Direct versus fully digital indirect bracket bonding: a split-mouth randomized clinical trial on accuracy.

OBJECTIVES: The primary aim is to assess differences in accuracy of orthodontic bracket positioning between fully digital indirect bracket bonding (IDB) and conventional direct bracket bonding (DBB). The secondary aims are to assess differences in bracket bonding failures, bracket repositioning need, clinician experience and patient satisfaction. MATERIALS AND METHODS: This prospective study was designed as a split-mouth randomized clinical trial. In total, 35 patients were analyzed with a six month follow-up period. Translational and orientational deviations from the planned bracket position were determined. Clinician experience and patient satisfaction were evaluated by means of a survey. RESULTS: The difference in translation was 0.34 mm (95% CI: 0.238-0.352, p = 0.017), the difference in orientation was 4.80˚ (95% CI: 3.858-5.727, p < 0.001), both in favour of IDB. IDB showed significantly more immediate (IDB: 3.9%, DBB: 0%) and late (IDB: 5.4%, DBB: 2.5%, p = 0.008) bonding failures. Clinicians and patients experienced a shorter clinical chair time with indirect bonding over direct bonding. CONCLUSIONS: IDB bracket positioning leads to significant smaller translation and orientation deviations from digital IDB planning, than DBB bracket positioning. However, IDB leads to more immediate bonding failures than DBB. The majority of patients preferred IDB over DBB, due to a shorter clinical chair time. CLINICAL RELEVANCE: This study adds to the knowledge of IDB in orthodontics and contributes to evidence on this technique. This evidence is applicable in everyday orthodontics, with respect to patient satisfaction and technical limits of IDB. The trial was registered in the Dutch Trial Register and the International Clinical Trials Registry Platform (ICTRP) of the World Health Organization (WHO), number NL9411.

The effect of surface roughening on the success of orthodontic mini-implants: A systematic review and meta-analysis.

INTRODUCTION: Orthodontic mini-implants are a widely accepted treatment modality in orthodontics; however, the failure rate is moderately high. Surface roughening is the golden standard in conventional oral implantology, and this may prove beneficial for orthodontic mini-implants as well. The objective of this systematic review is to assess the effect of surface roughening on the success rate of orthodontic mini-implants in both adolescent and adult patients undergoing orthodontic treatment. METHODS: Randomized studies comparing the success of surface-roughened and smooth, machined-surface orthodontic mini-implants were included. A literature search was conducted for 6 electronic databases (Pubmed/Medline, Embase, Cochrane, CINAHL, Web of Science, and Scopus), Clinical trial registry (https://www. CLINICALTRIALS: gov), and grey literature (Google Scholar). A manual search of the reference lists of included studies was performed. Two authors independently performed the screening, data extraction, risk of bias, and quality assessments. The risk of bias was assessed with the Cochrane risk-of-bias 2.0 Tool. Data were synthesized using a random effect model meta-analysis presented as a forest plot. The certainty in the body of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation tool. RESULTS: A total of 4226 unique records were screened, and 6 of these were included in the quantitative analysis. Four additional articles were selected for a secondary outcome. A total of 364 orthodontic mini-implants were included in the primary outcome analysis. There was no statistically significant effect of surface roughening on the success of orthodontic mini-implants (odds ratio = 0.63 favoring roughened orthodontic mini-implants; 95% confidence interval, 0.35-1.14). The secondary outcome (ie, the overall failure rate of roughened orthodontic mini-implants) was 6% based on studies with high heterogeneity. Limitations of this study were the risk of bias, study imprecision, and possible publication bias, leading to a very low certainty in the body of evidence. CONCLUSIONS: There is very low-quality evidence that there is no statistically significant effect of surface roughening on the success of orthodontic mini-implants in humans. The overall failure rate of surface-roughened orthodontic mini-implants was 6%. FUNDING: No funding was received for this review. REGISTRATION: This study was preregistered in the Prospective Register of Systematic Reviews (CRD42022371830).

Novel SK channel positive modulators prevent ferroptosis and excitotoxicity in neuronal cells.

Small conductance calcium-activated potassium (SK) channel activity has been proposed to play a role in the pathology of several neurological diseases. Besides regulating plasma membrane excitability, SK channel activation provides neuroprotection against ferroptotic cell death by reducing mitochondrial Ca2+ uptake and reactive oxygen species (ROS). In this study, we employed a multifaceted approach, integrating structure-based and computational techniques, to strategically design and synthesize an innovative class of potent small-molecule SK2 channel modifiers through highly efficient multicomponent reactions (MCRs). The compounds' neuroprotective activity was compared with the well-studied SK positive modulator, CyPPA. Pharmacological SK channel activation by selected compounds confers neuroprotection against ferroptosis at low nanomolar ranges compared to CyPPA, that mediates protection at micromolar concentrations, as shown by an MTT assay, real-time cell impedance measurements and propidium iodide staining (PI). These novel compounds suppress increased mitochondrial ROS and Ca2+ level induced by ferroptosis inducer RSL3. Moreover, axonal degeneration was rescued by these novel SK channel activators in primary mouse neurons and they attenuated glutamate-induced neuronal excitability, as shown via microelectrode array. Meanwhile, functional afterhyperpolarization of the novel SK2 channel modulators was validated by electrophysiological measurements showing more current change induced by the novel modulators than the reference compound, CyPPA. These data support the notion that SK2 channel activation can represent a therapeutic target for brain diseases in which ferroptosis and excitotoxicity contribute to the pathology.

Maxillary sinus floor augmentation with injectable calcium phosphate cements: a pre-clinical study in sheep.

OBJECTIVES: The aim of this pre-clinical study was to evaluate the biological performance of two injectable calcium phosphate cement (CPC) composite materials containing poly(D,L-lactic-co-glycolic)acid (PLGA) microspheres with different properties in a maxillary sinus floor elevation model in sheep. MATERIALS AND METHODS: PLGA microspheres were made of either low molecular weight (~17 kDa) acid-terminated PLGA (PLGA(L-AT) ) or high molecular weight (~44 kDa) end-capped PLGA (PLGA(H-EC) ) and incorporated in CPC. Eight female Swifter sheep underwent a bilateral maxillary sinus floor elevation procedure via an extra-oral approach. All animals received both materials, alternately injected in the left and right sinus (split-mouth model) and a time point of 12 weeks was used. Analysis of biological performance was based on histology, histomorphometry, and evaluation of sequential fluorochrome labeling. RESULTS: Both types of CPC-PLGA composites showed biocompatibility and direct bone-cement contact. CPC-PLGA(L-AT) showed a significantly higher degradation distance compared to CPC-PLGA(H-EC) (1949 ± 1295 µm vs. 459 ± 267 µm; P = 0.0107). Further, CPC-PLGA(L-AT) showed significantly more bone in the region of interest (26.4 ± 10.5% vs. 8.6 ± 3.9% for PLGA(H-EC) ; P = 0.0009) and significantly less remaining CPC material (61.2 ± 17.7% vs. 81.9 ± 10.9% for PLGA(H-EC) ; P = 0.0192). CONCLUSIONS: Both CPC-PLGA(L-AT) and CPC-PLGA(H-EC) demonstrated to be safe materials for sinus floor elevation procedures in a large animal model, presenting biocompatibility and direct bone contact. In view of material performance, CPC-PLGA(L-AT) showed significantly faster degradation and a significantly higher amount of newly formed bone compared to CPC-PLGA(H-EC) .

Influence of bisphosphonate treatment on bone substitute performance in osteoporotic conditions.

OBJECTIVE: Considering the elevated number of osteoporotic patients in need of bone graft procedures, we here evaluated the effect of alendronate (ALN) treatment on the regeneration of bone defects in osteoporotic rats. Bone formation was histologically and histomorphometrically assessed in rat femoral condyle bone defects filled with bone graft (Bio-Oss®) or left empty. METHODS: Male Wistar rats were induced osteoporotic through orchidectomy (ORX) and SHAM-operated. The animals were divided into three groups: osteoporotic (ORX), osteoporotic treated with ALN (ORX + ALN) and healthy (SHAM). Six weeks after ORX or SHAM surgeries, bone defects were created bilaterally in femoral condyles; one defect was filled with Bio-Oss® and the other one left empty. Bone regeneration within the defects was analyzed by histology and histomorphometry after 4 and 12 weeks. RESULTS: Histological samples showed new bone surrounding Bio-Oss® particles from week 4 onward in all three groups. At week 12, the data further showed that ALN treatment of osteoporotic animals enhanced bone formation to a 10-fold increase compared to non-treated osteoporotic control. Bio-Oss® filling of the defects promoted bone formation at both implantation periods compared to empty controls. CONCLUSION: Our histological and histomorphometric results demonstrate that the enteral administration of alendronate under osteoporotic bone conditions leverages bone defect regeneration to a level comparable to that in healthy bone. Additionally, Bio-Oss® is an effective bone substitute, increasing bone formation, and acting as an osteoconductive scaffold guiding bone growth in both healthy and osteoporotic bone conditions. SIGNIFICANCE: Based on the results of this study, enteral use of ALN mitigates adverse effects of an osteoporotic condition on bone defect regeneration.

Innovative implant design for continuous implant stability: A mechanical and histological experimental study in the iliac crest of goats.

OBJECTIVES: this in vivo study reports on mechanical torque data as well as the biological evaluation up to 6 weeks after placement of implants with a unique wide knife thread design in a goat iliac crest model. We hypothesized that implants with this thread design would show substantial primary stability at a continuous level toward secondary stability. METHODS: 64 MegaGen Anyridge® implants were used with diameters 3.5 mm, 4.0 mm, 5.0 mm and 6.0 mm (n = 8). Implants were placed monocortically in the iliac crest of 16 healthy female Saanen goats, both on the right (for torque measurements) and left side (for histology/-morphometry). Torque-in at implant installation and torque-out at 2 and 6 weeks of implantation was measured, as well as bone-to-implant contact (BIC) and bone-area between the screw threads (BA). RESULTS: Histology showed intimate bone-to-implant contact with a maturating trabecular structure between 2 and 6 weeks. Torque values showed a dependency on implant diameter. For all implant diameters, torque-in values were similar to torque-out values at 2 weeks. At 6 weeks however, all torque-out values were significantly increased. BIC and BA percentages showed similar values for all diameters at both 2 and 6 weeks. CONCLUSIONS: These results prove the absence of a lag-phase in implant stability for MegaGen Anyridge® implants in the goat iliac crest model. The increased torque-out values at 6 weeks without increasing BIC and BA percentages correlate with the observed maturation of bone-to-implant contact quality over time. CLINICAL SIGNIFICANCE: It is a challenge to optimize implants with continuous primary stability and rapid transition into secondary stability to minimize the duration of the lag-phase. The results of this study prove the absence of a lag-phase in implant stability for MegaGen Anyridge® implants. Consequently, the data from this work are important for the treatment of individual patients 'translating' these findings into clinical implant procedures.

Late (> 5 years) regional lymph node metastasis of oral squamous cell carcinoma (SCC), proven by p53 mutation analysis.

BACKGROUND: A late (> 5 years) neck nodal metastasis of oral cancer, poses a problem to the clinician: is it a late metastasis or a metastasis of a (unknown) second primary tumour? METHODS: A 50-year-old male was seen with a contralateral lymph node metastasis, 5 1/2 years after treatment of a pT2N1M0 carcinoma in the floor of the mouth. Both the late metastasis and the original tumour specimen were analysed for p53 mutations. RESULTS: Both specimens showed an identical p53 mutation, thereby confirming the lymph node to be a late metastasis. CONCLUSIONS: A lymph node metastasis can occur more than 5 years after treatment of an oral squamous cell carcinoma. p53 mutation analysis is of help to discriminate it from a second primary tumour.

Effect of surface alkali-based treatment of titanium implants on ability to promote in vitro mineralization and in vivo bone formation.

This study investigated whether a novel alkali-based surface modification enhances in vitro mineralization as well as in vivo bone formation around titanium (Ti) implants in a femoral condyle model of 36 male Wister rats. All implant surfaces were grit-blasted and then received either acid-etching treatment, alkali-based treatment, or were left untreated (controls). Histological and histomorphometrical analyses were performed on retrieved specimens after 4 and 8weeks of healing to assess peri-implant bone formation. Results of implants surface characterisation showed notable differences in the topography and composition of alkali-treated surfaces, reflecting the formation of submicron-structured alkali-titanate layer. In the in vitro test, alkali-treated Ti surfaces showed the ability to stimulate mineralization upon soaking in simulated body fluid (SBF). In vivo histomorphometrical analyses showed similar values for bone area (BA%) and bone-to-implant contact (BIC%) for all experimental groups after both 4- and 8-week implantation periods. In conclusion, the surface topography and composition of the grit-blasted Ti implants was significantly modified using alkali-based treatment. With respect to the present in vivo model, the biological performance of alkali-treated Ti implants is comparable to the commercially available, grit-blasted, acid-etched Ti implants. STATEMENT OF SIGNIFICANCE: Since success rate of dental implants might be challenged in bone of low density, an optimum implant surface characteristic is demanding. In this work, alkali treatment of Ti implants showed significant advantage of surface mineralization upon soaking in simulated body fluid. Using an in vivo rat model, Ti surfaces with either acid-etching treatment or alkali-based treatment evoked robust bone formation around Ti implants. Such information may be utilized for the advancement of biomaterials research for bone implants in future.

Diabetes Mellitus and Bone Regeneration: A Systematic Review and Meta-Analysis of Animal Studies.

BACKGROUND: The regeneration of bone defects resulting from trauma, resection of tumors, infection, or congenital disease is a challenge, and bone grafts are utilized in a wide array of clinical settings to augment bone repair and regeneration. Diabetes mellitus (DM) is a chronic metabolic disease, which affects 8.3% of the world population, summing ∼387 million individuals. The consequences of the disease, for example, hyperglycemia, have been associated to a reduced capacity to form bone and poor bone quality, influencing bone healing. Our aim was to systematically review the literature to the effect of diabetic condition on bone regeneration in animal models, when using bone substitute materials from different origins, and perform a meta-analysis to quantitatively study the effect of DM on bone regeneration. METHODS: An extensive search strategy was carried out through PubMed and EMBASE to identify the potential relevant studies published from database inception until July 1, 2015. Initially, the title and abstract of 1409 studies were screened, after which inclusion criteria sorted 29 studies for full-text evaluation. After using exclusion criteria, a final number of seven studies could be included in the review. RESULTS: The seven included studies that passed our inclusion/exclusion criteria were all type 1 diabetes, comprising a total of 189 animals and 14 intrastudy comparisons. These studies presented a consistent and reduced risk of bias and showed a significant average effect size of -6.87% of bone formation for diabetes type 1 versus healthy condition [95% confidence interval: -10.55 to -3.18; I2 = 87.4%; p = 0.0003]. INTERPRETATION: These findings prove that DM type 1 negatively influences bone formation compared with a healthy condition, irrespective of the bone substitute material used.

Long-term biological performance of injectable and degradable calcium phosphate cement.

Enhancing degradation of poorly degrading injectable calcium phosphate (CaP) cements (CPCs) can be achieved by adding poly(lactic-co-glycolic acid) (PLGA) microparticles, generating porosity after polymer degradation. CPC-PLGA has proven to be biodegradable, although its long-term biological performance is still unknown. Optimization of injectability could be achieved via addition of carboxymethyl cellulose (CMC). Here, we evaluated the long-term in vivo performance of CPC-PLGA with or without the lubricant CMC in comparison to the devitalized bovine bone mineral (DBBM) predicate device Bio-Oss®. Rabbit femoral bone defects were injected with a CPC-formulation or filled with Bio-Oss® granules. Samples were retrieved at 6 and 26 weeks. Material degradation for Bio-Oss® was marginal, starting with 57% material remnants at implantation, 49% at 6 weeks, and 35% at 26 weeks, respectively. In contrast, CPC-PLGA and CPC-PLGA-CMC showed significant material degradation, starting with 100% material remnants at implantation, 56 and 78% at 6 weeks, and 8 and 21% at 26 weeks. Bone formation showed to be rapid for Bio-Oss®, with 24% at 6 weeks, and a similar value (27%) at 26 weeks. Both CPC-PLGA and CPC-PLGA-CMC showed a continuous temporal increase in bone formation, with 13 and 6% at 6 weeks, and 44 and 32% at 26 weeks. This study showed that CPC-PLGA induces favorable bone responses with >90% degradation and >40% new bone formation after an implantation period of 26 weeks.

[Management of patients with conversion disorder]. / Beleid bij patiënten met conversiestoornis.

The symptoms of conversion disorder are not due to conscious simulation. There should be no doubt that the symptoms of conversion disorder are genuine, even if scans do not reveal any abnormalities. The management of patients with conversion disorder starts with an explanation of the diagnosis. The essence of this explanation is that patients first hear about what the diagnosis actually means and only after this about what they do not have. When explaining the diagnosis it is a good idea to use metaphors. The treatment of patients with conversion disorder is carried out together with a physical therapist. The collaboration of healthcare professionals who are involved in the treatment of a patient with conversion disorder should preferably be coordinated by the patient's general practitioner.

Tantalum oxide and barium sulfate as radiopacifiers in injectable calcium phosphate-poly(lactic-co-glycolic acid) cements for monitoring in vivo degradation.

Monitoring the degradation of calcium phosphate-based bone substitute materials in vivo by means of noninvasive techniques (e.g., radiography) is often a problem due to the chemical resemblance of those substitutes with the mineral phase of bone. In the view of that, the present study aimed at enhancing the radiopacity of calcium phosphate cement enriched with poly(lactic-co-glycolic acid) (CPC-PLGA) microspheres, by adding tantalum oxide (Ta2O5) or the more traditional radiopacifier barium sulfate (BaSO4). The radiopacifying capacity of these radiopacifiers was first evaluated in vitro by microcomputed tomography (µCT). Thereafter, both radiopacifiers were tested in vivo using a distal femoral condyle model in rabbits, with subsequent ex vivo µCT analysis in parallel with histomorphometry. Addition of either one of the radiopacifiers proved to enhance radiopacity of CPC-PLGA in vitro. The in vivo experiment showed that both radiopacifiers did not induce alterations in biological performance compared to plain CPC-PLGA, hence both radiopacifiers can be considered safe and biocompatible. The histomorphometrical assessment of cement degradation and bone formation showed similar values for the three experimental groups. Interestingly, µCT analysis showed that monitoring cement degradation becomes feasible upon incorporation of either type of radiopacifier, albeit that BaSO4 showed more accuracy compared to Ta2O5.

The in vivo performance of CaP/PLGA composites with varied PLGA microsphere sizes and inorganic compositions.

Enrichment of calcium phosphate (CaP) bone substitutes with poly(lactic-co-glycolic acid) (PLGA) microspheres to create porosity overcomes the problem of poor CaP degradation. The degradation of CaP-PLGA composites can be customized by changing the physical and chemical properties of PLGA and/or CaP. However, the effect of the size of dense (solid rather than hollow) PLGA microspheres in CaP has not previously been described. The present study aimed at determining the effect of different dense (i.e. solid) PLGA microsphere sizes (small (S) ~20µm vs. large (L) ~130µm) and of CaP composition (CaP with either anhydrous dicalcium phosphate (DCP) or calcium sulphate dihydrate (CSD)) on CaP scaffold biodegradability and subsequent bone in-growth. To this end mandibular defects in minipigs were filled with pre-set CaP-PLGA implants, with autologous bone being used as a control. After 4weeks the autologous bone group outperformed all CaP-PLGA groups in terms of the amount of bone present at the defect site. On the other hand, at 12weeks substantial bone formation was observed for all CaP-PLGA groups (ranging from 47±25% to 62±15%), showing equal amounts of bone compared with the autologous bone group (82±9%), except for CaP with DCP and large PLGA microspheres (47±25%). It was concluded that in the current study design the difference in PLGA microsphere size and CaP composition led to similar results with respect to scaffold degradation and subsequent bone in-growth. Further, after 12weeks all CaP-PLGA composites proved to be effective for bone substitution.

Tantalumpentoxide as a radiopacifier in injectable calcium phosphate cements for bone substitution.

The chemical resemblance of calcium phosphate (CaP) cements and the mineral phase of bone is a problem in distinguishing CaP cement from bone tissue by means of common, noninvasive techniques (e.g., X-ray imaging and microcomputed tomography [µCT]). In this study, the feasibility of using tantalumpentoxide (Ta(2)O(5)) powder as radiopacifier in CaP cements was analyzed. A distal femoral condyle model in male adult Wistar rats was used. After 6 weeks of implantation time, the results were analyzed by means of µCT and histology. Unambiguous distinction of CaP cement from native bone tissue and volumetric measurements of the materials appeared to be possible by means of µCT scanning. Furthermore, there was no evidence of either inflammation or fibrous tissue around the implant materials or at the bone-material interface. In conclusion, the addition of Ta(2)O(5) as a radiopacifying additive to CaP cements allows discrimination between bone substitute and surrounding bone tissue. Consequently, Ta(2)O(5) represents an effective and biocompatible additive in CaP cements for in vivo monitoring purposes.

Functional renal volume: quantitative analysis at gadolinium-enhanced MR angiography--feasibility study in healthy potential kidney donors.

PURPOSE: To assess the feasibility of quantifying functional renal volume with gadolinium-enhanced magnetic resonance (MR) angiography. MATERIALS AND METHODS: Institutional review board approval was obtained, and all subjects gave informed consent. A contour-detection three-dimensional algorithm for determining renal volumes was developed. The method was validated in 18 cadaveric pig kidneys by measuring the water displacement caused by the kidneys. The kidney lengths and volumes in 19 consecutive potential kidney donors who underwent gadolinium-enhanced MR angiography of the renal arteries also were determined. Differences in volume measurements between men and women and between left and right kidneys were analyzed by using the Student t test. The volume of perfused renal cortex was calculated by extracting voxels on the basis of the cortex signal intensity threshold. The relevance of renal function parameters--namely, creatinine clearance rates--in the donor candidates was assessed by using a linear regression model. Intra- and interobserver variabilities of the measurements were determined by using the Bland-Altman method. RESULTS: Volume measurements of the cadaveric pig kidneys obtained by using MR angiography and the water displacement method were strongly correlated (r = 0.99). The mean total renal volume in the donor candidates was 196 mL (range, 136-295 mL). No significant differences in total renal volume between the men and women or between the left and right kidneys were found. The correlation between calculated renal cortex volumes (mean, 67 mL; range, 40-105 mL) and creatinine clearance rates was good (r = 0.69). Inter- and intraobserver variabilities were lower than 7%. CONCLUSION: Quantification of functional renal volume with three-dimensional gadolinium-enhanced MR angiography seems feasible with use of the described semiautomatic method.

Signaling of systemic acquired resistance in tobacco depends on ethylene perception.

The hypersensitive interaction between Tobacco mosaic virus (TMV) and tobacco results in accumulation of salicylic acid (SA), defense gene expression, and development of systemic acquired resistance (SAR) in uninfected leaves. The plant hormones SA and ethylene have been implicated in SAR. From a study with ethylene-insensitive (Tetr) tobacco, we concluded that ethylene perception is required to generate the systemic signal molecules in TMV-infected leaves that trigger SA accumulation, defense gene expression, and SAR development in uninfected leaves. Ethylene perception was not required for the responses of the plant to the systemic signal that leads to SAR development.