Treatment of COVID-19 patients with a SARS-CoV-2-specific siRNA-peptide dendrimer formulation.

BACKGROUND: Severe acute respiratory syndrome corona virus (SARS-CoV-2) infection frequently causes severe and prolonged disease but only few specific treatments are available. We aimed to investigate safety and efficacy of a SARS-CoV-2-specific siRNA-peptide dendrimer formulation MIR 19® (siR-7-EM/KK-46) targeting a conserved sequence in known SARS-CoV-2 variants for treatment of COVID-19. METHODS: We conducted an open-label, randomized, controlled multicenter phase II trial (NCT05184127) evaluating safety and efficacy of inhaled siR-7-EM/KK-46 (3.7 mg and 11.1 mg/day: low and high dose, respectively) in comparison with standard etiotropic drug treatment (control group) in patients hospitalized with moderate COVID-19 (N = 52 for each group). The primary endpoint was the time to clinical improvement according to predefined criteria within 14 days of randomization. RESULTS: Patients from the low-dose group achieved the primary endpoint defined by simultaneous achievement of relief of fever, normalization of respiratory rate, reduction of coughing, and oxygen saturation of >95% for 48 h significantly earlier (median 6 days; 95% confidence interval [CI]: 5-7, HR 1.75, p = .0005) than patients from the control group (8 days; 95% CI: 7-10). No significant clinical efficacy was observed for the high-dose group. Adverse events were reported in 26 (50.00%), 25 (48.08%), and 28 (53.85%) patients from the low-, high-dose and control group, respectively. None of them were associated with siR-7-EM/KK-46. CONCLUSIONS: siR-7-EM/KK-46, a SARS-CoV-2-specific siRNA-peptide dendrimer formulation is safe, well tolerated and significantly reduces time to clinical improvement in patients hospitalized with moderate COVID-19 compared to standard therapy in a randomized controlled trial.

Management of maxillofacial trauma in the elderly: A European multicenter study.

BACKGROUND/AIMS: Management of maxillofacial trauma in the geriatric population poses a great challenge due to anatomical variations and medical comorbidities. The aim of this study was to analyze the management variables, timing, and outcomes of facial fractures in elderly patients (aged 70 years or more) at several European departments of oral and maxillofacial surgery. MATERIALS AND METHODS: This study was based on a systematic computer-assisted database that allowed the recording of data from all geriatric patients with facial fractures from the involved maxillofacial surgical units across Europe between 2013 and 2017. RESULTS: A total of 1334 patients were included in the study: 665 patients underwent closed or open surgical treatment. A significant association (P < .005) was found between the presence of concomitant injuries and a prolonged time between hospital admission and treatment. The absence of indications to treatment was associated with comorbidities and an older age (P < .000005). CONCLUSIONS: Elderly patients require specific attention and multidisciplinary collaboration in the diagnosis and sequencing of trauma treatment. A prudent attitude may be kept in selected cases, especially when severe comorbidities are associated and function is not impaired.

The "European Mandibular Angle" Research Project: The Epidemiologic Results From a Multicenter European Collaboration.

PURPOSE: The aim of this study was to analyze the demographic variables and causes and characteristics of mandibular angle fractures managed at several European departments of maxillofacial surgery. MATERIALS AND METHODS: This study was based on a multicenter systematic database that allowed the recording of data from all patients with mandibular angle fractures between January 1, 2013, and December 31, 2017. The following data were recorded: gender, age, etiology, side of angle fracture, associated mandibular fractures, presence of third molar, intermaxillary fixation, and osteosynthesis. RESULTS: The study included 1,162 patients (1,045 male and 117 female patients). A significant association was found between the presence of a third molar and the diagnosis of an isolated angle fracture (P < .0000005). Furthermore, assaults were associated with the presence of voluptuary habits (P < .00005), a younger mean age (P < .00000005), male gender (P < .00000005), and left-sided angle fractures (P < .00000005). CONCLUSIONS: Assaults and falls actually represent the most frequent causes of angle fractures. The presence of a third molar may let the force completely disperse during the determination of the angle fracture, finding a point of weakness.

Epidemiology, etiopathogenesis, and management of MRONJ: A European multicenter study.

INTRODUCTION: The purpose of this European multicenter study was to describe the general characteristics and risk factors of MRONJ lesions as well as their clinical diagnosis and management at different European Oral and Maxillofacial Surgery centers, in order to minimize selections biases and provide information about the epidemiology, etiopathogenesis, and the current trends in the treatment of MRONJ across Europe. MATERIALS AND METHODS: The following data were registered for each patient: gender; age at MRONJ diagnosis; past medical history; indication for antiresorptive or antiangiogenic therapy; type of antiresorptive medication; local risk factor for MRONJ; MRONJ Stage; anatomic location and symptoms; treatment; surgical complications; recurrence. RESULTS: A total of 537 patients (375 females, 162 males) with MRONJ were included. Statistically significant associations were found between patients with metastatic bone disease and recurrences (P < 0.0005) and between advanced MRONJ stages (stages 2 and 3) and recurrences (P < 0.005). Statistically significant associations were also found between male gender and recurrences (P < 0.05), and between MRONJ maxillary sites and recurrences (P < 0.0000005). CONCLUSIONS: A longer mean duration of antiresorptive medications before MRONJ onset was observed in patients affected by osteoporosis, whereas a shorter mean duration was observed in all metastatic bone cancer patients, and in particular in those affected by prostate cancer with bone metastases or multiple myeloma. Surgery plays an important role for the management of MRONJ lesions.

An acceptance-based, intersectional stigma coping intervention for people with HIV who inject drugs-a randomized clinical trial.

Background: People with HIV who inject drugs experience intersecting forms of stigma that adversely impact care access. This RCT aimed to evaluate effects of a behavioral intersectional stigma coping intervention on stigma and care utilization. Methods: We recruited 100 participants with HIV and past-30-day injection drug use at a non-governmental harm reduction organization in St. Petersburg, Russia, and randomized them 1:2 to receive usual services only or an additional intervention of three weekly 2-h group sessions. Primary outcomes were change in HIV and substance use stigma scores at one month after randomization. Secondary outcomes were initiation of antiretroviral treatment (ART), substance use care utilization, and changes in frequency of past-30-days drug injection at six months. The trial was registered as NCT03695393 at clinicaltrials.gov. Findings: Participant median age was 38.1 years, 49% were female. Comparing 67 intervention and 33 control group participants recruited October 2019-September 2020, the adjusted mean difference (AMD) in change in HIV and substance use stigma scores one month after baseline were 0.40, (95% CI: -0.14 to 0.93, p = 0.14) and -2.18 (95% CI: -4.87 to 0.52, p = 0.11), respectively. More intervention participants than control participants initiated ART (n = 13, 20% vs n = 1, 3%, proportion difference 0.17, 95% CI: 0.05-0.29, p = 0.01) and utilized substance use care (n = 15, 23% vs n = 2, 6%, proportion difference 0.17, 95% CI: 0.03-0.31, p = 0.02). The adjusted median difference in change in injecting drug use frequency 6 months after baseline was -3.33, 95% CI: -8.51 to 1.84, p = 0.21). Five not intervention-related serious adverse events (7.5%) occurred in the intervention group, one (3.0%) serious adverse event in the control group. Interpretation: This brief stigma-coping intervention did not change stigma manifestations or drug use behaviors in people with HIV and injection drug use. However, it seemed to reduce stigma's impact as an HIV and substance use care barrier. Funding: R00DA041245, K99DA041245, P30AI042853.

The epidemiology and management of odontomas: a European multicenter study.

INTRODUCTION: Odontoma is the most commonly diagnosed odontogenic tumor of the oral cavity. The objective of the present study was to assess the demographic variables, patterns, diagnostic features, and management issues of odontomas treated at several European departments of maxillofacial and oral surgery. MATERIALS AND METHODS: This study was conducted at 8 European departments of oral surgery between January 1, 2004, and December 31, 2018. Only patients with odontomas were included. The following data were recorded for each patient: gender, age, comorbidities, site, size of odontomas, radiographic features, type of odontoma, treatment of odontomas, treatment of associated teeth, complications, and recurrence. RESULTS: A total of 127 patients (70 male and 57 female patients) with odontomas were included. The mean age was 22 years; 71 odontomas were found in the mandible, whereas 56 in the maxilla. In the mandible, the most frequently involved subsite was the parasymphysis, while in the maxilla, the most common subsite was the upper incisor region. The mean size of included odontomas was 15.3 mm. On the whole, 62 complex odontomas, 50 compound odontomas, and 15 mixed-type odontomas were observed. Complete excision of the odontomas was performed in 121 patients. In 24 patients, the extraction of deciduous teeth was performed, and in 43 patients, one or more permanent teeth were removed. Finally, in 9 patients, a partial excision of the odontoma was performed. Recurrence was observed in 4 cases out of 127 patients. CONCLUSIONS: Dental practitioners should be aware of the distinct clinical and radiographic features of odontoma in order to perform an appropriate and early diagnosis. Conventional radiography, such as panoramic radiograph, is often sufficient technique for a diagnosis after clinical suspicion or for an incidental diagnosis to prevent later complications, such as impaction or failure of eruption of teeth.

The epidemiology and management of odontogenic keratocysts (OKCs): A European multicenter study.

The objective of the present study was to assess the epidemiology including demographic variables, diagnostic features, and the management of odontogenic keratocyst (OKCs) at several European departments of maxillofacial and oral surgery. This study is based on a systematic computer-assisted database that allowed the recording of data from treated OKCs. The following data were recorded for each patient: gender, age, voluptuary habits, comorbidities, site, size, radiographic features, treatment of OKCs, length of hospital stay, complications, recurrence, management and complications of eventual recurrence. A total of 405 patients, 249 male and 156 female, with 415 OKCs (407 sporadic and 8 syndromic lesions) were included in the study: 320 lesions were found in the mandible, whereas 95 were found in the maxilla. In the mandible, the most frequently involved subsite was the angle, whereas in the maxilla it was the molar region. The most frequently performed treatment option was enucleation plus curettage/peripheral ostectomy in 204 OKCs (recurrence rate, 9%). Decompression without residual cystectomy (recurrence rate, 66%), marsupialization with residual enucleation with the use of Carnoy's solution (recurrence rate, 50%), decompression with residual cystectomy (recurrence rate, 43%), and simple enucleation (recurrence rate, 24%) were the treatment options with the highest recurrence rates. An appropriate management of odontogenic keratocysts should be individualized, taking into consideration clinical and radiological findings, as well as patients' age and comorbidities.

Imaging of odontogenic keratocysts: a pictorial review.

INTRODUCTION: The aim of the present article was to review and depict the main radiological features of odontogenic keratocysts (OKCs), thus helping the differential diagnoses from other odontogenic cysts and neoplasms. EVIDENCE ACQUISITION: A review of articles published between January 2000 and October 2020 using Medline and the MeSH Term "odontogenic keratocyst" in combination with the following terms "imaging," "radiology," "panoramic radiograph," and "computed tomography," was performed. EVIDENCE SYNTHESIS: Radiographically, OKCs are well-defined unilocular or multilocular radiolucencies bounded by corticated margins. Most lesions are unilocular; instead, multilocular OKCs represent about the 30% of cases, mainly involving the posterior mandible. When, particularly in large lesions, OKCs display a multilocular presentation with adjacent satellite cysts (daughter cysts) a "soap-bubble appearance" can be recognized. DISCUSSION: Panoramic radiograph and CT still play an important role in the diagnosis and treatment planning of OKCs. Unfortunately, it may not be easy to differentiate OKCs from other odontogenic lesions, especially when they are small and unilocular. CONCLUSIONS: Histopathological findings are still necessary to obtain a definitive diagnosis.

Quality of life following maxillofacial trauma in the elderly: a multicenter, prospective study.

BACKGROUND/AIMS: When facial trauma involves elderly patients, the possible presence of frailty and comorbidities in victims of trauma may worsen the posttraumatic symptoms and decrease quality of life. The aim of this multicenter study was to assess the quality of life following surgical or non-operative management of maxillofacial trauma in elderly patients. MATERIALS AND METHODS: This cohort study was based on the administration of validated self-administered questionnaires to all the geriatric patients (70 years or more) with facial fractures from the involved maxillofacial surgical units across Europe, since 1st January 2019 to 31st June 2019. The following questionnaires were administered: SF36 questionnaire; the VFQ-25 questionnaire; the Oral Health Impact Profile - 14 (OHIP14). Outcome variables were VFQ-25 and OHIP-14 results. RESULTS: A total of 37 patients (14 male and 23 female patients) met the inclusion criteria and were included in the study. Elderly patients had an improvement in almost all the categories examined by the SF-36 questionnaire 6 months after trauma, with the only exception of a worsening as for role limitations due to physical health. An improvement was observed in almost all the categories at SF-36 test. A worsening of scores of OHIP-14 for all the considered dimensions in the whole study population was observed too. CONCLUSIONS: Elderly patients following facial trauma experience significant emotional, social, and functional disturbances. We observed that emotional problems, energy/fatigue, social functioning, and generally social limitations played a great role in the decrease of QoL in elderly patients following maxillofacial trauma.

Addressing intersectional stigma as a care barrier for HIV-positive people who inject drugs: Design of an RCT in St. Petersburg, Russia.

BACKGROUND: HIV-positive people who inject drugs (PWID) experience stigma related to their substance use and HIV, with adverse consequences to their health care utilization and mental health. To help affected individuals cope with their intersectional stigma and reduce its negative impact on health and health care, we adapted a behavioral stigma coping intervention for this HIV key population. OBJECTIVE: To conduct a randomized controlled trial (RCT) testing the 'Stigma Coping to Reduce HIV risks and Improve substance use Prevention and Treatment' (SCRIPT) intervention, a community-based, adapted form of Acceptance and Commitment Therapy (ACT), for PWID living with HIV in St. Petersburg, Russia. METHODS: We recruited 100 PWID living with HIV from civil society organizations (CSO) delivering harm reduction and HIV prevention services in St. Petersburg, Russia. We randomized participants 2:1 to receive either the intervention (three adapted ACT sessions in a group format over one month and usual CSO care) or usual CSO care alone. ACT aims to help affected individuals cope with stigma by increasing their psychological flexibility to handle stigma-related negative expectations, emotions and experiences. The primary outcomes were satisfaction with the intervention, and changes in HIV and substance use stigma scores. CONCLUSIONS: Stigma coping interventions targeting HIV-positive PWID outside of formal health care settings may help them confront negativities in their lives originating from intersectional stigma and reduce stigma's impact as a health care barrier.

The epidemiology and management of ameloblastomas: A European multicenter study.

The present study aimed at assessing the epidemiology including demographic variables, diagnostic features, and management of ameloblastomas at several European departments of maxillofacial and oral surgery. The following data were recorded for each patient: gender, age, voluptuary habits, comorbidities, site, size, radiographic features, type, histopathological features, kind of treatment, length of hospital stay, complications, recurrence, management and complications of the recurrence. A total of 244 patients, 134 males and 110 females with ameloblastomas were included in the study. Mean age was 47.4 years. In all, 81% of lesions were found in the mandible, whereas 19% were found in the maxilla. Mean size of included ameloblastomas was 38.9 mm. The most frequently performed treatment option was enucleation plus curettage/peripheral ostectomy in 94 ameloblastomas, followed by segmental resection (60 patients), simple enucleation (46 patients), and marginal resection (40 patients). A recurrence (with a mean follow up of 5 years) was observed in 47 cases out of 244 ameloblastomas (19.3%). Segmental resection was associated with a low risk of recurrence (p = 0003), whereas enucleation plus curettage/peripheral ostectomy was associated with a high risk of recurrence (p = 0002). A multilocular radiographic appearance was associated with a high risk of recurrence (p < .05), as well as the benign solid/multicystic histologic type (p < .05). Within the limitations of the study it seems that the management of ameloblastomas will probably remain controversial even in the future. Balancing low surgical morbidity with a low recurrence rate is a difficult aim to reach.

Surgical management of unilateral body fractures of the edentulous atrophic mandible.

INTRODUCTION: Management of body fractures in patients with edentulous atrophic mandibles represents a challenging task due to patient's age, medical comorbidities, poor bone quality, and vascularity, as well as reduced contact area between the fracture ends. The aim of the study was to assess the demographic and clinical variables, the surgical technique, and outcomes of unilateral body fractures of the edentulous atrophic mandible managed at several European departments of oral and maxillofacial surgery. METHODS: This study is based on a systematic computer-assisted database that allowed the recording of data of all patients with fractures of the atrophic edentulous mandible from the involved maxillofacial surgical units across Europe between 2008 and 2017. The following data were recorded for each patient: gender, age, comorbidities, etiology, synchronous body injuries, degree of atrophy of the mandible according to Luhr classification, type of surgical approach and fixation, length of hospitalization, and presence and type of complications. RESULTS: A total of 43 patients were included in the study: 17 patients' mandibles were classified as class I according to Luhr, 15 as class II, and 11 as class III. All patients underwent open reduction and internal fixation by extraoral approach in 25 patients, intraoral in 15 patients, and mixed in 3 patients. A single 2.0 miniplate was used in 16 patients, followed by a single 2.4 reconstruction plate in 13 patients, by two 2.0 miniplates, and three 2.0 miniplates. Outcome was considered to be satisfying in 30 patients, with no complications. Complications were observed in 13 cases. CONCLUSIONS: Treatment of unilateral body fractures of the edentulous mandible must still be based on the type of fracture, degree of atrophy, experience of the surgeon, and patients' preference. An adequate stability can be obtained by different plating techniques that have to be appropriately tailored to every single specific patient.

The "European Mandibular Angle" research project: the analysis of complications after unilateral angle fractures.

OBJECTIVE: The aim of this study was to analyze the complications and outcomes of surgical treatment of angle fractures managed at departments of maxillofacial surgery in several European countries. STUDY DESIGN: Patients hospitalized with unilateral isolated angle fractures between 2013 and 2017 were included. The following data were recorded: gender and age of patients, fracture etiology, presence of the third molar, maxillomandibular fixation, osteosynthesis technique, and complications. RESULTS: In total, 489 patients were included in the study. The Champy technique was found to be the most frequently chosen osteosynthesis technique. Sixty complications were observed, at a rate of 12.3%. Complications were associated with the absence of third molars (P < .05). Instead, the Champy technique was associated with fewer complications (P < .05), in comparison with the other adopted techniques. CONCLUSIONS: The management of angle fractures still represents a challenging task with a significant complication rate. The Champy technique still seems to be a valid option for the treatment of such injuries.

The "European zygomatic fracture" research project: The epidemiological results from a multicenter European collaboration.

PURPOSE: Fractures of the zygomaticomaxillary complex (ZMC) are common injuries that may lead to loss of an aesthetically pleasing appearance and functional impairment. The aim of this study was to analyze the demographics, causes, characteristics, and outcomes of zygomatic fractures managed at several European departments of oral and maxillofacial surgery. MATERIALS AND METHODS: This study is based on a multicenter systematic database that allowed the recording of all patients with ZMC fractures between 1 January 2013 and 31 December 2017. The following data were recorded: gender, age, personal medical history, etiology, side of zygomatic fracture, classification of ZMC fracture, associated maxillofacial fractures, symptoms at diagnosis, type of performed treatment, and sequelae/complications. RESULTS: A total of 1406 patients (1172 males, 234 females) were included in the study. Statistically significant correlations were found between assault-related ZMC fractures and the A3 class (p < .0000005) and between Infraorbital Nerve (ION) anesthesia and B class (p < .00000005). CONCLUSION: The most frequent cause of ZMC fractures was assault, followed by falls. The most frequently involved decade of age was between 20 and 29 years. The decision and type of surgical treatment of ZMC fractures depends on several issues that need to be considered on a case by case basis.

The epidemiology of edentulous atrophic mandibular fractures in Europe.

INTRODUCTION: The objective of the present study was to assess the demographic variables, causes, and patterns of edentulous atrophic fractures of the mandible managed at several European departments of oral and maxillofacial surgery. The results of this multicenter collaboration over a 10-year period are presented. METHODS: The data of all patients with fractures of the atrophic edentulous mandible from the involved maxillofacial surgical units across Europe between January 1, 2008, and December 31, 2017 were recorded: gender; age; voluptuary habits; comorbidities; etiology; fracture sites; synchronous body injuries; atrophy of the mandible according to Luhr classification; eventual type of treatment; timing of the eventual surgery; length of hospital stay. RESULTS: A total of 197 patients (86 male and 111 female patients) with 285 mandibular fractures were included in the study. Mean age of the study population was 75 years. Statistically significant associations were found between Luhr classes I - II and condylar fractures on one hand (p < .0005), and between Luhr class III and body and parasymphyseal fractures on the other hand (p < .05). Finally, 135 patients underwent open reduction and internal fixation, 56 patients did not undergo any intervention, and 6 patients underwent closed reduction. No statistically significant association was observed between treatment, timing of treatment, comorbidities, and concomitant injuries. CONCLUSIONS: The management of edentulous atrophic mandibular fractures remains challenging. Treatment decisions should continue to be based on the clinician's previous experience and on the degree of bone resorption in edentulous mandible in relation to fracture subsites.

Identification, cloning and characterization of a new DNA-binding protein from the hyperthermophilic methanogen Methanopyrus kandleri.

Three novel DNA-binding proteins with apparent molecular masses of 7, 10 and 30 kDa have been isolated from the hyperthermophilic methanogen Methanopyrus kandleri. The proteins were identified using a blot overlay assay that was modified to emulate the high ionic strength intracellular environment of M.kandleri proteins. A 7 kDa protein, named 7kMk, was cloned and expressed in Escherichia coli. As indicated by CD spectroscopy and computer-assisted structure prediction methods, 7kMk is a substantially alpha-helical protein possibly containing a short N-terminal beta-strand. According to analytical gel filtration chromatography and chemical crosslinking, 7kMk exists as a stable dimer, susceptible to further oligomerization. Electron microscopy showed that 7kMk bends DNA and also leads to the formation of loop-like structures of approximately 43.5 +/- 3.5 nm (136 +/- 11 bp for B-form DNA) circumference. A topoisomerase relaxation assay demonstrated that looped DNA is negatively supercoiled under physiologically relevant conditions (high salt and temperature). A BLAST search did not yield 7kMk homologs at the amino acid sequence level, but based on a multiple alignment with ribbon-helix-helix (RHH) transcriptional regulators, fold features and self-association properties of 7kMk we hypothesize that it could be related to RHH proteins.

Amyloid fibrils from the mammalian protein prothymosin alpha.

Mammalian prothymosin alpha, a small (12 kDa) and extremely acidic protein (pI 3.5), is a member of the growing family of 'natively' unfolded proteins. We demonstrate that at low pH ( approximately 3) and high concentrations, prothymosin alpha is capable of forming regular elongated fibrils with flat ribbon structure 4-5 nm in height and 12-13 nm in width as judged from scanning force and electron microscopy. These aggregates induced a characteristic spectral shift of thioflavin T fluorescence and their circular dichroism spectra were indicative of significant beta-sheet content, suggesting formation of classical amyloid. Our findings indicate that natively unfolded proteins may have a general propensity to form amyloid fibrils under conditions inducing partially folded conformations.

Nucleosome-like complex of the histone from the hyperthermophile Methanopyrus kandleri (MkaH) with linear DNA.

The MkaH protein from the archaeon Methanopyrus kandleri, an unusual assembly of two histone-fold domains in a single polypeptide chain, demonstrates high structural similarity to eukaryal histones. We studied the DNA binding and self-association properties of MkaH by means of the electrophoretic mobility shift assay (EMSA), electron microscopy (EM), chemical cross-linking, and analytical gel filtration. EMSA showed an increased mobility of linear DNA complexed with MkaH protein with a maximum at a protein-DNA weight ratio (R(w)) of approximately 3; the mobility decreased at higher protein concentration. EM of the complexes formed at Rw or=9) thickened compact nucleoprotein structures were observed; no individual loops were seen within the complexes. Gel filtration chromatography and chemical fixation indicated that in the absence of DNA the dominant form of the MkaH in solution, unlike other archaeal histones, is a stable dimer (pseudo-tetramer of the histone-fold domain) apparently resembling the eukaryal (H3-H4)(2) tetramer. Similarly, dimers are the dominant form of the protein interacting with DNA. The properties of MkaH supporting the assignment of its intermediate position between other archaeal and eukaryal histones are discussed.