trial) for CS and US time point and lmer(data ∼ (1|subject) + group*condition*trial) for trace interval, significant ( | PMC9961363 |
Trace fear memory recall: exploratory analyses | memory retention | A group comparison of CS+/CS− differences in SCR, averaged over the entire recall session, revealed a significant group difference during the trace interval (Participants may have metabolized the study drug differently. We analyzed serum samples taken at the end of the study and investigated a relation of doxycycline serum level with SEBR and SCR during the trace interval within the doxycycline group (see We incidentally observed apparent sex differences in fear-potentiated SEBR: within the placebo group, females showed memory retention ( | PMC9961363 | |
Doxycycline serum levels | REGRESSION | Doxycycline serum levels differed between females (mean ± SD: 3.34 ± 1.12 mg/l) and males (mean ± SD: 2.21 ± 0.89 mg/l; Correlation of body weight with doxycycline level in serum after acquisition session visit 2. Individual serum levels for women are depicted in violet. Men are depicted in green. Dotted line shows regression regardless of sex. For details, see Extended Data Mediation analysis for effect of sex on doxycycline serum levels mediated by weight. Download | PMC9961363 | |
State anxiety | Anxiety, anxiety | We recorded state anxiety using the STAI (Anxiety ratings. | PMC9961363 | |
Discussion | Previous work has identified the MMP9 inhibiting drug doxycycline as a possible inhibitor of human fear memory consolidation (First, a likely conclusion from our study is that doxycycline has a smaller than anticipated – or no – impact on trace fear conditioning. This null finding contrasts with previous work on delay fear conditioning (Second, results from parallel methodological work and the current placebo group indicated that our preregistered and exploratory analyses were unexpectedly underpowered. Effect size to measure trace fear memory retention was smaller in the present placebo group (Cohen’s Finally, we found no evidence that shortcomings in experimental methodology account for the null result. We verified that in keeping with our previous work (Our approach to treatment development was based on preventing fear memory consolidation; but there are also other strategies. A somewhat related approach is to interfere with the reconsolidation of already-consolidated memory which relies on a similar molecular signaling cascade (To conclude, we found no evidence that doxycycline impacts on long-interval trace fear conditioning. Unexpectedly, effect sizes in our paradigm were generally low in several independent control samples, to the extent that replication studies with sufficient power might be impractical because of the required sample size (Acknowledgments: We thank Tamara Grossrieder, Julia Kapfer, Soraya Marques, Timothy Obergfell, Julia Schäfer, Léonie Seys, and Sarrina Tursunova for their help in data acquisition and Samuel Gerster for technical support. | PMC9961363 | ||
References | PMC9961363 | |||
Synthesis | LME, anxiety | SECONDARY, EVENT | Reviewing Editor: Ifat Levy, Yale University School of MedicineDecisions are customarily a result of the Reviewing Editor and the peer reviewers coming together and discussing their recommendations until a consensus is reached. When revisions are invited, a fact-based synthesis statement explaining their decision and outlining what is needed to prepare a revision will be listed below. The following reviewer(s) agreed to reveal their identity: NONE. Note: If this manuscript was transferred from JNeurosci and a decision was made to accept the manuscript without peer review, a brief statement to this effect will instead be what is listed below.In this randomized-control study the matrix metalloproteinase (MMP)-9 inhibitor antibiotic doxycycline was used to test whether MMP-9 blockade reduces fear memory retention in Pavlovian trace fear conditioning. The study was pre-registered and all analyses were closed before unblinding groups relation. The main pre-registered outcome was fear potentiated startle (FPS) and secondary outcome were skin conductance response (SCR), pupil size (PSR), and respiratory amplitude in the interaction between drug and condition (CS+/CS-) during the retention phase. The main outcome was no drug by condition interaction or effect for drug on FPS. Secondary outcomes show no drug by condition interaction in any of the secondary measures and main effect for drug only in SCR. An analysis with trial showed an interaction between trial and group, taken together suggesting an overall lower response in the placebo group.Major comment:This study is well designed, pre-registered and according to the method section well powered. However, the main point does not seem justified. With all 4 measures (FPS, SCR, PSR, and respiration) failing to show a group by condition interaction during retention, the data suggest no evidence for MMP-9 reducing fear memory. As these were the pre-registered hypotheses, the authors should stick to them as the main story, and only after that enter into exploratory analysis of additional factors such as sex and anxiety.Minor comments:- Similarly to comments from the previous reviewers, the text still needs editing. There is misuse of tenses such as line 53 “we find”; missing parts of sentences, e.g. line 219 “During a 180-min metabolization interval”; Sentences over 40 words long; over- and misuse of acronyms (is SEBR different from FPS?) Line 194 “doxycycline is detectable in CSF, the cerebrospinal fluid (CSF)”. Titles of the physiological measures are acronyms such as the SEBR, or no new line for the SCR, which is written as SC.- The methods should be streamlined. Currently, some parts are introduced in an order that makes it hard to understand. For example, the CS+, CS- and US are introduced, but the reinforcement rate is in a completely different segment, which makes it hard to understand the flow of the experiment. The methods lack details about how the responses were quantified. As this is a trace fear conditioning, what was the event the analysis was locked to, in the FPS, to the sound, in the SCR to the CS, the CS onset, but for the trace? Did you look for a peak? Or measure tonic response? What units did you measure (microsiemens)?- The analysis plan is hard to follow. In all tests you started with a t-test and later moved to higher order analysis. Why is that? Start with ANOVA or LME and then go to the post hoc t-tests. In the current analysis there are dozens of results, if you try to correct the article for multiple tests you will likely find that most are nullified. Why are you using repeated measures ANOVA in the FPS and LME in the SCR? The r commands are mentioned (aov(), lme()) instead of the package you used (lme4; add citation).- As this substance is given 3 and a half hours before fear memory is created, what are the clinical implications? Using a reconsolidation paradigm might be more clinically relevant. | PMC9961363 |
Background | swelling | COMPLICATIONS | Among the post-surgical complications of lower wisdom teeth surgery, swelling is considered by patients one of the most impairing, with both social and biological influences and impacting patients' quality of life. Aim of the study was to evaluate the swelling following the osteotomy when performed with drilling burs versus piezo-electric instruments in the mandibular impacted third molar extraction, using a facial reconstruction software. | PMC10120228 |
Materials and methods | TEMPOROMANDIBULAR JOINT DISORDER | A randomized, split-mouth, single-blind study was conducted on patients, ranging between 18 and 40 years of age, requiring lower third molars extraction and referred at the Oral Surgery Unit of the School of Dentistry of the University of Messina. Twenty-two patients were recruited during an 8 months period according to the following criteria: good general health conditions; bilateral, symmetrical, impacted third molars; no use of medication that would influence or alter wound healing; no temporomandibular joint disorder history; no smoking. All patients underwent bilateral surgical removal. For each patient, a facial scan was obtained prior to the surgical procedures. The two extractions were conducted performing, in a randomized way, osteotomy with rotatory burs or use of piezo surgical instruments. Facial scans were repeated at 3 and 7 days after the surgical procedures. Volumetric differences were calculated via superimposition using a dedicated software. The data obtained were processed using paired t-test. | PMC10120228 | |
Results | The results obtained from our study showed no significant differences between two groups regarding post-operative swelling. To the best of our knowledge, this study represents the first experience of using an objective method that can be reproducible on the collection of patients' clinical parameters. | PMC10120228 | ||
Conclusions | swelling | The 3D digital analysis, in the evaluation of facial swelling, is a technique of simple application, objective, reproducible, reliable, decreasing the variables of error.Based on these data, it is possible to conclude that piezo surgery is a safe way for performing the osteotomies during third molar surgery. However, regarding the post-operative swelling, it does not show an advantage over classical rotary instruments. | PMC10120228 | |
Trial registration | Registered on ClinicalTrials.gov (ID: NCT05488028, on 04/08/2022).Approved by Ethical Committee of Messina: (ID 01–2020, on 27/04/2020). | PMC10120228 | ||
Keywords | PMC10120228 | |||
Introduction | swelling, lockjaw, paresthesia, pain, trismus, oedema | TRISMUS, POSTOPERATIVE COMPLICATIONS, PARESTHESIA, BONE NECROSIS, OEDEMA, SEQUELAE, COMPLICATIONS | Included wisdom teeth surgery is one of the most common procedures performed by oral surgeons, usually associated with intraoperative and postoperative complications [The most significant post-surgical complications are pain, swelling, lockjaw, and even paresthesia of the lower lip or tongue, which can have both social and biological impact and can compromise patients' quality of life [Conventional surgery using rotary instruments is the most common technique in extraction procedures.The conventional technique has disadvantages, such as the excessively high temperature produced during osteotomy that can cause marginal bone necrosis and compromise hard and soft tissue healing [In the last decades, technological innovations have been introduced in oral surgery to allow less invasive approaches, ranging from use of piezoelectric instruments to dynamic navigated surgery [In particular, the advent of ultrasound, in surgery, has improved several oral surgical procedures, such as the extraction of impacted third molars.According to a systematic review with meta-analysis by AL-Moraissi et all. in 2016, the piezo electric surgical technique used in third molar extractions shows a significant reduction in post-operative sequelae (oedema, pain, trismus). The low incidence of post-operative sequelae seems to be related to the atraumatic and micrometric cutting action of the instrument [Piezo surgery is effective in osteotomy because it works selectively, being inert against soft tissue, nerves and blood vessels. This represents a significant advantage over a bur [When used appropriately, piezo surgery causes less structural and cellular damage than conventional surgery. In addition, the formation of new bone is faster than with rotary burs [Several studies have shown that the micrometric cutting action of piezo surgery requires a longer intervention time than the use of a bur, potentially causing more discomfort in the postoperative period [The aim of this study is to evaluate, in an innovative way, the facial swelling following the osteotomy performed with rotary instrument (R group) versus piezo electric instrument (P group) in the mandibular impacted third molar extraction, using a facial reconstruction software. | PMC10120228 |
Materials and methods | PMC10120228 | |||
Sample and study design | swelling, Lindemann stainless steel | TEMPOROMANDIBULAR JOINT DISORDER, IMPACTED TEETH, BLIND | A randomized, split-mouth, single-blind study was conducted on patients referred at the Oral Surgery Unit of the School of Dentistry of the University of Messina, ranging between 18 and 40 years of age and requiring lower third molars extraction. Study protocol was based on an already validated operative scheme [Sample size was calculated using the data derived from a preliminary analysis on 10 subjects previously conducted by the authors in order to estimate the considered main outcome (swelling) variation. Values obtained from the preliminary analysis and used to perform the sample size calculation of R group and P group were 1.62 and 1.38 respectively, with a shared standard deviation (σ) of 0.28; power analysis was performed setting α = 0.5 and 0.8 power level. A sample size of 22 subjects was therefore obtained.Twenty-two patients were recruited during an 8 months period according to the following criteria: good general health conditions; no clinical evidence of major facial asymmetry; presence of bilateral and symmetrical impacted third molars (according to the classifications of Winter and Pell and Gregory); no use of medication that would influence or alter wound healing; no temporomandibular joint disorder history; no smoking.The patients were included in the study after the registration of personal and clinical data and the collection of TC scan of the teeth to be extracted.The local Ethical Committee of Messina approved the study protocol (ID 01–2020, on 04/27/2020), in accordance with the Helsinki declarations. The study was registered on ClinicalTrials.gov (ID: NCT05488028).Patients had given their consent to treatment and were informed that their data would be used for statistical analyses related to this study; informed consent was obtained from all participants.Randomization was conducted with a table of casual numbers by an investigator who was not part of the study and who was blind to the identity of the procedures.All patients were enrolled in two groups, P group included all the surgeries carried out with piezoelectric technique, while operations carried out with the bur were assigned to R group.All patients underwent a 3-d facial scan before the surgical teeth removal using Bellus 3D Dental Pro (Bellus 3D, Inc. 1901 S. Bascom Ave. Suite 1300 Campbell, CA 95,008 USA).Bellus 3D Dental Pro is a dental app for iOS devices that uses the integrated to scan and reproduce the face of a subject with a 3-dimensional render in less than 15 s. The facial scan can be subsequently exported in various formats, such as STL.For each patient, the impacted teeth were extracted in two different phases, separated by a 30-day time interval. All procedures were performed by a single experienced oral surgeon.The study involved three time points:• reference scan (T0), face scan before surgery, at time 0;• target scans (T1) and (T2), respectively at 3 and 7 days, after each surgery, both with rotating and piezoelectric instrumentation for a total of 5 scans.The Esacrom Piezosurgery device (Esacrom electronics and medical devices, Imola, Italy) was used for ultrasonic osteotomies according to the manufacturer's instructions using a specific insert for osteotomies (ES07WT).The Lindemann stainless steel bur (shank diameter 2.35 mm; length 44 mm) mounted on a high-speed straight surgical handpiece was used for osteotomies with conventional technique. | PMC10120228 |
Study outcome measures | swelling | Main outcome of the study was the evaluation of postoperative facial swelling (assessed via digital comparison of facial scans obtained at 3 and 7 days after lower third molar removal to a presurgical baseline scan) using different surgical techniques. | PMC10120228 | |
Surgical and post-surgical variables | Nerve block, swelling, tooth | ALLERGY TO PENICILLIN | Preoperatively, all patients underwent three-dimensional facial scanning (Fig. Scan T0Three-dimensional images were captured by the Bellus 3D Dental Pro app.The first extraction of the included lower third molar was performed.Each of the two extractions was conducted using standardized procedures. Nerve block of the inferior alveolar and buccal nerve with mepivacaine hydrochloride 3% with adrenaline 1:100,000 was performed. A full-thickness envelope flap with a vertical releasing incision was reflected, and osteotomy were subsequently performed (Fig. Sample of the surgery of symmetrical inferior impacted third molarsBoth the side of the surgery and the technique to be used were decided at random. The osteotomy was performed on one side with piezoelectric instrumentation and the other side with rotary instrumentation.When necessary, tooth sectioning was performed with a high-speed tungsten carbide slit drill under saline irrigation and the tooth removed in single or multiple segments.The mucoperiosteal flap was repositioned and the surgical wound was closed with a 5–0.After surgery, the pharmacological therapy was prescribed to each patient for each intervention (Amoxicillin 1gr cpr with posology 1 cpr every 12 h for 6 days; in case of allergy to penicillins, clarithromycin 500 mg with posology 1 cpr every 12 h for 6 days was prescribed; chlorhexidine mouthwash at 0.20% to be used three times a day for 10 days after surgery, to reduce the bacterial load). The patient received all indications regarding postoperative management.Three days after each of the two surgeries, the second 3D scan of the face (T1) was performed to assess facial swelling (Fig. Scan T1(P-R)Scans (T2) were performed at 7 days after each surgery (Fig. Scan T2(P-R) | PMC10120228 |
3d images evaluation | Scans were exported in STL (Standard Triangulation Language) files and imported within a dental application software “Medit Compare” (MEDIT corp. 23 Goryeodae-ro 22 gil, Seongbuk-gu, Seoul, Korea).Medit Model Builder software allows the user to create physical models from digital facial scans.T0-T1 and T0-T2 scans were opened and superimposed through three reference points:Endocanthion left (inner most point on commissure of left eye fissure), endocanthion right (inner most point on commissure of right eye fissure) and subnasale (mid-point of columella) (Fig. T0-T1 and T0-T2 scans superimposition | PMC10120228 | ||
Data analysis | Scans were exported in STL "Standard Triangulation Language" files and imported within a dental application software. Statistical analyses were carried out using Minitab, version 21.1.Data are summarized as mean ± standard deviation.A t Test was conducted twice to compare the averages and see if there is a significant difference between the averages of the groups. | PMC10120228 | ||
Results | adverse drug reactions, alveolitis, swelling | ADVERSE DRUG REACTIONS, SITE INFECTION, ALVEOLITIS | A total of 22 patients (16 F, 6 M), aged 18 to 40 years, with symmetrical impacted lower third molars were included in the study. Their mean age was 24.70 years.No cases of post extraction alveolitis or site infection were reported during follow-up, and no adverse drug reactions were observed.Data regarding facial swelling measured comparing T1 and T2 facial scan to baseline (T0) are reported in Table Average measurements of the 22 patients at T0-T1 and T0-T2 (R) and (P)Among the considered sample, the average of the mean values obtained from matching the T0-T1(R) scans for the rotating instruments was 1.66 ± 0.6, whereas in the case of the piezosurgery the average of T0-T1(P) was 1.39 ± 0.4 (Fig. Mean ± standard deviation T0-T1(P) vs T0-T1(R)Two-Sample T-Test and CI: T0-T1 (P); T0-T1 (R)Regarding the assessment of swelling at T0-T2, the mean of the recorded values was T0-T2(P) 0.92 ± 0.3 and T0-T2(R) 1.04 ± 0.4 (Fig. Mean ± standard deviation T0-T2(P) vs T0-T2(R)Two-Sample T-Test and CI: T0-T2 (P); T0-T2 (R)The two-sample t Test showed no statistically significant variation between groups at any given timepoint in regards to postoperative swelling. | PMC10120228 |
Discussion | bleeding, postoperative swelling, swelling, pain, hematoma, trismus | BLEEDING, SEQUELAE, HAND SWELLING, HEMATOMA, TRISMUS, COMPLICATIONS | Third molar surgery can be complicated. Clinicians' priority is to promote optimal treatment outcomes while maintaining the integrity of the noble structures.In oral surgery, conventional instrumentation for bone removal is performed with rotary handpieces. In recent years, piezo surgery has gained popularity. It has been considered safe and effective and uses micro vibrations with ultrasonic frequency [It promotes bone healing as it does not produce high temperatures [However, the operating time is longer compared to the use of rotary instruments [It is necessary to differentiate true complications from sequelae that are part of the postoperative course such as pain, swelling, trismus, moderate bleeding, and hematoma. These complaints are typically present in 35% of cases during the first postoperative day, 25% at 7 days, and 4% at 14 days [The incidence of complications depends on the difficulty of treatment, the severity of inclusion, and the age of the patient [Some authors have shown that pain and swelling are directly proportional to the difficulty of the procedure and the treatment time [In this split-mouth study, postoperative swelling was evaluated with facial 3d scan by comparing two different surgical techniques (piezo surgery vs. rotary instruments) in the extraction of impacted third molars.According to Winter and Pell and Gregory's classifications, included third molars were evaluated.Only patients with the same classification for third molars were enrolled.A homogeneous sample of patients and teeth was selected as age, position and anatomy may influence the postoperative course.Post-surgical facial swelling is difficult to accurately quantify because measurements are made on an irregular surface.Several papers have assessed postoperative swelling, after lower third molar surgery, by face measurements with manual techniques, obtained with a tape measure [However, this technique is operator-dependent and for that reason not objective.To date, there is no accurate and reliable measurement method in the literature for evaluating facial swelling after third molar surgery.In this study, innovative, digital measurements were used that allowed us to obtain reliable data for objective comparison.The Bellus 3D application, for scanning patients' faces, and the dental application software for obtaining the results, showed ease of use.The results obtained from our study showed no significant differences between two groups regarding postoperative swelling which contradict with other reports in the literature [We argue that this may be related to the reduced number of patients.To the best of our knowledge, this study represents the first experience of using an objective method that can be reproducible on the collection of patients' clinical parameters, on the other hand, the use of the application and software has financial implications.Consequently, this study is added to others in a constant effort to obtain increasingly reliable data. The main limitation of our study is represented by the small sample size. However, while image acquisition through the Bellus 3D app can be considered a very simple and straightforward procedure, image processing to evaluate swelling requires a well-versed operator and may present a steep learning curve. Moreover, every surgical procedure was performed by a single experienced oral surgeon, so results may vary together with operator skills. | PMC10120228 |
Acknowledgements | None. | PMC10120228 | ||
Authors’ contributions | Conceptualization, G.O. and A.M.; methodology, G.O. and M.P.; data curation, A.C. and E.R.; writing—original draft preparation, A.C.and E.R.; writing—review and editing, G.O., M.P. and R.N.; supervision, R.N. and A.M.B. All authors have read and agreed to the published version of the manuscript. The author(s) read and approved the final manuscript. | PMC10120228 | ||
Funding | None. | PMC10120228 | ||
Availability of data and materials | Study dataset can be find at the following link: Missing data from 4 patients were not uploaded due to technical problems (files were either corrupted or unretrievable from our archives). | PMC10120228 | ||
Declarations | PMC10120228 | |||
Ethics approval and consent to participate | The study was carried out in accordance with the Declaration of Helsinki.The local Ethical Committee of Messina approved the study protocol (ID 01–2020, on 04/27/2020), in accordance with the Helsinki declarations. The study was registered on ClinicalTrials.gov (ID: NCT05488028).Patients had given their informed consent to treatment and were informed that their data would be used for statistical analyses related to this study. | PMC10120228 | ||
Consent for publication | Informed consent was obtained from each participant, for both study participation and publication of identifying information/images. Participants were also informed that the study could be submitted to and published in an online open-access journal. No minors were included in the present trial. | PMC10120228 | ||
Competing interests | None. | PMC10120228 |
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