Systematic review of medication related osteonecrosis of the jaw (MRONJ) in patients undergoing only antiangiogenic drug therapy: surgery or conservative therapy?

Osteonecrosis of the jaw is a severe adverse condition affecting patients exposed to specific types of medications. Previous studies have highlighted that osteonecrosis of the jaw is triggered by invasive dental procedures and can be very challenging to manage, especially in patients with cancer. The primary aim of this review was to analyse all available evidence on the management (surgical and/or conservative) of medication related osteonecrosis of the jaws (MRONJ) in patients with a history of antiangiogenic drugs therapy and who had not been previously exposed to any antiresorptive drug treatments. A multi-database search (PubMed, MEDLINE, EMBASE and CINAHL) was performed to identify related multi-language papers published from January 2003 until November 2020. Data were extracted from relevant papers and analysed according to the outcomes selected in this review. The search generated 28 studies eligible for the analysis. The total number of patients included in the analysis was 36. Sixteen patients were treated with anti-vascular endothelial growth factor drugs (anti-VEGF) while the remaining patients were administered a combination of antiangiogenic drugs. The most common MRONJ site was the mandible in 29 patients. MRONJ recurrence after treatment was only reported in six patients, the majority of which were treated conservatively. The data reviewed confirmed that an invasive procedure was the most common trigger of MRONJ with relatively high frequency of postoperative recurrence following treatment. However, due to the low quality of available research in the literature, it is difficult to draw a definitive conclusion on the validity of the presented treatment to manage patients affected by MRONJ associated with angiogenic therapy.

Is there any biomaterial substitute for peri-implant soft tissue phenotype modification? A network meta-analysis of the appraisal literature.

Evidence shows that an increased width and thickness of the keratinized mucosa favours peri-implant health. The aim of this network meta-analysis was to compare the clinical effects of alternative biomaterials for peri-implant soft tissue phenotype modification (PSPM) in patients with dental implants when compared to autologous tissue grafts. An electronic search without language or date limitations was performed in four databases and the grey literature for articles published until November 2020. The eligibility criteria included randomized clinical trials (RCTs) evaluating the clinical outcomes of biomaterials for PSPM. A pairwise and network meta-analysis was conducted for each parameter to assess and compare the outcomes between the different treatment arms for the primary and secondary outcomes. A total of 11 RCTs were included in this review. The free gingival graft (FGG) showed the best clinical effect for increasing keratinized mucosa width (KMW). When compared in a network, the FGG demonstrated the best treatment ranking of probability results, followed by connective tissue graft (CTG), acellular dermal matrix (ADM), and xenogeneic collagen matrix (XCM). For the parameters 'mucosa thickness' and 'participant satisfaction with aesthetics', the results were CTG > ADM > XCM and XCM > ADM > CTG, respectively. Autogenous tissue grafts (FGG/CTG) demonstrate the best results in increasing KMW and mucosa thickness when compared to the other biomaterials.

Use of YouTube™ as a self-directed learning resource in oral surgery among undergraduate dental students: a cross-sectional descriptive study.

This cross-sectional descriptive study was done to assess the use and effectiveness of YouTube™ as a learning resource for oral surgery by fourth and final-year dental students at a single university. A study-specific survey was distributed to fourth (n=83) and final-year (n=86) dental students during a six-week period. In total, 122 (72%) responded. Most (n=82, 67%) used YouTube™ as study material, and 50 (41%) stated that the videos had influenced their practice. Generally, the quality was rated as good, and YouTube™ was a popular and influential learning resource. However, the material was not always consistent with that of the curriculum, and students should use it with caution as there is no quality assurance with respect to educational content or learning outcomes. Institutions should provide recorded learning material and teach students skills in the critical appraisal of contemporary teaching materials such as open-resource videos.

Multiscalar cellular automaton simulates in-vivo tumour-stroma patterns calibrated from in-vitro assay data.

BACKGROUND: The tumour stroma -or tumour microenvironment- is an important constituent of solid cancers and it is thought to be one of the main obstacles to quantitative translation of drug activity between the preclinical and clinical phases of drug development. The tumour-stroma relationship has been described as being both pro- and antitumour in multiple studies. However, the causality of this complex biological relationship between the tumour and stroma has not yet been explored in a quantitative manner in complex tumour morphologies. METHODS: To understand how these stromal and microenvironmental factors contribute to tumour physiology and how oxygen distributes within them, we have developed a lattice-based multiscalar cellular automaton model. This model uses principles of cytokine and oxygen diffusion as well as cell motility and plasticity to describe tumour-stroma landscapes. Furthermore, to calibrate the model, we propose an innovative modelling platform to extract model parameters from multiple in-vitro assays. This platform provides a novel way to extract meta-data that can be used to complement in-vivo studies and can be further applied in other contexts. RESULTS: Here we show the necessity of the tumour-stroma opposing relationship for the model simulations to successfully describe the in-vivo stromal patterns of the human lung cancer cell lines Calu3 and Calu6, as models of clinical and preclinical tumour-stromal topologies. This is especially relevant to drugs that target the tumour microenvironment, such as antiangiogenics, compounds targeting the hedgehog pathway or immune checkpoint inhibitors, and is potentially a key platform to understand the mechanistic drivers for these drugs. CONCLUSION: The tumour-stroma automaton model presented here enables the interpretation of complex in-vitro data and uses it to parametrise a model for in-vivo tumour-stromal relationships.

Ice slurry ingestion does not enhance self-paced intermittent exercise in the heat.

This study aimed to determine if ice slurry ingestion improved self-paced intermittent exercise in the heat. After a familiarisation session, 12 moderately trained males (30.4 ± 3.4 year, 1.8 ± 0.1 cm, 73.5 ± 14.3 kg, V˙O2max 58.5 ± 8.1 mL/kg/min) completed two separate 31 min self-paced intermittent protocols on a non-motorised treadmill in 30.9 ± 0.9 °C, 41.1 ± 4.0% RH. Thirty minutes prior to exercise, participants consumed either 7.5 g/kg ice slurry (0.1 ± 0.1 °C) (ICE) or 7.5 g/kg water (23.4 ± 0.9 °C) (CONTROL). Despite reductions in Tc (ΔTc : -0.51 ± 0.3 °C, P < 0.05) and thermal sensation prior to exercise, ICE did not enhance self-paced intermittent exercise compared to CONTROL. The average speed during the walk (CONTROL: 5.90 ± 1.0 km, ICE: 5.90 ± 1.0 km), jog (CONTROL: 8.89 ± 1.7 km, ICE: 9.11 ± 1.5 km), run (CONTROL: 12.15 ± 1.7 km, ICE: 12.54 ± 1.5 km) and sprint (CONTROL: 17.32 ± 1.3 km, ICE: 17.18 ± 1.4 km) was similar between conditions (P > 0.05). Mean Tsk , Tb , blood lactate, heart rate and RPE were similar between conditions (P > 0.05). The findings suggest that lowering Tc prior to self-paced intermittent exercise does not translate into an improved performance.

Atypical small acinar proliferation (ASAP): Is a repeat biopsy necessary ASAP? A multi-institutional review.

BACKGROUND: Atypical small acinar proliferation (ASAP) occurs in approximately 5% of prostate biopsies. Approximately 30-40% of patients with ASAP may develop prostate cancer (PCa) within a 5-year period. Current guidelines recommend a repeat biopsy within 3-6 months after the initial diagnosis. Our objective was to examine the association between ASAP and subsequent diagnosis of high-grade PCa and to evaluate the need for immediate repeat biopsy. METHODS: A retrospective multi-institutional review identified 264 patients who underwent prostate biopsy from 2000 to 2013 (Brown), 2008 to 2013 (University of Massachusetts) and 1994 to 2005 (Mayo) and were diagnosed with ASAP. Patients underwent transrectal ultrasound-guided biopsies for elevated PSA and/or abnormal digital rectal exam. Clinicopathologic features were assessed, including rates of subsequent PCa detection of any high-grade (Gleason 7-10) PCa. Comparison was made between those with subsequent PCa on repeat biopsy and those with benign repeat pathology. RESULTS: All 264 patients included underwent repeat biopsy with a median follow-up of 5.4 years (interquartile range: 4.6, 6.7). Of these patients, 89 (34%) were subsequently diagnosed with PCa including 21 (8%) with high-grade PCa. Pre-biopsy PSA was higher among patients subsequently diagnosed with (6.7 vs 5.8, P<0.001). Of those diagnosed with subsequent PCa, 69/89 (78%) had less than or equal to Gleason 3+3 disease and only 15/89 (17%) had Gleason 7 and 6/89 (6%) revealed Gleason ⩾8-10. Radical prostatectomy was performed on 36/89 (40%) patients. Surgical pathology revealed 11 patients ⩾Gleason 8-10 PCa. CONCLUSIONS: Although 34% of patients with an initial diagnosis of ASAP who had repeat biopsy were subsequently diagnosed with PCa only, only 22% (8% of the total cohort) were found to have high-grade disease. Higher PSA was associated with increased risk of identifying PCa on repeat biopsy. These findings suggest that immediate repeat biopsy may be omitted in the majority of men with ASAP.

High-plasticity mesenchymal stem cells isolated from adult-retained primary teeth and autogenous adult tooth pulp--A potential source for regenerative therapies?

PURPOSE: The objective of this study was to compare the growth rate, morphology, immunohistology and plasticity of autogenous adult-retained SHEDs (arSHEDs) and adult dental pulp stem cells (DPSCs) obtained from the same donor. METHODS: Expression of the mesenchymal stem cell markers CD44, CD90, CD105, caspase-3 and GAPDH were assessed using RT-PCR. Caspase-3 and CD44 were also evaluated at the protein level by western blotting of cell lysates. Plasticity of DPSCs and arSHEDs were tested by culture in adipogenic, chondrogenic, osteogenic and Schwann cells induction media. RESULTS: DPSCs and arSHEDs were isolated by explant culturing and were similarly positive for growth rate and all tested markers. Furthermore, DPSCs and arSHEDs could be driven to adipocyte, chondrocyte, osteocyte and Schwann cells lineages thus indicating similar plasticity as precursor cells. CONCLUSION: This study demonstrates the similarities between DPSCs and arSHEDs in a unique situation, where both stem cells (SC) types were obtained from a single patient and thus represent an alternative source of SC's for tissue engineering and regeneration.

Global quantitative analysis of phosphorylation underlying phencyclidine signaling and sensorimotor gating in the prefrontal cortex.

Prepulse inhibition (PPI) is an example of sensorimotor gating and deficits in PPI have been demonstrated in schizophrenia patients. Phencyclidine (PCP) suppression of PPI in animals has been studied to elucidate the pathological elements of schizophrenia. However, the molecular mechanisms underlying PCP treatment or PPI in the brain are still poorly understood. In this study, quantitative phosphoproteomic analysis was performed on the prefrontal cortex from rats that were subjected to PPI after being systemically injected with PCP or saline. PCP downregulated phosphorylation events were significantly enriched in proteins associated with long-term potentiation (LTP). Importantly, this data set identifies functionally novel phosphorylation sites on known LTP-associated signaling molecules. In addition, mutagenesis of a significantly altered phosphorylation site on xCT (SLC7A11), the light chain of system xc-, the cystine/glutamate antiporter, suggests that PCP also regulates the activity of this protein. Finally, new insights were also derived on PPI signaling independent of PCP treatment. This is the first quantitative phosphorylation proteomic analysis providing new molecular insights into sensorimotor gating.

Revolution vs status quo? Non-intervention strategy of asymptomatic third molars causes harm.

The Faculty of Dental Surgery of the Royal College of Surgeons of England has prompted the National Institute for Health and Care Excellence to urgently re-assess the TA1 guidance on extractions of wisdom teeth and highlighted required amendments to the present version in light of published evidence concerning the harm caused by wisdom tooth retention. This article seeks to address the recent concerns relating the increasing frequency of distal-cervical caries in lower second molar teeth when associated with asymptomatic partially erupted mesial or horizontal impacted mandibular third molars. Such acute angle impactions are classified as partially erupted when one of the third molar cusps breached the epithelial attachment of the distal aspect of the second molar, thus prevents the formation of a gingival seal. At its earliest stage the wisdom tooth appears clinically absent or unerupted, yet histologically the architecture of the gingival epithelium has been disrupted allowing ingress of microbes, demineralisation and succeeding cavitation to take place on the distal aspect of the second molar. We hope to highlight the difficulties faced in addressing this growing clinical problem and encourage clinicians to re-evaluate their own caries risk assessment and caries prevention strategy in relation to mesial and horizontal third molar extractions.

Evidence-based outcomes following inferior alveolar and lingual nerve injury and repair: a systematic review.

The inferior alveolar nerve (IAN) and lingual (LN) are susceptible to iatrogenic surgical damage. Systematically review recent clinical evidence regarding IAN/LN repair methods and to develop updated guidelines for managing injury. Recent publications on IAN/LN microsurgical repair from Medline, Embase and Cochrane Library databases were screened by title/abstract. Main texts were appraised for exclusion criteria: no treatment performed or results provided, poor/lacking procedural description, cohort <3 patients. Of 366 retrieved papers, 27 were suitable for final analysis. Treatment type for injured IANs/LNs depended on injury type, injury timing, neurosensory disturbances and intra-operative findings. Best functional nerve recovery occurred after direct apposition and suturing if nerve ending gaps were <10 mm; larger gaps required nerve grafting (sural/greater auricular nerve). Timing of microneurosurgical repair after injury remains debated. Most authors recommend surgery when neurosensory deficit shows no improvement 90 days post-diagnosis. Nerve transection diagnosed intra-operatively should be repaired in situ; minor nerve injury repair can be delayed. No consensus exists regarding optimal methods and timing for IAN/LN repair. We suggest a schematic guideline for treating IAN/LN injury, based on the most current evidence. We acknowledge that additional RCTs are required to provide definitive confirmation of optimal treatment approaches.

Intellectual abilities in tuberous sclerosis complex: risk factors and correlates from the Tuberous Sclerosis 2000 Study.

BACKGROUND: Tuberous sclerosis complex (TSC) is associated with intellectual disability, but the risk pathways are poorly understood. METHOD: The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of the natural history of TSC. One hundred and twenty-five UK children age 0-16 years with TSC and born between January 2001 and December 2006 were studied. Intelligence was assessed using standardized measures at ≥2 years of age. The age of onset of epilepsy, the type of seizure disorder, the frequency and duration of seizures, as well as the response to treatment was assessed at interview and by review of medical records. The severity of epilepsy in the early years was estimated using the E-Chess score. Genetic studies identified the mutations and the number of cortical tubers was determined from brain scans. RESULTS: TSC2 mutations were associated with significantly higher cortical tuber count than TSC1 mutations. The extent of brain involvement, as indexed by cortical tuber count, was associated with an earlier age of onset and severity of epilepsy. In turn, the severity of epilepsy was strongly associated with the degree of intellectual impairment. Structural equation modelling supported a causal pathway from genetic abnormality to cortical tuber count to epilepsy severity to intellectual outcome. Infantile spasms and status epilepticus were important contributors to seizure severity. CONCLUSIONS: The findings support the proposition that severe, early onset epilepsy may impair intellectual development in TSC and highlight the potential importance of early, prompt and effective treatment or prevention of epilepsy in tuberous sclerosis.

Non-invasive 3D time-of-flight imaging technique for tumour volume assessment in subcutaneous models.

Subcutaneous tumour xenograft volumes are generally measured using callipers. This method is susceptible to inter- and intra-observer variability and systematic inaccuracies. Non-invasive 3D measurement using ultrasound and magnetic resonance imaging (MRI) have been considered, but require immobilization of the animal. An infrared-based 3D time-of-flight (3DToF) camera was used to acquire a depth map of tumour-bearing mice. A semi-automatic algorithm based on parametric surfaces was applied to estimate tumour volume. Four clay mouse models and 18 tumour-bearing mice were assessed using callipers (applying both prolate spheroid and ellipsoid models) and 3DToF methods, and validated using tumour weight. Inter-experimentalist variability could be up to 25% in the calliper method. Experimental results demonstrated good consistency and relatively low error rates for the 3DToF method, in contrast to biased overestimation using callipers. Accuracy is currently limited by camera performance; however, we anticipate the next generation 3DToF cameras will be able to support the development of a practical system. Here, we describe an initial proof of concept for a non-invasive, non-immobilized, morphology-independent, economical and potentially more precise tumour volume assessment technique. This affordable technique should maximize the datapoints per animal, by reducing the numbers required in experiments and reduce their distress.

Evidence of frequent dosing errors in paediatrics and intervention to reduce such prescribing errors.

WHAT IS KNOWN AND OBJECTIVE: Drug prescribing is an essential part of inpatient care, and prescription errors/omissions have the potential to lead to disastrous consequences. Paediatric inpatient prescribing is particularly sensitive to error due to the weight-adjusted dosing of many medications prescribed in the acute setting. Previous studies have described a high incidence of error in adult drug chart completion, although no studies to date have assessed the error seen in the paediatric setting or accuracy of weight-adjusted dosing. Our objective was to determine the degree of error seen in paediatric drug prescribing for patients admitted under the care of oral and maxillofacial surgery and to explore practical and accessible methods through which error can be reduced. METHODS: We retrospectively evaluated inpatient drug charts to assess the prescribing practices seen for patients admitted under the care of oral and maxillofacial surgery in an NHS children's hospital and compared these findings against established hospital standards. The study also examined the distribution and variability of weight-adjusted dose prescribing in an attempt to set targets for auditing improvements following the implementation of changes. RESULTS AND DISCUSSION: Prescriptions were completed by a combination of doctors from maxillofacial and anaesthetic teams, with similar error rates seen in both specialties. 13% of drug charts contained one or more errors in frequency prescribing. For weight-adjusted drugs, a median under-dosage of -5·4% was noted, with an IQR of -12 to -0·6. Our study has confirmed that errors are common both in the manual completion of paediatric prescription charts and in the calculation of weight-adjusted doses. WHAT IS NEW AND CONCLUSION: We conclude that inaccuracies in prescription chart completion are a frequent occurrence and that dosage and frequency-prescribing errors may potentially act synergistically to create a significant disparity between the recommended and actual amount of drug that is delivered. Our study demonstrates a clear bias towards under-prescribing weight-adjusted doses which may be contributing to reduced efficacy of analgesia, among other drugs. Simple methods can be implemented on a specialty basis to improve the accuracy of both drug chart completion and weight-adjusted dosing.

Treatment of the edentulous atrophic maxilla using zygomatic implants: evaluation of survival rates over 5-10 years.

The aim of this retrospective observational cohort study was to analyse and report the 5-10-year survival rates of endosseous zygomatic implants used in the rehabilitation of the atrophic maxilla. Forty-three consecutive zygomatic implant placements in 25 patients were evaluated over a 5-10-year period. All zygomatic implant surgery was carried out under general anaesthesia. Nobel Biocare zygomatic machined-surface implants were used, and placement was undertaken using the modified sinus slot method. The main outcome measures and determinants for success were survival of the restored implants and the proportion of originally planned prostheses delivered to patients. Of the 25 patients treated, 12 were male and 13 were female; 19 were non-smokers, and the mean age at time of surgery was 64 years. Patients were treatment-planned for implant-retained bridgework, a removable prosthesis retained by fixed cast gold or milled titanium beams, or magnet-retained removable prostheses. A combination of zygomatic and conventional implants was used in all but one patient. In this study it was shown that the overall success rate for zygomatic implants was 86%, with six of the implants either failing to integrate or requiring removal due to persistent infection associated with the maxillary sinus. All patients received their planned prosthesis, although in six cases the method of retention required modification. This study illustrates that zygomatic implants are a successful and important treatment option when trying to restore the atrophic maxilla, with the potential to avoid additional augmentation/grafting procedures and resulting in a high long-term success rate.

A case report describing a suspected rivaroxaban hypersensitivity reaction in a surgical patient.

WHAT IS KNOWN AND OBJECTIVE: Rivaroxaban is an oral anticoagulant, currently licensed for use as a venous thromboembolism (VTE) prophylaxis, and recommended by the National Institute for Clinical Excellence (NICE) for all patients undergoing elective hip and knee replacement surgery in the UK. We present the first case of a suspected hypersensitivity to rivaroxaban. CASE SUMMARY: A 57-year-old man with no previous allergies underwent an uncomplicated, elective partial knee replacement, after which he was prescribed a routine 2-week course of rivaroxaban 10 mg. He developed an allergic response requiring readmission for assessment and treatment 7 days post-operatively. WHAT IS NEW AND CONCLUSION: We believe this to be the first published case of hypersensitivity associated with rivaroxaban. More research is needed to determine this association. At the same time, given the growing range and increasing use of anticoagulants, particular vigilance is required regarding potential side effects so that these may be managed quickly and effectively in the early stages.

BMK1 is involved in the regulation of p53 through disrupting the PML-MDM2 interaction.

Promyelocytic leukemia protein (PML) modulates the p53 tumor suppressor through its interaction with p53 and MDM2. We found that activated big MAP kinase 1 (BMK1) preferentially associates with PML isoform IV and disrupts PML-MDM2 interaction. Doxorubicin, a common chemotherapeutic agent, is known to promote PML-mediated p53 activation in part by promoting PML-dependent MDM2 nucleolar sequestration. We discovered that BMK1 deactivation coupled with doxorubicin synergistically enhanced MDM2 nucleolar sequestration and, consequently, promoted PML-mediated p53 upregulation leading to tumor cell apoptosis in vitro and tumor regression in vivo. Collectively, these results not only suggest that BMK1 activity has a role in suppressing p53 by blocking the interaction between PML and MDM2, but also implicate that pharmacological BMK1 inhibitor should significantly enhance the anticancer capacity of doxorubicin-based chemotherapy.

Patterns of scald injuries in children--has anything changed?

The objective was to study presentation patterns of scald injuries in children and suggest potential countermeasures to reduce these injuries. We retrospectively studied scald injuries in children attending an urban paediatric emergency department between January 1st and December 31st 2008. Data was extracted from our emergency department database using search terms 'burn', 'scald', 'other burn'. Scalds were analysed for; age at presentation, sex, time of presentation, causal agent, scald outcome and treatment required. Burns accounted for 280 (0.66%) of total attendees, 161 (57%) were scalds. 127 (79%) were under 5 years old (mean age 42 months). 104 (65%) were caused by hot beverages, 25 (16%) hot water and 16 (10%) hot food stuffs. 97 (60%) presented within 1 hour of injury. 40 (25%) received first aid. The most affected areas were upper limbs 79 (35%) and upper trunk 74 (33%). Overall 45 (28%) were discharged home requiring no further treatment, 9 (6%) were admitted to hospital and 101 (63%) attended dressing clinic or plastic surgery OPD. Our results are consistent with other studies and illustrate that the incidence and pattern of scald injuries have not changed over the past decade. Scalds will continue to be a significant cause of unintentional injury and morbidity among young children unless preventative strategies are devised and employed.

Scientific frontiers: emerging technologies for salivary diagnostics.

Saliva, a biofluid historically well-studied biochemically and physiologically, has entered the post-genomic 'omics' era, where its proteomic, genomic, and microbiome constituents have been comprehensively deciphered. The translational path of these salivary constituents has begun toward a variety of personalized individual medical applications, including early detection of cancer. Salivary diagnostics is a late-comer, but it is catching up where dedicated resources, like the Salivaomics Knowledge Base (SKB), now have taken center stage in the dissemination of the diagnostic potentials of salivary biomarkers and other translational and clinical utilities.