Improved surrogates in inertial confinement fusion with manifold and cycle consistencies.

Neural networks have become the method of choice in surrogate modeling because of their ability to characterize arbitrary, high-dimensional functions in a data-driven fashion. This paper advocates for the training of surrogates that are 1) consistent with the physical manifold, resulting in physically meaningful predictions, and 2) cyclically consistent with a jointly trained inverse model; i.e., backmapping predictions through the inverse results in the original input parameters. We find that these two consistencies lead to surrogates that are superior in terms of predictive performance, are more resilient to sampling artifacts, and tend to be more data efficient. Using inertial confinement fusion (ICF) as a test-bed problem, we model a one-dimensional semianalytic numerical simulator and demonstrate the effectiveness of our approach.

Critical analysis of the reporting quality of randomized trials within Endodontics using the Preferred Reporting Items for RAndomized Trials in Endodontics (PRIRATE) 2020 quality standard checklist.

AIM: To critically evaluate the reporting quality of a random sample of clinical trials published in Endodontics against the PRIRATE 2020 checklist and to analyse the association between the quality of reported trials and a variety of parameters. METHODOLOGY: Fifty randomized clinical trials relating to Endodontics were randomly selected from the PubMed database from 2015 to 2019 and evaluated by two independent reviewers. For each trial, a score of '1' was awarded when it fully reported each item in the PRIRATE guidelines whereas a score of '0' was awarded when an item was not reported; when the item was reported inadequately a score of '0.5' was awarded. For the items that were not relevant to the trial, 'Not Applicable (NA)' was given. Based on the interquartile range of the overall scores received, trials were categorized into 'Low' (0-58.4%), 'Moderate' (58.5-72.8%) and 'High' (72.9-100%) quality. The associations between characteristics and quality of clinical trials were investigated. Descriptive statistics, frequency analysis and percentage analyses were used to describe the data. To determine the significance of categorical data, the chi-square test was used. The probability value 0.05 was considered as the level of significance. RESULTS: Based on the overall scores, 13 (26%), 25(50%) and 12 (24%) of the reports of clinical trials were categorized as 'High', 'Moderate' and 'Low' quality, respectively. Three items (1b, 6d, 11e) were adequately reported in all manuscripts whilst two items (5k, 5m) were scored 'NA' in all the reports. The reports published from Europe had a significantly greater percentage of 'High'-quality scores, compared to Asia, Middle East, North America and South America (P = 0.0002). The 'High'-quality reports were published significantly more often in impact factor journals (P = 0.045). Reports of clinical trials published in journals that adhered to the CONSORT guidelines had significantly more 'High' scores compared to those that did not (P = 0.008). Clinical trials with protocols registered a priori had a significantly greater percentage of 'High' scores compared to the trials that were not registered in advance (P = 0.003). No significant difference occurred between the quality of clinical trials and the number of authors, journal (Endodontic specialty vs. Non-Endodontic specialty) or year of publication. CONCLUSIONS: Reports of randomized clinical trials published in the speciality of Endodontics had a substantial number of deficiencies. To create high-quality reports of clinical trials, authors should comply with the PRIRATE 2020 guidelines.

PRIASE 2021 guidelines for reporting animal studies in Endodontology: explanation and elaboration.

Laws and ethics require that before conducting human clinical trials, a new material, device or drug may have to undergo testing in animals in order to minimize health risks to humans, unless suitable supporting grandfather data already exist. The Preferred Reporting Items for Animal Studies in Endodontology (PRIASE) 2021 guidelines were developed exclusively for the specialty of Endodontology by integrating and adapting the ARRIVE (Animals in Research: Reporting In Vivo Experiments) guidelines and the Clinical and Laboratory Images in Publications (CLIP) principles using a validated consensus-based methodology. Implementation of the PRIASE 2021 guidelines will reduce potential sources of bias and thus improve the quality, accuracy, reproducibility, completeness and transparency of reports describing animal studies in Endodontology. The PRIASE 2021 guidelines consist of a checklist with 11 domains and 43 individual items and a flowchart. The aim of the current document is to provide an explanation for each item in the PRIASE 2021 checklist and flowchart and is supplemented with examples from the literature in order for readers to understand their significance and to provide usage guidance. A link to the PRIASE 2021 explanation and elaboration document and PRIASE 2021 checklist and flowchart is available on the Preferred Reporting Items for study Designs in Endodontology (PRIDE) website (http://pride-endodonticguidelines.org/priase/).

PRIASE 2021 guidelines for reporting animal studies in Endodontology: a consensus-based development.

Animal testing is crucial in situations when research on humans is not allowed because of unknown health risks and ethical concerns. The current project aims to develop reporting guidelines exclusively for animal studies in Endodontology, using an established consensus-based methodology. The guidelines have been named: Preferred Reporting Items for Animal Studies in Endodontology (PRIASE) 2021. Nine individuals (PD, VN, AK, PM, MN, JF, EP, JJ and SJ), including the project leaders (PD, VN) formed a steering committee. The steering committee developed a novel checklist by adapting and integrating their animal testing and peer review experience with the Animals in Research: Reporting In Vivo Experiments (ARRIVE) guidelines and also the Clinical and Laboratory Images in Publications (CLIP) principles. A PRIASE Delphi Group (PDG) and PRIASE Online Meeting Group (POMG) were also formed. Thirty-one PDG members participated in the online Delphi process and achieved consensus on the checklist items and flowchart that were used to formulate the PRIASE guidelines. The novel PRIASE 2021 guidelines were discussed with the POMG on 9 September 2020 via a Zoom online video call attended by 21 individuals from across the globe and seven steering committee members. Following the discussions, the guidelines were modified and then piloted by several authors whilst writing a manuscript involving research on animals. The PRIASE 2021 guidelines are a checklist consisting of 11 domains and 43 individual items together with a flowchart. The PRIASE 2021 guidelines are focused on improving the methodological principles, reproducibility and quality of animal studies in order to enhance their reliability as well as repeatability to estimate the effects of endodontic treatments and usefulness for guiding future clinical studies on humans.

PRIRATE 2020 guidelines for reporting randomized trials in Endodontics: explanation and elaboration.

Well-designed and properly conducted randomized clinical trials provide a true estimate of the effects of interventions and are acknowledged as the gold standard in terms of clinical study design. However, the quality of randomized clinical trials published in the field of Endodontics is suboptimal. The Preferred Reporting Items for RAndomized Trials in Endodontics (PRIRATE) 2020 guidelines were developed exclusively for Endodontics by integrating and adapting the CONsolidated Standards of Reporting Trials (CONSORT) statement and Clinical and Laboratory Images in Publications (CLIP) principles, through an accepted and well-documented consensus process. Full implementation of the PRIRATE 2020 guidelines will minimize potential sources of bias and thus enhance the standard of manuscripts submitted for publication, which will ultimately improve the reporting of randomized clinical trials in Endodontics. The aim of this document is to provide an explanation for each item in the PRIRATE 2020 checklist and flowchart with examples from the literature in order to help authors understand their rationale and significance. A link to this PRIRATE 2020 explanation and elaboration document is available on the Preferred Reporting Items for study Designs in Endodontology (PRIDE) website at http://www.pride-endodonticguidelines.org/prirate/.

PRICE 2020 guidelines for reporting case reports in Endodontics: explanation and elaboration.

Case reports play a key role in showcasing new, unusual or rare disease(s), and the impact of newer therapeutic approaches or interventions. The Preferred Reporting Items for Case reports in Endodontics (PRICE) 2020 guidelines are being introduced exclusively for Endodontics by adapting and integrating the CAse REport (CARE) guidelines and Clinical and Laboratory Images in Publications principles. The PRICE 2020 guidelines have been developed to help authors improve the completeness, accuracy and transparency of case reports in Endodontics and thus enhance the standard of manuscripts submitted for publication. The aim of this document is to provide a comprehensive explanation for each item in the PRICE 2020 checklist along with examples from the literature that demonstrate compliance with these guidelines. This information will highlight the importance of each item and provide practical examples to help authors understand the necessity of providing comprehensive information when preparing case reports. A link to this PRICE 2020 explanation and elaboration document is available on the Preferred Reporting Items for study Designs in Endodontology website at http://www.pride-endodonticguidelines.org.

PRICE 2020 guidelines for reporting case reports in Endodontics: a consensus-based development.

Case reports can provide early information about new, unusual or rare disease(s), newer treatment strategies, improved therapeutic benefits and adverse effects of interventions or medications. This paper describes the process that led to the development of the Preferred Reporting Items for Case reports in Endodontics (PRICE) 2020 guidelines through a consensus-based methodology. A steering committee was formed with eight members (PD, VN, BC, PM, PS, EP, JJ and SP), including the project leaders (PD, VN). The steering committee developed an initial checklist by combining and modifying the items from the Case Report (CARE) guidelines and Clinical and Laboratory Images in Publications (CLIP) principles. A PRICE Delphi Group (PDG) and PRICE Face-to-Face Meeting Group (PFMG) were then formed. The members of the PDG were invited to participate in an online Delphi process to achieve consensus on the wording and utility of the checklist items and the accompanying flow chart that was created to complement the PRICE 2020 guidelines. The revised PRICE checklist and flow chart developed by the online Delphi process was discussed by the PFMG at a meeting held during the 19th European Society of Endodontology (ESE) Biennial Congress in Vienna, Austria, in September 2019. Following the meeting, the steering committee created a final version of the guidelines, which were piloted by several authors during the writing of a case report. In order to help improve the clarity, completeness and quality of case reports in Endodontics, we encourage authors to use the PRICE 2020 guidelines.

Preferred Reporting items for OBservational studies in Endodontics (PROBE) guidelines: a development protocol.

Observational studies have a significant role in establishing the prevalence and incidence of diseases in populations, as well as determining the benefits and risks associated with health-related interventions. Observational studies principally encompass cohort, case-control, case series and cross-sectional designs. Inadequate reporting of observational studies is likely to have a negative impact on decision-making in day-to-day clinical practice; however, no reporting guidelines have been published for observational studies in Endodontics. The aim of this project is to develop reporting guidelines for authors when creating manuscripts describing observational studies in the field of Endodontology in an attempt to improve the quality of publications. The new guidelines for observational studies will be named: 'Preferred Reporting items for OBservational studies in Endodontics (PROBE)'. A steering committee was formed by the project leaders (PD, VN) to develop the guidelines through a five-phase consensus process. The steering committee will review and adapt items from the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement and the Clinical and Laboratory Images in Publications (CLIP) principles, as well as identify new items that add value to Endodontics. The steering committee will create a PROBE Delphi Group (PDG), consisting of 30 members across the globe to review and refine the draft checklist items and flowchart. The items will be assessed by the PDG on a nine-point Likert scale for relevance and inclusion. The agreed items will then be discussed by a PROBE Face-to-Face meeting group (PFMG) made up of 20 individuals to further refine the guidelines. After receiving feedback from the PFMG, the steering committee will pilot and finalize the guidelines. The approved PROBE guidelines will be disseminated through publication in relevant journals, and be presented at national and international conferences. The PROBE checklist and flowchart will be available and downloadable from the Preferred Reporting Items for study Designs in Endodontics (PRIDE) website: www.pride-endodonticguidelines.org. The PROBE steering committee encourages clinicians, researchers, editors and peer reviewers to provide feedback on the PROBE guidelines to inform the steering group when the guidelines are updated.

PRIRATE 2020 guidelines for reporting randomized trials in Endodontics: a consensus-based development.

In evidence-based health care, randomized clinical trials provide the most accurate and reliable information on the effectiveness of an intervention. This project aimed to develop reporting guidelines, exclusively for randomized clinical trials in the dental specialty of Endodontology, using a well-documented, validated consensus-based methodology. The guidelines have been named Preferred Reporting Items for RAndomized Trials in Endodontics (PRIRATE) 2020. A total of eight individuals (PD, VN, HD, LB, TK, JJ, EP and SP), including the project leaders (PD and VN) formed a steering committee. The committee developed a checklist based on the items in the Consolidated Standards of Reporting Trials (CONSORT) guidelines and Clinical and Laboratory Images in Publications (CLIP) principles. A PRIRATE Delphi Group (PDG) and PRIRATE Face-to-Face Meeting group (PFMG) were also formed. Thirty PDG members participated in the online Delphi process and achieved consensus on the checklist items and flowchart that make up the PRIRATE guidelines. The guidelines were discussed at a meeting of the PFMG at the 19th European Society of Endodontology (ESE) Biennial congress, held on 13 September 2019 in Vienna, Austria. A total of 21 individuals from across the globe and four steering committee members (PD, VN, HD and LB) attended the meeting. As a consequence of the discussions, the guidelines were modified and then piloted by several authors whilst writing a manuscript. The PRIRATE 2020 guidelines contain a checklist consisting of 11 sections and 58 individual items as well as a flowchart, considered essential for authors to include when writing manuscripts for randomized clinical trials in Endodontics.

Effectiveness of technology-enhanced learning in Endodontic education: a systematic review and meta-analysis.

The aim of the present systematic review was to evaluate the effectiveness of technology-enhanced learning (TEL) in the field of Endodontics to improve educational outcomes compared to traditional learning methods. Randomized controlled studies published in English were identified from two electronic databases (PubMed and Scopus) up to May 2018. Two authors independently performed study selection, data extraction and assessed the risk of bias (ROB). Any teaching method using TEL was considered as the intervention, and this was compared to traditional methods. The outcome measuring the effectiveness of learning activities was evaluated by Kirkpatrick's four-level training evaluation model. The four levels of training outcomes are as follows: Reaction, Learning, Behaviour and Results. A meta-analysis was performed to estimate the standardized mean difference (SMD) by the random effects model. In total, 13 studies were included in the systematic review. Only three studies were assessed as 'low' ROB. A meta-analysis could not be performed in the domains of Reaction and Behaviour. No significant difference was observed in knowledge gain (Learning domain) between TEL and traditional methods (SMD, 0.14 (95% CI -0.10 to 0.39) I2  = 62.7%). Similarly, no difference was observed in performance (Behaviour domain). A variable response was found in attitude (Reaction domain). From the available evidence, it can be concluded that TEL is equally as effective as traditional learning methods.

Preferred Reporting Items for RAndomized Trials in Endodontics (PRIRATE) guidelines: a development protocol.

Randomized clinical trials are acknowledged as the most appropriate methodology for demonstrating the efficacy or effectiveness of one intervention as opposed to another and thus play a major role in clinical decision-making. However, it is recognized that despite the existence of various guidelines, for example, the Consolidated Standards for Reporting Trials (CONSORT) statement, the quality of manuscripts describing randomized trials is often suboptimal. The current project aims to develop and disseminate new guidelines, Preferred Reporting Items for RAndomized Trials in Endodontics (PRIRATE), to improve the planning and reporting quality of randomized trials in the field of Endodontics. The project leads (VN, PD) designed a robust process to develop the PRIRATE guidelines. At first, a steering committee of eight members, including the project leads, was formed. Thereafter, a five-stage consensus process will be followed: initial steps, pre-meeting activities, face-to-face consensus meeting, post-meeting activities and post-publication activities. The steering committee will develop the first draft of the PRIRATE guidelines by identifying relevant and important items from various sources including the CONSORT guidelines and the Clinical and Laboratory Images in Publications (CLIP) principles. This will be followed by the establishment of a PRIRATE Delphi Group (PDG) consisting of 30 members. The individual items of the first draft of the PRIRATE guidelines developed by the steering committee will be evaluated and scored on a 9-point Likert scale by the PDG members. Items with a score of seven and above by more than 70% of PDG members will be included in the second draft of the guidelines, and the Delphi process will be repeated until each item fulfils the set conditions. After obtaining consensus from the PDG, the PRIRATE guidelines will be discussed by 20 selected individuals within a PRIRATE Face-to-face Consensus Meeting Group (PFCMG) to arrive at a final consensus. The final PRIRATE guidelines will be accompanied with an explanation and elaboration document developed by the steering committee and approved by six members, three from the PDG and three from the PFCMG. The PRIRATE guidelines will be published in journals and actively disseminated to educational institutions, national and international academic societies and presented at scientific meetings. The steering committee will periodically revise and update the PRIRATE guidelines based on feedback from stakeholders.

Guidelines for reporting the quality of clinical case reports in Endodontics: a development protocol.

Case reports are used to communicate interesting, new or rare condition/s, innovative treatment approaches or novel techniques. Apart from informing readers, such information has the potential to contribute towards further scientific studies and the development of newer management modalities. In that context, it is important that case reports are presented accurately and deliver all the necessary and pertinent information to the reader. Reporting guidelines are used to inform authors of the quality standards required to ensure their manuscripts are accurate, complete and transparent. The aim of this project is to develop and disseminate new guidelines - Preferred Reporting Items for Case reports in Endodontics (PRICE). The primary aim is to aid authors when constructing case reports in the field of Endodontics to ensure the highest possible reporting standards are adopted. The project leaders (PD and VN) formed a steering committee comprising six additional members. Subsequently, a five-phase consensus process will be used. The steering committee will develop the PRICE guidelines (PRICE checklist and flow chart) by identifying relevant items (quality standards) derived from the CAse REport guidelines and Clinical and Laboratory Images in Publications principles, focussing on the content of case reports. Following this, the steering committee will identify a PRICE Delphi Group (PDG) consisting of 30 members including academicians, practitioners, and members of the public. The individual items (components) of the PRICE checklist will be evaluated by the PDG based on a 9-point Likert scale. Only items scored between 7 and 9 by 70% or more members will be included in the draft checklist. The Delphi process will be continued until a consensus is reached and a final set of items agreed by the PDG members. Following this, a PRICE Face-to-Face meeting group (PFMG) will be formed with 20 members to achieve a final consensus. The final consensus-based checklist and flow chart will be evaluated and approved by selected members of the PDG and PFMG. The approved PRICE guidelines will be published in relevant journals and disseminated via contacts in academic institutions and national endodontic societies, as well as being presented at scientific/clinical meetings.

Preferred Reporting Items for Animal Studies in Endodontology: a development protocol.

The regulated use of animals in endodontic research is often necessary to investigate the biological mechanisms of endodontic diseases and to measure the preclinical efficacy, biocompatibility, toxicology and safety of new treatments, biomaterials, sealers, drugs, disinfectants, irrigants, devices and instruments. Animal testing is most crucial in situations when research on humans is not ethical, practical or has unknown health risks. Currently, there is a wide variability in the quality of manuscripts that report the results of animal studies. Towards the goal of improving the quality of publications, guidelines for preventing disability, pain, and suffering to animals, and enhanced reporting requirements for animal research have been developed. These guidelines are referred to as Animals in Research: Reporting In Vivo Experiments (ARRIVE). Henceforth, causing any form of animal suffering for research purposes is not acceptable and cannot be justified under any circumstances. The present report describes a protocol for the development of welfare and reporting guidelines for animal studies conducted in the specialty of Endodontology: the Preferred Reporting Items for Animal Studies in Endodontology (PRIASE) guidelines. The PRIASE guidelines will be developed by adapting and modifying the ARRIVE guidelines and the Clinical and Laboratory Images in Publication (CLIP) principles. The development of the new PRIASE guidelines will include a five-step consensus process. An initial draft of the PRIASE guidelines will be developed by a steering committee. Each item in the draft guidelines will then be evaluated by members of a PRIASE Delphi Group (PDG) for its clarity using a dichotomous scale (yes or no) and suitability for its inclusion using a 9-point Likert scale. The online surveys will continue until each item achieves this standard, and a set of items are agreed for further analysis by a PRIASE Face-to-face Consensus Meeting Group (PFCMG). Following the consensus meeting, the steering committee will finalize and confirm the PRIASE guidelines taking into account the responses and comments of the PFCMG. The PRIASE guidelines will be published and disseminated internationally and updated periodically based on feedback from stakeholders.

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.

STAT4-associated natural killer cell tolerance following liver transplantation.

OBJECTIVE: Natural killer (NK) cells are important mediators of liver inflammation in chronic liver disease. The aim of this study was to investigate why liver transplants (LTs) are not rejected by NK cells in the absence of human leukocyte antigen (HLA) matching, and to identify a tolerogenic NK cell phenotype. DESIGN: Phenotypic and functional analyses on NK cells from 54 LT recipients were performed, and comparisons made with healthy controls. Further investigation was performed using gene expression analysis and donor:recipient HLA typing. RESULTS: NK cells from non-HCV LT recipients were hypofunctional, with reduced expression of NKp46 (p<0.05) and NKp30 (p<0.001), reduced cytotoxicity (p<0.001) and interferon (IFN)-γ secretion (p<0.025). There was no segregation of this effect with HLA-C, and these functional changes were not observed in individuals with HCV. Microarray and RT-qPCR analysis demonstrated downregulation of STAT4 in NK cells from LT recipients (p<0.0001). Changes in the expression levels of the transcription factors Helios (p=0.06) and Hobit (p=0.07), which control NKp46 and IFNγ expression, respectively, were also detected. Hypofunctionality of NK cells was associated with impaired STAT4 phosphorylation and downregulation of the STAT4 target microRNA-155. Conversely in HCV-LT NK cell tolerance was reversed, consistent with the more aggressive outcome of LT for HCV. CONCLUSIONS: LT is associated with transcriptional and functional changes in NK cells, resulting in reduced activation. NK cell tolerance occurs upstream of major histocompatibility complex (MHC) class I mediated education, and is associated with deficient STAT4 phosphorylation. STAT4 therefore represents a potential therapeutic target to induce NK cell tolerance in liver disease.

KIR haplotypes are associated with late-onset type 1 diabetes in European-American families.

Classical human leukocyte antigens (HLA) genes confer the strongest, but not the only, genetic susceptibility to type 1 diabetes. Killer cell immunoglobulin-like receptors (KIR), on natural killer (NK) cells, bind ligands including class I HLA. We examined presence or absence, with copy number, of KIR loci in 1698 individuals, from 339 multiplex type 1 diabetes families, from the Human Biological Data Interchange, previously genotyped for HLA. Combining family data with KIR copy number information allowed assignment of haplotypes using identity by descent. This is the first disease study to use KIR copy number typing and unambiguously define haplotypes by gene transmission. KIR A1 haplotypes were positively associated with T1D in the subset of patients without the high T1D risk HLA genotype, DR3/DR4 (odds ratio=1.29, P=0.0096). The data point to a role for KIR in type 1 diabetes risk in late-onset patients. In the top quartile (age of onset>14), KIR A2 haplotype was overtransmitted (63.4%, odds ratio=1.73, P=0.024) and KIR B haplotypes were undertransmitted (41.1%, odds ratio=0.70, P=0.0052) to patients. The data suggest that inhibitory 'A' haplotypes are predisposing and stimulatory 'B' haplotypes confer protection in both DR3/DR4-negative and late-onset patient groups.

LILRA6 copy number variation correlates with susceptibility to atopic dermatitis.

Leukocyte immunoglobulin-like receptors (LILR) are expressed mostly on myelomonocytic cells where they are mediators of immunological tolerance. Two LILR genes, LILRA3 and LILRA6, exhibit marked copy number variation. We assessed the contribution of these genes to atopic dermatitis (AD) by analysing transmission in 378 AD families. The data indicated that copies of LILRA6 were over-transmitted to affected patients. They are consistent with a contribution of LILR genes to AD. They could affect the equilibrium between activating and inhibitory signals in the immune response.

2DL1, 2DL2 and 2DL3 all contribute to KIR phenotype variability on human NK cells.

Natural killer (NK) cells are lymphocytes that function as part of the innate immune system. Their activity is controlled by a range of inhibitory and activating receptors, including the important killer-cell immunoglobulin-like receptors (KIR). The KIR are a multi-gene family of receptors that interact with the human leukocyte antigen (HLA) class I family of molecules and are characterised by extensive allelic polymorphism. Their expression on the cell surface of NK cells is highly variable, but the factors responsible for this variability are not yet clearly understood. In the current study, we investigated KIR expression in a healthy human cohort that we had previously characterised in depth at a genetic level, with KIR allele typing and HLA class I ligand genotypes available for all donors (n=198). Allelic polymorphism significantly affected the phenotypic expression of all KIR analysed, whereas HLA ligand background influenced the expression levels of 2DL1 and 2DL3. In particular, we found that although 2DL2 may influence 2DL1 expression, this appears to be owing to variation in 2DL1 copy number. Finally, the inhibitory receptor LILRB1 had higher expression levels in individuals with B/B KIR genotypes, suggesting a possible relationship between KIR and non-KIR receptors, which serves to balance NK cell activation potential.

Training calibration-based counterfactual explainers for deep learning models in medical image analysis.

The rapid adoption of artificial intelligence methods in healthcare is coupled with the critical need for techniques to rigorously introspect models and thereby ensure that they behave reliably. This has led to the design of explainable AI techniques that uncover the relationships between discernible data signatures and model predictions. In this context, counterfactual explanations that synthesize small, interpretable changes to a given query while producing desired changes in model predictions have become popular. This under-constrained, inverse problem is vulnerable to introducing irrelevant feature manipulations, particularly when the model's predictions are not well-calibrated. Hence, in this paper, we propose the TraCE (training calibration-based explainers) technique, which utilizes a novel uncertainty-based interval calibration strategy for reliably synthesizing counterfactuals. Given the wide-spread adoption of machine-learned solutions in radiology, our study focuses on deep models used for identifying anomalies in chest X-ray images. Using rigorous empirical studies, we demonstrate the superiority of TraCE explanations over several state-of-the-art baseline approaches, in terms of several widely adopted evaluation metrics. Our findings show that TraCE can be used to obtain a holistic understanding of deep models by enabling progressive exploration of decision boundaries, to detect shortcuts, and to infer relationships between patient attributes and disease severity.