"Time Saved" Calculations to Improve Decision-Making in Progressive Disease Studies.

BACKGROUND: Disease modifying therapies (DMTs) may be most beneficial in early disease, when progression is slow and changes small, with clinical relevance difficult to interpret. OBJECTIVES: Time component tests (TCTs) translate differences between treatments from mean change, vertical distance between longitudinal trajectories, into intuitively understood time saved, horizontal distance between trajectories, which can be readily combined across endpoints in a global TCT (gTCT). DESIGN: The value of composites, time savings estimates, and combination scores to optimize measurement and interpretation of DMTs are demonstrated, along with construction details and simulation studies. SETTING: TCT methods were applied to a randomized phase II clinical trial. PARTICIPANTS: Patients with early Alzheimer's disease (N=332). INTERVENTION: Three treatment groups with AFFITOPE® AD02 and two control groups with aluminum oxyhydroxide, AD04. MEASUREMENTS: The co-primary efficacy outcomes were an adapted ADAS-Cog (aADAS) and adapted ADCS-ADL (aADL), which were optimized composite scales specific to cognitive and functional domains. A composite based on these two scores was the study's prespecified primary outcome. The CDR-sb and standard non-adapted ADCS-ADL and ADAS-Cog scales were prespecified secondary outcomes. RESULTS: The AD04 2 mg group showed some statistically significant effects compared with other study arms. It is unclear whether the observed 3.8-point difference on the composite is clinically meaningful. TCT results show a time savings of 11 months in an 18-month study with AD04 2 mg. CONCLUSION: The relevance of 11 months saved is more universally understood than a mean difference of 3.8 points in the composite outcome. These results suggest that a combination of a composite approach and a time savings interpretation offers a powerful approach for detecting and interpreting disease modifying effects.

Cdk12 maintains the integrity of adult axons by suppressing actin remodeling.

The role of cyclin-dependent kinases (CDKs) that are ubiquitously expressed in the adult nervous system remains unclear. Cdk12 is enriched in terminally differentiated neurons where its conical role in the cell cycle progression is redundant. We find that in adult neurons Cdk12 acts a negative regulator of actin formation, mitochondrial dynamics and neuronal physiology. Cdk12 maintains the size of the axon at sites proximal to the cell body through the transcription of homeostatic enzymes in the 1-carbon by folate pathway which utilize the amino acid homocysteine. Loss of Cdk12 leads to elevated homocysteine and in turn leads to uncontrolled F-actin formation and axonal swelling. Actin remodeling further induces Drp1-dependent fission of mitochondria and the breakdown of axon-soma filtration barrier allowing soma restricted cargos to enter the axon. We demonstrate that Cdk12 is also an essential gene for long-term neuronal survival and loss of this gene causes age-dependent neurodegeneration. Hyperhomocysteinemia, actin changes, and mitochondrial fragmentation are associated with several neurodegenerative conditions such as Alzheimer's disease and we provide a candidate molecular pathway to link together such pathological events.

Gaussian Process-based prediction of memory performance and biomarker status in ageing and Alzheimer's disease-A systematic model evaluation.

Neuroimaging markers based on Magnetic Resonance Imaging (MRI) combined with various other measures (such as genetic covariates, biomarkers, vascular risk factors, neuropsychological tests etc.) might provide useful predictions of clinical outcomes during the progression towards Alzheimer's disease (AD). The use of multiple features in predictive frameworks for clinical outcomes has become increasingly prevalent in AD research. However, many studies do not focus on systematically and accurately evaluating combinations of multiple input features. Hence, the aim of the present work is to explore and assess optimal combinations of various features for MR-based prediction of (1) cognitive status and (2) biomarker positivity with a multi-kernel learning Gaussian process framework. The explored features and parameters included (A) combinations of brain tissues, modulation, smoothing, and image resolution; (B) incorporating demographics & clinical covariates; (C) the impact of the size of the training data set; (D) the influence of dimensionality reduction and the choice of kernel types. The approach was tested in a large German cohort including 959 subjects from the multicentric longitudinal study of cognitive impairment and dementia (DELCODE). Our evaluation suggests the best prediction of memory performance was obtained for a combination of neuroimaging markers, demographics, genetic information (ApoE4) and CSF biomarkers explaining 57% of outcome variance in out-of-sample predictions. The highest performance for Aß42/40 status classification was achieved for a combination of demographics, ApoE4, and a memory score while usage of structural MRI further improved the classification of individual patient's pTau status.

Orifice barriers to prevent coronal microleakage after root canal treatment: systematic review and meta-analysis.

AIMS: This systematic review aimed to compare the efficiency of orifice barriers in preventing coronal microleakage in vitro. METHODS: Articles published in English, German and Chinese were searched for studies describing microleakage assays for the bacterial penetration of root canal-treated teeth in vitro. The final sample included 18 articles for review and meta-analysis. Risk ratios and confidence intervals were determined for dichotomous variables. Ten publications using bacterial leakage models contributed to the meta-analysis. RESULTS: The addition of orifice barriers to a root canal filling was overall effective, shown by risk ratios (RR) and 95% confidence intervals (CI) demonstrating reduced microleakage with glass ionomer cement (GIC) (RR 0.37, 95% CI 0.26-0.53, P < 0.001), resin-modified GIC (RR 0.32, 95% CI 0.15-0.67, P = 0.01), composite resin (RR 0.54, 95% CI 0.38-0.75, P < 0.001), mineral trioxide aggregate (MTA) (RR 0.25, 95% CI 0.12-0.52, P < 0.001) and Cavit (RR 0.23, 95% CI 0.14-0.39, P < 0.001). There were no significant differences between GIC, resin-modified GIC, composite resin and MTA orifice barriers. CONCLUSIONS: Placement of an orifice barrier over the root canal filling is effective in the prevention of coronal microleakage in vitro. Other parameters may also affect the effectiveness of orifice barriers, including thickness and duration of exposure to the oral environment. © 2023 Australian Dental Association.

Endodontic knowledge, attitudes and referral patterns in Australian general dentists.

BACKGROUND: General dental practitioners often perceive root canal treatments as complex, and specialist referrals are commonplace in general dental practice. Therefore, the aim of this study was to better understand the knowledge of Australian general dentists and their attitudes regarding endodontics in general, and specifically (RCT), to highlight barriers and facilitating factors in the provision of endodontic care. METHODS: A combined paper-based and online survey was sent to general dental practitioners. The questionnaire consisted of 27 items, presented as checkboxes and in Likert scale format. Responses were tabled and statistically contrasted using Chi-square tests and linear regression analysis. RESULTS: A significant proportion of surveyed dentists were not confident in their ability to provide endodontic care, specifically root canal treatments (RCT). Confidence depended on factors, such as time in practice, participation in continuing professional development as well as fear of litigation and type of treatment. Other factors such as the availability of appropriate instruments and referral options, had comparatively little impact on practitioner confidence. DISCUSSION: While almost all general dental practitioners (GDPs) surveyed in this study believe RCT is important for improving the long-term retention of a tooth, just over half of the GDPs say they feel confident in their knowledge and provision of root canal treatment procedures.

Dietary patterns are related to cognitive functioning in elderly enriched with individuals at increased risk for Alzheimer's disease.

PURPOSE: To investigate cross-sectional associations between dietary patterns and cognitive functioning in elderly free of dementia. METHODS: Data of 389 participants from the German DELCODE study (52% female, 69 ± 6 years, mean Mini Mental State Score 29 ± 1) were included. The sample was enriched with elderly at increased risk for Alzheimer's disease (AD) by including participants with subjective cognitive decline, mild cognitive impairment (MCI) and siblings of AD patients. Mediterranean and MIND diets were derived from 148 Food Frequency Questionnaire items, and data-driven patterns by principal component analysis (PCA) of 39 food groups. Associations between dietary patterns and five cognitive domain scores were analyzed with linear regression analyses adjusted for demographics (model 1), and additionally for energy intake, BMI, other lifestyle variables and APOe4-status (model 2). For PCA-derived dietary components, final model 3 included all other dietary components. RESULTS: In fully adjusted models, adherence to Mediterranean and MIND diet was associated with better memory. The 'alcoholic beverages' PCA component was positively associated with most cognitive domains. Exclusion of MCI subjects (n = 60) revealed that Mediterranean and MIND diet were also related to language functions; associations with the alcoholic beverages component were attenuated, but most remained significant. CONCLUSION: In line with data from elderly population samples, Mediterranean and MIND diet and some data-derived dietary patterns were related to memory and language function. Longitudinal data are needed to draw conclusions on the putative effect of nutrition on the rate of cognitive decline, and on the potential of dietary interventions in groups at increased risk for AD.

What is of interest in Endodontology? A bibliometric review of research published in the International Endodontic Journal and the Journal of Endodontics from 1980 to 2019.

AIM: To report the most common terminology used in titles of scientific papers published in the International Endodontic Journal (IEJ) and Journal of Endodontics (JOE) between 1980 and 2019 and to identify the most-cited papers in these journals. METHODOLOGY: The Web of Science database was searched to retrieve all the manuscripts published in the IEJ and JOE between 1980 and 2019. The articles were analysed using the VOS viewer software and the terms within the titles extracted. The top-10 terms were categorized according to the number of occurrences and the decade of publication. Maps were created using the text data for each decade of publication. Classic papers were identified when the number of citations was >400. During the same period of time, highly cited studies were identified including the authors, institutions and countries associated with these papers. RESULTS: Terms such as canal, molar and periapical lesion were the most commonly used in titles between 1980 and 1999. The terms instruments, expression, case report and cell were the most often terms used between 2000 and 2019. During the last 10 years, an increase in the number of reviews and papers on cone beam computed tomography occurred. The organizations with the largest number of citations in each decade were University of São Paulo, University College London, Loma Linda University and United States Army. The country with the largest number of citations and greatest number of top 10 and top 100 manuscripts was the United States. A paper had to be associated with more than 167 citations to be included in the top-100 most-cited list; at least 14 papers met the criteria to be categorized as a citation classic (>400 citations). CONCLUSION: While many diverse areas of endodontics have been explored in the last 40 years within the IEJ and JOE, only a relatively few topics are highly cited and can be considered as classics.

A BODIPY-functionalized PdII photoredox catalyst for Sonogashira C-C cross-coupling reactions.

We report for the first time a BODIPY-functionalized dichloro(1,10-phenanthroline)palladium(ii) complex as an efficient photoredox catalyst for the Sonogashira C-C cross-coupling between phenylacetylene derivatives and iodobenzene derivatives with yields up to 92% under visible light illumination at room temperature.

A protocol for developing reporting guidelines for laboratory studies in Endodontology.

Laboratory-based research studies are the most common form of research endeavour and make up the majority of manuscripts that are submitted for publication in the field of Endodontology. The scientific information derived from laboratory studies can be used to design a wide range of subsequent studies and clinical trials and may have translational potential to benefit clinical practice. Unfortunately, the majority of laboratory-based articles submitted for publication fail the peer-review step, because unacceptable flaws or substantial limitations are identified. Even when apparently well-conducted laboratory-based articles are peer-reviewed, they can often require substantial corrections prior to the publication. It is apparent that some authors and reviewers may lack the training and experience to have developed a systematic approach to evaluate the quality of laboratory studies. Occasionally, even accepted manuscripts contain limitations that may compromise interpretation of data. To help authors avoid manuscript rejection and correction pitfalls, and to aid editors/reviewers to evaluate manuscripts systematically, the purpose of this project is to establish and publish quality guidelines for authors to report laboratory studies in the field of Endodontology so that the highest standards are achieved. The new guidelines will be named-'Preferred Reporting Items for Laboratory studies in Endodontology' (PRILE). A steering committee was assembled by the project leads to develop the guidelines through a five-phase consensus process. The committee will identify new items as well as review and adapt items from existing guidelines. The items forming the draft guidelines will be reviewed and refined by a PRILE Delphi Group (PDG). The items will be evaluated by the PDG on a nine-point Likert scale for relevance and inclusion. The agreed items will then be discussed by a PRILE face-to-face consensus meeting group (PFCMG) formed by 20 individuals to further refine the guidelines. This will be subject to final approval by the steering committee. The approved PRILE guidelines will be disseminated through publication in relevant journals, presented at congresses/meetings, and be freely available on a dedicated website. Feedback and comments will be solicited from researchers, editors and peer reviewers, who are invited to contact the steering committee with comments to help them update the guidelines periodically.

Methods for measurement of root canal curvature: a systematic and critical review.

The assessment of root canal curvature is essential for clinical and research purposes. This systematic review presents an overview of the published techniques for the measurement of root canal curvature features using imaging and to provide a critique of their clinical application. A database search in PubMed, PubMed Central, Embase, Scopus, EBSCO Dentistry & Oral Sciences Source and Virtual Health Library was conducted, using appropriate key words to identify measurement methods for root canal curvatures. The search strategy retrieved 10594 records in total, and 31 records fulfilled the inclusion criteria. From 2D image acquisitions, eleven studies measured exclusively the angle of curvature, an additional thirteen measured other curvature features (level, height, radius, length and shape). Seven reports described methods from 3D imaging (CBCT, µCT). Root canal curvatures should be measured, for clinical proposes, to facilitate endodontic treatment planning, and in research, to reduce the risk of selection bias. This review has revealed that there are many methods described in the literature; however, no consensus exists on which method should be used. Some of the methodologies have potential clinical translation, whereas others are suitable for research purpose only, as they require a specific software or radiographic exposure in the mesiodistal direction.

Correlation of CSF- and MRI-Biomarkers and Progression of Cognitive Decline in an Open Label MCI Trial.

BACKGROUND: In several randomized controlled trials (RCT) acetylcholinesterase-inhibitors (AChE-I) were tested in patients with mild cognitive impairment (MCI) but were ineffective in delaying disease progression as determined by neuropsychological testing only. Here we present data from an open label observational extension of a multicenter RCT in order to assess if biomarkers are providing useful additional information about a drug's efficacy. We followed 83 amnestic MCI patients and performed correlational analyses of Aß 1-42 and total-Tau in the cerebrospinal fluid (CSF), hippocampal and amygdala volume at baseline, the total duration of blinded and open label AChE-I treatment and the outcome 24 months after inclusion into the RCT. Twelve out of 83 amnestic MCI (14%) had progressed to Alzheimer's disease (AD). Overall, worsening and disease progression as measured by the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog), Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) and Clinical Dementia Rating (CDR) did not correlate with the duration of AChE-I treatment. However, a specific multidimensional biomarker profile at baseline indicated more reliably than cognitive testing alone progression to AD. We conclude that pharmacological RCTs testing symptomatic treatment effects in MCI should include biomarker assessment.

Lipoxin A4 Attenuates the Inflammatory Response in Stem Cells of the Apical Papilla via ALX/FPR2.

Similar to the onset phase of inflammation, its resolution is a process that unfolds in a manner that is coordinated and regulated by a panel of mediators. Lipoxin A4 (LXA4) has been implicated as an anti-inflammatory, pro-resolving mediator. We hypothesized that LXA4 attenuates or prevents an inflammatory response via the immunosuppressive activity of Stem Cells of the Apical Papilla (SCAP). Here, we report for the first time in vitro that in a SCAP population, lipoxin receptor ALX/FPR2 was constitutively expressed and upregulated after stimulation with lipopolysaccharide and/or TNF-α. Moreover, LXA4 significantly enhanced proliferation, migration, and wound healing capacity of SCAP through the activation of its receptor, ALX/FPR2. Cytokine, chemokine and growth factor secretion by SCAP was inhibited in a dose dependent manner by LXA4. Finally, LXA4 enhanced immunomodulatory properties of SCAP towards Peripheral Blood Mononuclear Cells. These findings provide the first evidence that the LXA4-ALX/FPR2 axis in SCAP regulates inflammatory mediators and enhances immunomodulatory properties. Such features of SCAP may also support the role of these cells in the resolution phase of inflammation and suggest a novel molecular target for ALX/FPR2 receptor to enhance a stem cell-mediated pro-resolving pathway.

Association of manual or engine-driven glide path preparation with canal centring and apical transportation: a systematic review.

The role and effect of glide path preparation in root canal treatment remain controversial. This systematic review aims to compare apical transportation and canal centring of different glide path preparation techniques, with or without subsequent engine-driven root canal preparation. A database search in PubMed, PubMed Central, Embase, Scopus, EBSCO Dentistry & Oral Sciences Source and Virtual Health Library was conducted, using appropriate key words to identify the effect of glide path preparation (or its absence) on apical transportation and canal centring. An assessment for the risk of bias in included studies was carried out. Amongst 2146 studies, 18 satisfied the inclusion criteria. Nine studies assessed glide path preparation per se, comparing apical transportation and canal centring of rotary systems and/or manual files; eleven further investigations examined the efficacy of the glide path prior to final canal preparation with different engine-driven systems. Risk of bias and other study design features with potential influence on study outcomes and clinical implications were assessed. Based on the available evidence, and within the limitation of the studies included, preparation of a glide path using rotary sequences performs similarly (in most of the component studies) or significantly better than manual preparation when assessing apical transportation or canal centring. When compared to the absence of a glide path, canal shaping following glide path preparation was of similar, or significantly better quality, in regard to apical transportation or canal centring.