An investigation into the reliability of a mobile app designed to assess orthodontic treatment need and severity.

Aim To investigate reliability of the Easy IOTN app between clinicians with different levels of experience in determining Index of Orthodontic Treatment Need (IOTN) Dental Health Component (DHC) and Aesthetic Component (AC) scores from study models. The accuracy of each clinician in discriminating treatment need using the app against the 'gold standard' conventional assessment at the threshold of treatment acceptance criteria was also explored.Materials and methods In total, 150 sets of pre-treatment study models were assessed by six clinicians using the app on two separate occasions (T1 and T2). A single IOTN-calibrated clinician also scored the models using the conventional technique. Clinician scores for both intra- and inter-rater reliability were assessed using Cohen's Kappa. The performance of each clinician in discriminating treatment need using the app against the conventional assessment method at the threshold of treatment acceptance criteria was also assessed using the area under the curve-receiver operating characteristic.Results The intra-rater agreement for the clinician undertaking the conventional assessment of the models was 1.0. Intra-rater agreement scores for clinicians using the Easy IOTN app ranged between 0.37-0.87 (DHC) and 0.22-0.44 (AC). Inter-rater agreement scores at T2 were 0.59 (DHC) and 0.23 (AC). Based on the IOTN DHC, all clinicians displayed an excellent level of accuracy in determining malocclusions qualifying for treatment (range 81.7-90.0%). Based on the IOTN AC, all clinicians showed an acceptable level of accuracy in determining malocclusions qualifying for treatment (range 71.9-79.2%).Conclusions The Easy IOTN app was shown to have moderate inter-rater reliability. Variation in the intra-rater reliability was evident between clinicians of different grades/level of experience. Importantly, the diagnostic accuracy of the app to discriminate between malocclusions that qualify for NHS treatment was rated as excellent (IOTN DHC) and acceptable (IOTN AC) and independent of clinician grade or level of experience.

Physical properties of conventional and Super Slick elastomeric ligatures after intraoral use.

OBJECTIVE: To investigate the change in the physical properties of conventional and Super Slick elastomeric ligatures after they have been in the mouth. MATERIALS AND METHODS: Nine healthy volunteers took part. One orthodontic bracket was bonded to a premolar tooth in each of the four quadrants of the mouth. Two conventional and two Super Slick elastomeric ligatures were placed at random locations on either side of the mouth. The ligatures were collected after various time intervals and tested using an Instron Universal testing machine. The two outcome measures were failure load and the static frictional resistance. RESULTS: The failure load for conventional ligatures was reduced to 67% of the original value after 6 weeks in situ. Super Slick elastomeric ligatures showed a comparable reduction after 6 weeks in situ (63% of original value). There were no statistical differences in the static friction between conventional and Super Slick elastomerics that had been in situ for either 24 hours (P = .686) or 6 weeks (P = .416). There was a good correlation between failure load and static friction (r = .49). CONCLUSIONS: There were statistically significant differences in the failure loads of elastomerics that had not be placed in the mouth and those that had been in the mouth for 6 weeks. There were no differences in the static frictional forces produced by conventional and Super Slick ligatures either before or after they had been placed in the mouth. There appears to be a direct proportional relationship between failure load and static friction of elastomeric ligatures.

Impaired attention is central to the cognitive deficits observed in alpha 7 deficient mice.

alpha7-Nicotinic acetylcholine receptors (alpha7-nAChR) have been implicated in a range of cognitive deficits in schizophrenia. Therefore we examined alpha7-nAChR knockout (KO), heterozygote (HT) and wildtype (WT) littermate mice in the 5-CSR (a rodent model of sustained attention) and odour span (a novel mouse working memory paradigm) tasks, and related performance to nAChR density. Whilst there was no difference between groups in baseline 5-CSR task performance, alpha7-nAChR KO's exhibited significantly higher omission levels compared to WT mice on increasing the attentional load, with HT mice performing at an intermediate level. Furthermore, alpha7-nAChR KO mice were significantly impaired in the odour span task when compared to WT mice, in a pattern consistent with impaired attention. These behavioural deficits were associated with the loss of alpha7-nAChRs, as alpha4beta2-nAChR density was unaltered in these mice. Thus these studies intimate that the attentional impairment in alpha7-nAChR transgenic mice maybe core to other deficits in cognition.

Double permanent incisor teeth: management of three cases.

Double teeth in the permanent dentition have a reported incidence of 0.1% for Caucasian groups. Common associated problems include adverse aesthetics, caries, periodontal disease, and malocclusions. Management can be challenging, often requiring a multidisciplinary approach. Three cases are presented illustrating the variety of treatments available.

Identification and Characterization of MEDI4736, an Antagonistic Anti-PD-L1 Monoclonal Antibody.

Programmed cell-death 1 ligand 1 (PD-L1) is a member of the B7/CD28 family of proteins that control T-cell activation. Many tumors can upregulate expression of PD-L1, inhibiting antitumor T-cell responses and avoiding immune surveillance and elimination. We have identified and characterized MEDI4736, a human IgG1 monoclonal antibody that binds with high affinity and specificity to PD-L1 and is uniquely engineered to prevent antibody-dependent cell-mediated cytotoxicity. In vitro assays demonstrate that MEDI4736 is a potent antagonist of PD-L1 function, blocking interaction with PD-1 and CD80 to overcome inhibition of primary human T-cell activation. In vivo MEDI4736 significantly inhibits the growth of human tumors in a novel xenograft model containing coimplanted human T cells. This activity is entirely dependent on the presence of transplanted T cells, supporting the immunological mechanism of action for MEDI4736. To further determine the utility of PD-L1 blockade, an anti-mouse PD-L1 antibody was investigated in immunocompetent mice. Here, anti-mouse PD-L1 significantly improved survival of mice implanted with CT26 colorectal cancer cells. The antitumor activity of anti-PD-L1 was enhanced by combination with oxaliplatin, which resulted in increased release of HMGB1 within CT26 tumors. Taken together, our results demonstrate that inhibition of PD-L1 function can have potent antitumor activity when used as monotherapy or in combination in preclinical models, and suggest it may be a promising therapeutic approach for the treatment of cancer. MEDI4736 is currently in several clinical trials both alone and in combination with other agents, including anti-CTLA-4, anti-PD-1, and inhibitors of IDO, MEK, BRAF, and EGFR.

Nicotine improves sustained attention in mice: evidence for involvement of the alpha7 nicotinic acetylcholine receptor.

In humans, nicotine has been shown to improve attention in both normal and impaired individuals. Observations in rats reflect some, but not all aspects of the nicotine-induced improvements in humans. To date these findings have not been replicated in mice. To examine the effect of nicotine on sustained attention in mice, we have established a version of the 5-choice serial reaction-time (5-CSR) task with graded levels of difficulty, based upon spatial displacement and a variable intertrial interval. Using this paradigm, microgram doses of nicotine produced a consistent reduction in the level of omissions and an improvement in proportion correct in normal mice. This improvement in sustained attention was made irrespectively of whether mice had previously received nicotine. In an attempt to elucidate which nicotinic acetylcholine receptor (nAChR) subtype(s) mediate this effect, we examined the performance of alpha7 nAChR knockout (KO) mice in the 5-CSR task. alpha7 nAChR KO mice not only acquired the task more slowly than their wild-type littermates, but on attaining asymptotic performance, they exhibited a higher level of omissions. In conclusion, by increasing the level of task difficulty, the performance of mice was maintained at sufficiently low levels to allow a demonstrable improvement in performance upon nicotine administration. Furthermore, as alpha7 KO mice are clearly impaired in the acquisition and asymptotic performance of this task, the alpha7 nAChR may be involved in mediating these effects of nicotine.

Age-related changes in tolerance to the marine algal excitotoxin domoic acid.

During an incident of toxic mussel poisoning, the epileptogenic excitotoxin domoic acid (DOM) was associated with lasting neurological deficits mainly in older patients (), suggesting supersensitivity to excitotoxins is a feature of brain aging. Here, hippocampal slices from young (3 months) and aged (26-29 months) Sprague Dawley rats were assessed by CA1 field potential analysis before and after preconditioning with DOM. In naïve slices from young animals, DOM produced initial hyperexcitability followed by significant dose-dependent reductions in population spike amplitude during prolonged application. Following toxin washout, only small changes in neuronal activity were evident during a second application of DOM, suggesting that a resistance to the effects of DOM occurs in hippocampal slices which have undergone prior exposure to DOM. This inducible tolerance was not antagonized by the NMDA receptor blockers APV or MK-801, nor was it diminished by the group I, II or III mGluR blockers AIDA, CPPG and EGLU. Likewise, neither the AMPA/KA blocker CNQX nor the VSCC blocker nifedipine were effective in blocking tolerance induction in young slices. Field potential analysis revealed significant age-related reductions in CA1 EPSP strength, population spike amplitude and paired-pulse inhibition, but aged slices did not differ in sensitivity to DOM relative to young. However, aged CA1 failed to exhibit any tolerance to DOM following preconditioning, suggesting that a loss of inducible neuroprotective mechanisms may account for increased sensitivity to excitotoxins during aging.

A novel insulin receptor-signaling platform and its link to insulin resistance and type 2 diabetes.

Insulin-induced insulin receptor (IR) tyrosine kinase activation and insulin cell survival responses have been reported to be under the regulation of a membrane associated mammalian neuraminidase-1 (Neu1). The molecular mechanism(s) behind this process is unknown. Here, we uncover a novel Neu1 and matrix metalloproteinase-9 (MMP-9) cross-talk in alliance with neuromedin B G-protein coupled receptor (GPCR), which is essential for insulin-induced IR activation and cellular signaling. Neu1, MMP-9 and neuromedin B GPCR form a complex with IRß subunit on the cell surface. Oseltamivir phosphate (Tamiflu®), anti-Neu1 antibodies, broad range MMP inhibitors piperazine and galardin (GM6001), MMP-9 specific inhibitor (MMP-9i), and GPCR neuromedin B specific antagonist BIM-23127 dose-dependently inhibited Neu1 activity associated with insulin stimulated rat hepatoma cells (HTCs) that overly express human IRs (HTC-IR). Tamiflu, anti-Neu1 antibodies and MMP-9i attenuated phosphorylation of IRß and insulin receptor substrate-1 (IRS1) associated with insulin-stimulated cells. Olanzapine, an antipsychotic agent associated with insulin resistance, induced Neu3 sialidase activity in WG544 or 1140F01 human sialidosis fibroblast cells genetically defective in Neu1. Neu3 antagonist 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA) and anti-Neu3 antibodies inhibited sialidase activity associated with olanzapine treated murine Neu4 knockout macrophage cells. Olanzapine attenuated phosphorylation of IGF-R and IRS1 associated with insulin-stimulated human wild-type fibroblast cells. Our findings identify a novel insulin receptor-signaling platform that is critically essential for insulin-induced IRß tyrosine kinase activation and cellular signaling. Olanzapine-induced Neu3 sialidase activity attenuated insulin-induced IGF-R and IRS1 phosphorylation contributing to insulin resistance.

Pattern of clinical genetics referral following perinatal postmortems.

Fetal loss can be spontaneous or induced following findings on the anomaly scan. This study aims to (1) ascertain referral rates and patterns of referral to clinical genetics (CG) triggered by postmortem (PM) findings and (2) improve the quality of care offered to those families at risk of recurrence. A review of all PM reports during 2007 and 2008 was undertaken. We collected clinical and demographic information on all those cases in which a recommendation for referral had been or should have been made. During the study period, 549 PMs were conducted, of which 72 (13%) had a recommendation for referral to CG. A further 30 (5%) cases were identified in which a recommendation for referral to CG should have been made. Of the 72 cases with a recommendation for referral to CG, 54 cases were identified within the catchment area. Of these, 29 (54%) resulted in a referral to Sheffield CG, with an average of 17 weeks' waiting time for referral. In >90% of cases it was possible to clarify diagnosis and offer additional information. A small proportion of families declined referral to CG. By mapping the process from PM report to potential referral to CG, we have been able to highlight areas of clinical concern and improve clinical practice. This study has also enabled us to gain a better understanding of the patient referral and clinical care pathways involved. This, in turn, has provided a clinical focus within the joint histopathology-genetics multidisciplinary meetings to enable discussion of potential referrals.