Comparison of accuracy and reliability of working length determination using cone beam computed tomography and electronic apex locator: a systematic review

Aim: To compare the accuracy and reliability of cone beam computed tomography (CBCT) and electronic apex locator (EAL) in determining working length (WL). Background: A comprehensive literature search was conducted across several databases and grey literature. 1358 potentially relevant journal articles were identified with publication dates ranging from 1996-2017. After screening and applying the inclusion and exclusion criteria, five studies were identified as eligible for review. Data extraction was completed in two blinded pairs, cross-referenced and subsequently merged. Discrepancies were resolved through collaborator mediation. Meta-analysis was not undertaken due to heterogeneity between included studies. Review Results: In all five studies, no statistically significant difference was found between CBCT and EAL measurements of WL. The reliability of CBCT compared with EAL was not determined. Conclusion: Due to significant heterogeneity between the included studies, the accuracy of CBCT compared to EAL couldn't be determined. Based on limited evidence, CBCT appeared to be as accurate as EAL. There was weak evidence suggesting that CBCT was reliable. Also the superiority of one method over the other couldn’t be determined. These results should be interpreted judiciously. Further research is required to conclusively evaluate the accuracy and reliability of CBCT compared with EAL. Clinical significance: Pre-existing CBCT scans may be appropriate for W

Age and gender correlation of gonial angle, ramus height and bigonial width in dentate subjects in a dental school in Far North Queensland

Background: This study aimed to determine if mandibular parameters (gonial angle, bigonial width and ramus height) measured from panoramic radiographs, can be used to determine a correlation with an individual’s age and gender in dentate subjects in Far North Queensland. Material and Methods: The study utilised 2699 randomly selected panoramic radiographs of patients between the ages of 19-69 years, from which 220 fulfilled the inclusion criteria. Each panoramic radiograph was analysed and the above three parameters recorded and measured. These values were collated into appropriate age and gender groups and subjected to statistical analysis. Results: The mean age of the participants was 44.1±14.41, with males being shown to have a statistically significant larger ramus height and bigonial width than females ( P <0.0001 for both). Females, on the other hand, were shown to have a significantly larger gonial angle than males ( P <0.0002). General trends revealed gonial angle to increase with age, whilst bigonial width and ramus height were shown to decrease with age. Conclusions: The assessment of mandibular morphology through radiographic measurements may be useful in estimating an individual’s age and gender when comparing to a known population standar

Comparative Immunogenicity of Na-GST-1 Human Hookworm Vaccine with Synthetic Glucopyranosyl Lipid Adjuvant (GLA) in BALB/c Mice

More than 740 million people worldwide are infected with Hookworm. Hookworm infection is most prevalent in the poorest of the poor populations of the world, and has serious health effects. Hookworm infection causes blood loss leading to iron deficiency anemia and protein energy malnutrition, which results in a compromised immune response. Consequently, the target human population suffers from an increased susceptibility to infectious diseases including hookworm infection. We have developed recombinant adult hookworm vaccines against hookworm infection to break this vicious cycle. Toll-like receptor (TLR) 4 agonist are known to boost immune response in healthy and immunocompromised individuals. We believe that co-injecting Synthetic Glucopyranosyl Lipid Adjuvant (GLA) a novel TLR-4 agonist with adult hookworm Na-GST-1 + Alhydrogel® vaccine will produce a robust and sustainable immune response in this target human population. Here, we discuss the rationale of using GLA, study designs and the results of the pre-clinical immunogenicity studies of the Human Hookworm Na-GST-1 + Alhydrogel® Vaccine in BALB/c mice with and without GLA. We conclude that, GLA enhanced the immunogenicity of co-administered adult hookworm Na-GST-1 + Alhydrogel® vaccine, producing a strong anti-Na-GST-1 IgG response. These preclinical results lay the foundation of co-administrating GLA with adult hookworm Na-GST-1 + Alhydrogel® vaccine in Phase 1 clinical trial in Brazil

Potency Testing for NTD Vaccines: Determining Relative Potency for the Na-GST-1 Human Hookworm Vaccine

Over the next decade, a new generation of vaccines will target the neglected tropical diseases (NTDs) . The goal of most NTD vaccines will be to reduce the morbidity and decrease the chronic debilitating nature of these often-forgotten infections - outcomes that are hard to measure in the traditional potency-testing paradigm . The absence of measurable correlates of protection, a lack of permissive animal models for lethal infection, and a lack of clinical indications that do not include the induction of sterilizing immunity required us to reconsider the traditional bioassay methods for determining vaccine potency . Owing to these limitations, potency assay design for NTD vaccines will increasingly rely on a paradigm where potency testing is one among many tools to ensure that a manufacturing process yields a product of consistent quality . This potency test is a bioassay using BALB/c mice, which evaluates the immunogenicity of the vaccine at set time interval post manufacture . Herein, we discuss the results of 12 month potency testing of Necator americanus-glutathione-S- transferase-1 (Na-GST-1) vaccine . The Effective Dose 50 (ED50), with its 95% fiducial limits (FL) for each time point was determined along with the Relative Potency with its 95% FL for 3, 6, 9 and 12 months post manufacture . Potency testing has shown that storage at 4° C decreases the ED50 and increases the relative potency of Na-GST-1 vaccine . We proposed that the change in ED50 and relative potency coincide with higher affinity binding of the Na-GST-1 to the Alhydrogel® that occurred during storage at 4° C . These preclinical results lay the foundation for moving forward with Phase 1 clinical trial in Brazil

Vaccination with Human Hookworm Vaccine Necator americanus Aspartic Protease-1 M74 Generates Neutralizing Antibodies and a Potent Immune Response in BALB/c Mice

Backgound: Human Hookworm Infection, a neglected tropical disease infects more than 600 million people around the world. Hookworms ingest hemoglobin containing erythrocytes and Necator americanus Aspartic Protease-1 wild type (Na-APR-1wt) a hemoglobinase cleaves hemoglobin to form Heme and Globin. Globin is further digested by other gut enzymes and the nutritional end products are absorbed by the hookworm’s gut wall. Also, Heme which is toxic to hookworm is detoxified by the Necator americanus Glutathione Transferase-1 (Na-GST-1) a detoxification enzyme secreted by the gut of the hookworm. Necator americanus Aspartic Protease-1 M74 (Na-APR-1 M74) is the new vaccine for the Human Hookworm Infection which is currently under pre-clinical development. Na-APR-1 M74 vaccine is an Alhydrogel® adjuvanted vaccine containing the mutant form of the Na-APR-1wt. Neutralizing Na-APR-1wt by potent antibodies (IgG) in the vaccinees will block the initiation of the hemoglobin digestion cascade and starve the hookworms from essential nutrition, leading to their death. Here, we report the results of the neutralizing capacity of antibodies and potency (immunogenicity) of Na-APR-1 M74 vaccine in BALB/c mice. Methods: Serum for IgG was generated by vaccinating BALB/c mice twice subcutaneously with Na-APR-1 M74 an enzymatically inactive mutant form of Na-APR-1wt formulated with Alhydrogel®. Assessment of neutralizing capacity of IgG was performed using the standard Cathepsin-D protease assay using MOCAc substrate. Dose response (% Inhibition vs Dose) was assessed using linear regression analysis. Potency testing of the Na-APR-1M74 clinical drug product was performed by standard bioassay. Median Effective Dose 50 (ED50) with the 95% fiducial limits (95%FL) was estimated using Probit Analysis (SAS® 9.3). Also, Relative Potency (RP) was estimated by the methods described in European Pharmacopeia\u27s Chapter 5.3. Results: Five microgram of IgG neutralized 51.06% of the enzymatic activity of 250ng of Na-APR-1wt. An excellent dose response was also observed. ED50 of 14.15μg (95%FL = 10.47μg -- 18.93μg) and 11.46μg (95%FL = 4.86μg --27.42μg) was estimated for time 1 and 7 month post manufacture respectively. RP at 7 months was found to be 1.23 (95%FL = 0.792--1.917). Conclusion: These preclinical results of the Na-APR-1 M74 vaccine lay the foundation for a Phase 1 Clinical Trial in USA and Brazil. This Na-APR-1 M74 vaccine will be subsequently combined with Necator americanus Glutathione transferase-1 (Na-GST-1) vaccine to form a multivalent human hookworm vaccine

Bullets over ballots: Islamist groups, the state and electoral violence in Egypt and Morocco

This article is concerned with state-sponsored electoral violence in liberalized autocracies. The first section of the paper identifies a number of variables that can help explain the decision calculus of authoritarian incumbents to deploy force against strong electoral challengers. The second section then examines these propositions with reference to Egypt and Morocco. Drawing on recent parliamentary elections in both countries the article questions why, despite facing the challenge of political Islam, the two regimes differed so markedly in their willingness to manipulate the polls by recourse to violence. Whilst the Egyptian authorities decided to abrogate all pretence of peaceful elections in favour of violent repression against the Muslim Brotherhood candidates and sympathizers, no such tactics were deployed by the ruling elite in Morocco. We suggest that three principal factors influenced the regimes' response to this electoral challenge: (1) the centrality of the elected institution to authoritarian survival; (2) the availability of alternative electioneering tools; and (3) the anticipated response of the international community. The article concludes by suggesting that in order to understand better when and how states deploy violence in elections, we need to focus on a more complex set of factors rather than simply on the electoral potency of key opposition challengers or the authoritarian nature of the state

Nivolumab With or Without Ipilimumab in Pediatric Patients With High-Grade CNS Malignancies: Safety, Efficacy, Biomarker, and Pharmacokinetics: CheckMate 908

BACKGROUND: Therapeutic options are limited in pediatric CNS malignancies. CheckMate 908 (NCT03130959) is an open-label, sequential-arm, phase 1b/2 study investigating nivolumab (NIVO) and NIVO+ipilimumab (IPI) in pediatric patients with high-grade CNS malignancies. METHODS: Patients (N=166) in 5 cohorts received NIVO 3 mg/kg every 2 weeks (Q2W) or NIVO 3 mg/kg+IPI 1 mg/kg every 3 weeks (4 doses) followed by NIVO 3 mg/kg Q2W. Primary endpoints included overall survival (OS; newly diagnosed diffuse intrinsic pontine glioma [DIPG]) and progression-free survival (PFS; other recurrent/progressive or relapsed/resistant CNS cohorts). Secondary endpoints included other efficacy metrics and safety. Exploratory endpoints included pharmacokinetics and biomarker analyses. RESULTS: As of January 13, 2021, median OS (80% CI) was 11.7 (10.3-16.5) and 10.8 (9.1-15.8) months with NIVO and NIVO+IPI, respectively, in newly diagnosed DIPG. Median PFS (80% CI) with NIVO and NIVO+IPI was 1.7 (1.4-2.7) and 1.3 (1.2-1.5) months, respectively, in recurrent/progressive high-grade glioma; 1.4 (1.2-1.4) and 2.8 (1.5-4.5) months in relapsed/resistant medulloblastoma; and 1.4 (1.4-2.6) and 4.6 (1.4-5.4) months in relapsed/resistant ependymoma. In patients with other recurrent/progressive CNS tumors, median PFS (95% CI) was 1.2 (1.1-1.3) and 1.6 (1.3-3.5) months, respectively. Grade 3/4 treatment-related adverse-event rates were 14.1% (NIVO) and 27.2% (NIVO+IPI). NIVO and IPI first-dose trough concentrations were lower in youngest and lowest-weight patients. Baseline tumor programmed death ligand 1 expression was not associated with survival. CONCLUSIONS: NIVO±IPI did not demonstrate clinical benefit relative to historical data. The overall safety profiles were manageable with no new safety signals

“It Happens to Girls All the Time”: Examining Sexual Assault Survivors’ Reasons for Not Using Campus Supports

Sexual assault is a prevalent problem in higher education, and despite the increasing availability of formal supports on college campuses, few sexual assault survivors use them. Experiencing sexual assault can have devastating consequences on survivors’ psychological and educational wellbeing, which may intensify if survivors do not receive adequate care. Drawing from existing theoretical frameworks and empirical research, this study used a mixed methodological approach to examine why survivors did not use three key campus supports—the Title IX Office, the sexual assault center, and housing staff—and if these reasons differed across the three supports. Using data from 284 women who experienced sexual assault in college, our qualitative findings identified four overarching themes, including logistical issues (e.g., lacking time and knowledge), feelings, beliefs, and responses that made it seem unacceptable to use campus supports, judgments about the appropriateness of the support, and alternative methods of coping. Quantitative findings revealed that survivors’ reasons for not seeking help differed across supports. Collectively, our findings suggest that community norms and institutional policies can make it challenging for survivors to use campus supports. We propose several suggestions for institutional change (e.g., taking a stronger stance against “less serious” forms of sexual assault, reducing a quasi‐criminal justice approach to investigation and adjudication, limiting mandated reporting).HighlightsIdentifies reasons why college students who experience sexual assault do not use formal sources of support on campus.Examines how reasons for not using formal supports differ across sources of support: Title IX Office, sexual assault center, and housing staff.Provides an in‐depth, contextual understanding of sexual assault survivors’ use and avoidance of campus supports in the wake of substantial policy change.Contributes recommendations for institutional policy and practice based on findings, including taking a stronger stance against “less serious” forms of sexual assault, reducing a quasi‐criminal justice approach to investigation and adjudication, and limiting mandated reporting.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136479/1/ajcp12126.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136479/2/ajcp12126_am.pd

The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants

Multiple independent genomic profiling efforts have recently identified clinically and molecularly distinct subgroups of ependymoma arising from all three anatomic compartments of the central nervous system (supratentorial brain, posterior fossa, and spinal cord). These advances motivated a consensus meeting to discuss: (1) the utility of current histologic grading criteria, (2) the integration of molecular-based stratification schemes in future clinical trials for patients with ependymoma and (3) current therapy in the context of molecular subgroups. Discussion at the meeting generated a series of consensus statements and recommendations from the attendees, which comment on the prognostic evaluation and treatment decisions of patients with intracranial ependymoma (WHO Grade II/III) based on the knowledge of its molecular subgroups. The major consensus among attendees was reached that treatment decisions for ependymoma (outside of clinical trials) should not be based on grading (II vs III). Supratentorial and posterior fossa ependymomas are distinct diseases, although the impact on therapy is still evolving. Molecular subgrouping should be part of all clinical trials henceforth

Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause.

Most aldosterone-producing adenomas (APAs) have gain-of-function somatic mutations of ion channels or transporters. However, their frequency in aldosterone-producing cell clusters of normal adrenal gland suggests a requirement for codriver mutations in APAs. Here we identified gain-of-function mutations in both CTNNB1 and GNA11 by whole-exome sequencing of 3/41 APAs. Further sequencing of known CTNNB1-mutant APAs led to a total of 16 of 27 (59%) with a somatic p.Gln209His, p.Gln209Pro or p.Gln209Leu mutation of GNA11 or GNAQ. Solitary GNA11 mutations were found in hyperplastic zona glomerulosa adjacent to double-mutant APAs. Nine of ten patients in our UK/Irish cohort presented in puberty, pregnancy or menopause. Among multiple transcripts upregulated more than tenfold in double-mutant APAs was LHCGR, the receptor for luteinizing or pregnancy hormone (human chorionic gonadotropin). Transfections of adrenocortical cells demonstrated additive effects of GNA11 and CTNNB1 mutations on aldosterone secretion and expression of genes upregulated in double-mutant APAs. In adrenal cortex, GNA11/Q mutations appear clinically silent without a codriver mutation of CTNNB1