Antenatal clinical practice guidelines recommend routine assessment of women’s alcohol consumption during pregnancy. The delivery of advice and referral when necessary are also recommended. However, evidence suggests there are barriers to the uptake of best-care guidelines. Effective, cost-effective and affordable implementation strategies are needed to ensure the intended benefits of guidelines are realised through addressing identified barriers. This paper describes the protocol for evaluating the efficiency and affordability of a practice change intervention compared to the usual practice in an implementation trial.The effectiveness of the intervention will be evaluated in a stepped-wedge randomised controlled implementation trial, conducted in an Australian setting. An economic evaluation will be conducted alongside the trial to assess intervention efficiency. A budget impact assessment will be conducted to assess affordability. The prospective trial-based economic evaluation will identify, measure and value key resource and outcome impacts arising from the multi-strategy practice change intervention compared with usual practice. The evaluation will comprise (i) cost-consequence analyses, where a scorecard approach will be used to show the costs and benefits given the multiple primary outcomes included in the trial, and (ii) cost-effectiveness analyses, where the primary outcome will be incremental cost per percent increase in participants reporting receipt of antenatal care for maternal alcohol consumption consistent with the guideline recommendations. Intervention affordability will be evaluated using budget impact assessment and will estimate the financial implications of adoption and diffusion of this implementation strategy from the perspective of relevant fundholders. Results will be extrapolated to estimate the cost and cost-effectiveness of rolling out the model of care.Uptake of clinical guidelines requires practice change support. It is hypothesized that the implementation strategy, if found to be effective, will also be cost-effective, affordable and scalable. This protocol describes the economic evaluation that will address these hypotheses.ACTRN12617000882325. Registered on 16 June 2017Australian and New Zealand Clinical Trials Registry,  Contributions to the literatureResearch has shown the development and dissemination of clinical guidelines alone are insufficient to change practice and deliver improved patient outcomes. Further investment in strategies to increase adoption of guideline recommendations is required.Given escalating healthcare costs and constrained budgets in public health systems, effective, cost-effective and affordable implementation strategies are needed to ensure the intended benefits of clinical guidelines are realised.This protocol details the research methods that will be used to answer the following question: From the Australian healthcare system perspective, what is the cost and cost-effectiveness of the practice change intervention to increase the routine provision of antenatal care for maternal alcohol consumption compared to usual practice, and is it an affordable model for local health services?To prevent the potential adverse obstetric and foetal outcomes associated with women’s alcohol consumption during pregnancy , clinicaThe development and dissemination of clinical guidelines alone are insufficient to change the current practice and deliver improved patient outcomes . FurtherThe multi-strategy practice change implementation trial will be a randomised, stepped-wedge controlled trial. The protocol has been previously published . In brieRepeated cross-sectional outcome data will be gathered on a weekly basis across the three sectors for a period of 34 months. Baseline data collection, representing usual practice (control), will be collected for the three sectors from 7 months prior to the commencement of the intervention in the first sector to the start of the intervention in each sector. Follow-up data will be collected for the three sectors 7 months following completion of the intervention in the third and last sectors. The outcome results will be determined by comparing practice change outcomes between the baseline and follow-up periods for the three sectors combined.Usual practice comprises the antenatal care for addressing maternal alcohol consumption during pregnancy that is provided in the baseline period prior to the introduction of the intervention. It is anticipated that such care is likely to vary by antenatal service and clinician. This is due to variability in local practice across the 3 sectors covering metropolitan, regional and rural localities, as well as the lack of an existing health district-wide guideline or procedure specifying the provision of routine care for addressing alcohol consumption during pregnancy.The development and dissemination of the clinical practice guidelines have already taken place in Australia with the result that their associated costs and effects are common to both intervention and control study periods.A multi-strategy practice change intervention has been developed to support antenatal care staff to implement a model of care consistent with clinical guidelines. The multiple strategies included in the intervention are presented in Appendix This economic evaluation has been conducted and reported in accordance with the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) publication guidelines and good reporting practices .Cost, cost-consequence and cost-effectiveness analyses will be undertaken comparing the intervention against the usual practice from a public health service perspective. This perspective is justified because ongoing funding for this intervention, especially if it translates into routine practice, will fall on public health services. To further aid decision-makers, budget impact analysis, including scale-up cost scenarios, will be presented alongside the cost-effectiveness findings. Costs will be reported in 2019 Australian dollars ($AUD). The time horizon for the inclusion of relevant costs and consequences will be the course of the trial (34 months). Costs and benefits occurring after 12 months will be discounted using an annual discount rate of 3% in the base case. Annual discount rates of 0 and 5% will be applied in a sensitivity analysis. The conduct, analysis and reporting of the economic analyses will adhere to the cost and economic analysis guidelines , 15, 25 Common to all forms of economic evaluation is the analysis of cost. In this study, costing and budget impact assessments will be conducted to quantify how much more it will cost to pursue implementation efforts to affect practice change. The budget impact assessment will translate the health economic findings into more meaningful and relevant results for healthcare decision-makers and funders. In its simplest form, economic evaluation involves a listing of all cost/benefit implications of the alternatives under consideration, as in cost-consequences analyses . A cost-Being assessed for alcohol consumption and level of risk using the AUDIT-CBeing provided with brief advice related to alcohol consumption during pregnancyReceiving, relative to their level of risk, the relevant elements of antenatal care for addressing alcohol consumption during pregnancy (advise and refer)Being assessed for alcohol consumption and level of risk using the AUDIT-C and receiving, relative to their level of risk, the relevant elements of antenatal care for addressing alcohol consumption during pregnancy (advise and refer)It has been suggested that one of the ways to improve efficiency in conducting economic evaluations of implementation interventions is to confine studies to measures of the care process or intermediate outcomes , for exaReceipt of care will be measured by participant report during a computer-assisted telephone survey conducted after an antenatal consultation, at each of the three time points .A secondary outcome will also be included. For women attending antenatal appointments at ‘booking in’, 27–28 weeks gestation and 35–36 weeks gestation, alcohol consumption since pregnancy recognition will be collected. Outcome measurement will be based on self-report of women using the total AUDIT-C score. AUDIT-C is a validated tool for assessing the risk of harm due to alcohol consumption [Cost data pertaining to the development and implementation of the practice change intervention will be collected prospectively using a resource use capture tool in tangent with trial administrative records. The intervention programme logic will be used to identify all the relevant costs directly and indirectly associated with the intervention. The cost capture tool, developed in Microsoft Excel (2013), allows researchers to prospectively document the activity and materials consumed at different phases of the intervention  from all relevant stakeholders. The cost capture tool includes the following categories: (1) labour , (2) materials , (3) joint costs , and (4) miscellaneous costs . To maintain a conservative approach to cost estimation, the non-capital implementation costs will not be amortised.Resource use valuation will be based on the concept of opportunity cost, that is, the value of the benefit forgone in not employing a resource for a different use. Market prices will be used as a proxy for the ‘value of benefit’ forgone .Appendix As outlined above, the range of outcomes measured in the implementation trial is diverse, which lends well to a cost-consequence analysis. The analysis will adopt a scorecard approach to show a comparison of the costs and benefits associated with the intervention and usual practice. An economic summary measure is not calculated. A programme logic model will be developed to describe all possible inputs (costs) and impacts (consequences) associated with the intervention and usual care Appendix : Fig. 1.The cost-effectiveness analysis will be conducted subject to the assessment of intervention efficacy. The economic summary measure will be an incremental cost-effectiveness ratio (ICER). The ICER represents the additional cost required to achieve an additional unit of benefit , 29. ForDistributional cost-effectiveness analysis (DCEA) is a framework for incorporating health inequality concerns into the economic evaluation of health sector interventions. Full DCEA requires the distribution of direct health benefits to be estimated from a decision-analytic model or trial-based analysis using parameter estimates specific to socioeconomic groups. However, a simplified version providing healthcare decision-makers and stakeholders with an evidence-based technique for evaluating whether new interventions can help to achieve the objective of health inequality reduction can be used when conducting a full DCEA is not practical or feasible . To asseEconomic evaluations and budget impact analyses share many of the same data elements and methodological requirements and should be viewed as complementary. However, there are important differences in their methods and use cases . The budA model will be developed to describe the financial resources associated with the usual practice over the course of health districts’ budgeting cycles. This will represent the base case or ‘reference case’. The comparative scenario will model the required changes in health service resourcing that are expected to result from the adoption of this alternate model of care, including indirect and downstream impacts on other parts of the health service. Resource use data will be sourced from the implementation trial and costing analysis. All model assumptions and data inputs will be described in full. Justification for the inclusion or exclusion of relevant model parameters will be provided.The budget impact assessment will adhere to the relevant local and international guidelines, as well as recommended formats for presenting the results so they are most useful to decision-makers , 33.All analyses will be subject to one-way and probabilistic sensitivity analyses. These analyses test the impacts of plausible variation in data parameters on the cost outcomes and economic summary measure and provide an understanding of which values are associated with the greatest amount of uncertainty. Differences in costs or outcomes that can be explained by variations between subgroups of patients with different baseline characteristics or other observed variabilities in effects that are not reducible by more information will be reported.In addition, scenario analyses will be undertaken to explore the efficiency and budget impact of the state-wide implementation of the practice change model of care in maternity services across the whole state of NSW.This protocol sets out the plan to assess the cost, efficiency and affordability of a multi-strategy practice change implementation intervention compared to usual practice. The purpose of publishing this protocol is twofold; first, setting an a priori plan for the proposed analyses can reduce potential biases made from ad hoc analytic decisions. Deviations from this protocol will require description and justification in the final analyses. Second, there are benefits to the research and broader community in a greater understanding of economic evaluation, especially with respect to their conduct alongside implementation trials. There is a clear absence of research evidence of the effectiveness, cost, cost-effectiveness and budget impact of implementation strategies to improve antenatal care that addresses maternal alcohol consumption during pregnancy . The appThis protocol outlines the assessment of cost, efficiency and affordability of a multi-strategy practice change implementation intervention compared to the usual practice. The outcomes of this economic evaluation will provide insight into the cost, cost-consequence and cost-effectiveness of implementation strategies designed to improve antenatal care addressing the recognised risk of alcohol consumption to the health and wellbeing of both the mother and child , and inf


Caenorhabditis elegans. An amenability to genetic and cell biological approaches, well-studied development and a short life cycle make C. elegans a powerful system to investigate the diversity of chromo domain protein functions in metazoans. We will highlight recent insights into the roles of chromo domain proteins in the regulation of heterochromatin and the spatial conformation of the genome as well as their functions in cell fate, fertility, small RNA pathways and transgenerational epigenetic inheritance. The spectrum of different chromatin readers may represent a layer of regulation that integrates chromatin landscape, genome organization and gene expression.In most eukaryotes, the genome is packaged with histones and other proteins to form chromatin. One of the major mechanisms for chromatin regulation is through post-translational modification of histone proteins. Recognition of these modifications by effector proteins, often dubbed histone “readers,” provides a link between the chromatin landscape and gene regulation. The diversity of histone reader proteins for each modification provides an added layer of regulatory complexity. In this review, we will focus on the roles of chromatin organization modifier (chromo) domain containing proteins in the model nematode,  Eukaryotic chromatin is highly regulated to ensure proper gene expression in different cell types and across developmental stages. The combined application of high-resolution microscopy and genome-wide sequencing approaches now provides a comprehensive view of the organization of the genome into more transcriptionally active and accessible regions of euchromatin or less active and more compact regions of heterochromatin. These chromatin states are characterized by different patterns of histone modifications and spatial separation within the nucleus , as welC. elegans germ cell fate (C. elegans, which lacks the key insulator and architectural protein CTCF (Another fundamental question concerns the mechanisms that maintain boundaries between active and inactive chromatin domains [reviewed in ell fate . In addiein CTCF .C. elegans and other model systems will undoubtedly continue to provide fundamental insight into these aspects of genome organization.Finally, distinguishing the functional relevance of large-scale chromatin architecture and discrete or locus-specific regulation in the phenotypes described here is an important but challenging goal. Addressing these mechanisms will likely involve the experimental manipulation of the genome and epigenome [reviewed in All authors wrote the manuscript and contributed to the article and approved the submitted version. TL and CL prepared the figure and table.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background and Objectives: Caudal duplication syndrome is a rare association of anatomical anomalies describing duplication of the hindgut, spine, and uro-genital structures, leading to varied clinical presentations. The current literature focuses on case reports which describe the embryological etiology and anatomical spectrum of the condition giving little attention to the surgical preparation, the need for a well-structured follow-up program, or the transition into adult healthcare of these complex patients. No reviews have been published regarding this complex pathology. Materials and Methods: A review of caudal duplication syndrome cases was done to assess the range of the clinical malformations, timing, and types of surgical interventions. Inconsistencies in multidisciplinary care, follow-up, and risk events were described. Results: Hindgut duplication always involved the anorectal region. Anorectal malformations were evenly distributed as unilateral and bilateral. Colon duplication extended from the anal region to the transverse colon or ascending colon in most of the cases and less to terminal. In females, genital duplication was present in all cases. The follow-up period varied between 3 months and 12 years. In all adult females, the motive of presentation was related to pregnancy  or late complications . Conclusions: Complex malformations affecting multiple caudal organs may have a strong impact in many aspects of the long-term quality of life; therefore, patients with caudal duplication syndrome need increased awareness and joined multidisciplinary treatment. Caudal duplication syndrome (CDS) is a very rare congenital cluster of anomalies. Dominguez et al. 1993) defined it as an association of hindgut duplication, duplication of the lower uro-genital tract, spinal cord, and vertebral anomalies at heterogeneous degrees of severity resulting from a fetal insult at different stages of embryogenesis 993 defin. Considering the very low incidence of this malformation and the variety of clinical presentations, the majority of published literature focus on description of the anatomical spectrum and the possible embryological etiology and less on the short- and long-term surgical planning, implementation of a structured follow-up plan, and the responsibility for transition of care into adult healthcare of these complex patients ,4.Each type of gastrointestinal, genitourinary, and/or distal spine duplication, either partial or complete cannot be discussed separately but together and its management must be adjusted to each individual case. The purpose of treatment is to preserve or improve fecal and urinary continence, maintain reproductive potential, allow a satisfactory sexual life with acceptable cosmetic appearance of the perineum, and manage other neurological disabilities. All these will impact the long-term morbidities and quality of life .The impact of the malformations severity on the prognosis and risks of potential complications of the surgical treatment can be reduced by a comprehensive anatomical and functional preoperative evaluation, prospective multidisciplinary surgical planning, and active involvement of the patient and family to assure collaboration and adherence to the follow-up plan. The objective of this review is to recognize possible surgical management patterns used to treat different clinical presentations of CDS, to examine the presence of gaps in patients’ care, to assess risk events which can occur during life and might signal the need for planned intervention and identify groups of patients with CDS which require special attention.A literature review with the search term “caudal duplication syndrome” was done using open access search engines PubMed, Science Direct, and Google Scholar by two independent reviewers. We excluded duplicate references, conference abstracts, articles not in English, and cases which did not describe the surgical management. Articles which described patients with duplicated digestive system, genitourinary tract, spinal column, and the neural tube but also included duplications of the lower limb were not included. A total of 279 articles were retrieved during the systematic search using the specified criteria. The full text articles were reviewed, and the selected articles were saved using reference management software. A total of 17 articles (3 case series and 14 case reports) with a total of 23 patients were selected for meeting the criteria. No literature or systematic review articles could be found.Hindgut duplication in CDS always included the anorectal region .At anal level, anorectal malformation (ARM) was present at least on one duplicated side in all cases with the exception of three patients without hindgut duplication and one patient with intra-sphincteric location of both anal openings. Unilateral anorectal malformation was present in 7/23 cases (30.43%), bilateral ARM in 7/23 cases (30.43%), and five cases were not described. The most common types of anorectal malformation are perineal fistula or recto vestibular fistula. Colon duplication extended from anal region to the transverse colon in 5/23 cases (21.73%), to ascending colon in 4/23 cases (17.39%), and to terminal ileum in 2/23 (8.69%). In eight patients, the level of duplication was not specified. In one patient, the appendix and proximal colon was duplicated while the sigmoid and anorectal region was triplicated. Bladder and urethral duplication were always in the sagittal plane and was present in all cases with the exception of two female patients (one with unspecified anatomy). In males, genital involvement with complete or partial shaft duplication (glans duplication and one shaft) was present in five out of seven patients. In females, genital duplication was present in all cases. Spinal cord malformations  were reported in half of the cases. The vertebral spine, most commonly defects of fusion and hemivertebrae, was involved in 14/23 cases (60.86%). Associated anomalies outside of the caudal region included the abdominal wall , cardiac malformations , gastro-intestinal , or limb malformations , without being consistent in prevalence. Prenatal ultrasound evaluation was done in only 2 patients without a prenatal diagnosis of CDS and no further Magnetic resonance imaging (MRI) evaluation. In 19/23 cases (82.60%), the child was evaluated in the first year of life due to the evident malformations of the perineum. In cases with non-obstructive symptoms due to less severe malformations or inconsistent follow-up, evaluation was delayed until complications occurred. The most common surgical interventions in the first month of life were colostomy for anorectal malformation with obstructive symptoms, acute abdomen  or omphalocele repair. After this age, the motive of presentation was related to complications: severe dermatitis because continuous dribbling urine, fecal incontinence, long term constipation or for cosmetic correction of the perineal region in asymptomatic female patients. Functional evaluation of the bladder is inconsistently reported and was done in cases of urinary incontinence. The most common associated urologic pathology was unilateral or bilateral vesico-ureteral reflux. In male patients, penectomy or penile reconstruction was done in 3/5 cases or was planned for future reconstruction in the rest of the cases. Only one author opted for vaginoplasty with resection of the common wall for cosmetic reasons in two patients and in one other case one side of the duplication was removed. All adult cases (age between 22 and 39 years) were females and the motive of presentation was related to pregnancy  or late complications . All cases had limited surgical history  with no subsequent events. All four female patients were sexually active with one or bilateral side vaginal use retained the double vagina, all became pregnant and delivered by cesarean section. The main reasons for delayed presentation were non-obstructive colorectal malformation (stooling present with the help with suppository), no need for toilet training until school age , or lack of caregiver awareness. The follow-up period varied between 3 months and 12 years and was longer in cases with fecal or urinary incontinence. Three of the adult females with history of colorectal surgery as infants had no reported follow-up until presentation for current problems as adults. The life events with the highest impact on occurrence of complications were the type of colorectal surgical procedure , neglect or lack of awareness from caregivers  and pregnancy. A case of a 39-year-old female is presented with a history of three pregnancies, delivered with cesarean section and no prior medical history. After deliveries, the patient had one side hysterectomy for leiomyomas, two interventions for vaginal prolapse, one side ureteral reimplantation, three transurethral incisions of the bladder neck for inefficient bladder emptying, and one transurethral bulking agent injection in the bladder neck for stress incontinence.The very low incidence of caudal duplication syndrome makes it difficult to develop expertise and assemble a multidisciplinary team with participation in all the steps of care. Because of the evident clinical features of the perineum, these cases are first assessed at birth. Prenatal examination can diagnose clusters of severe anomalies which might not be recognized as CDS because of the low awareness of this syndrome ,7.Management of colorectal duplicationIf the baby has efficient bowel movements, is preferably breastfed, is gaining weight, and no other severe associated malformations require surgical intervention, we recommend delaying further treatment until a complete assessment of the types and extension of malformations is done and an individually tailored treatment plan can be made bringing the family together with the multidisciplinary team. The type of malformation determines the surgical strategy at birth: primary repair (not the best choice in these complex patients), temporary anal calibrations to ensure efficient bowel movements until definitive repair or colostomy creation. The purpose of surgical reconstruction is to have a single anal opening located within the complex muscle either by removal of the anal side opening outside of the sphincter ,8 or joiManagement of bladder and urethral duplicationSagittal urethral duplication (side-by-side) is associated with bladder duplication and is specific for CDS. The two bladders can be completely separate or have a sagittal septum (most commonly two asymmetric sides) each with a ureter from the ipsilateral kidney and its own urethra. Urologic management in the first year of life is almost always conservative. Anatomic evaluation should be complemented with bladder function assessment especially in symptomatic patients. The goal is to avoid recurrent urinary infections, to ensure there is efficient emptying of both bladders and urinary continence. In most female patients, unilateral removal of the urethra is not necessary if asymptomatic. In males, the urethra will be excised when the decision for cosmetical penectomy is made , and it Assessment of continence potential is important in the development of any anorectal and urinary reconstruction plan. The type and severity of spinal cord and sacrum malformation have a direct role in predicting the fecal and urinary continence ,15. ThisManagement of genital duplicationGender distribution shows a predilection of CDS in females with a complete but well-developed duplicated external and internal genital organ and preserved ovarian function. Almost always, corrective genital surgery in females is not necessary unless one side is hypoplastic and might cause menstrual flow obstruction or for cosmetic concerns, in which case, it can be removed . If congSupport groups and quality of lifeThe importance of active involvement of family members and the patient itself is well recognized, but not always available. Parents must cope with the difficulty of accepting and adjusting to their child’s condition, coordinate appointments with different healthcare providers, find information about their child’s malformations, manage the financial demands of long-term medical care, and locate appropriate care centers ,22. FactOur literature review has numerous limitations which influence the value and objectivity in making recommendations. We are aware of the difficulty of extracting consistent data and providing statistically significant results. There is a high heterogeneity in data reporting in case reports or case series articles, with ambiguous nomenclature used to describe the anatomy or details regarding surgical procedures and incomplete information about the extent of multi-organ malformations. The term “caudal duplication syndrome” was introduced in 1993, but there still are inconsistent ways of naming it .Caudal duplication syndrome should receive more attention from the pediatric surgical community regarding team approach and data collection. It is not sufficient to report the anatomical particularities of a case. Similar to other rare and complex malformations which affect the caudal region and have an impact on the quality of life , patients with caudal duplication syndrome deserve a better integrated care to improve outcomes.


The cuneiform script provides a glimpse into our ancient history. However, reading age-old clay tablets is time-consuming and requires years of training. To simplify this process, we propose a deep-learning based sign detector that locates and classifies cuneiform signs in images of clay tablets. Deep learning requires large amounts of training data in the form of bounding boxes around cuneiform signs, which are not readily available and costly to obtain in the case of cuneiform script. To tackle this problem, we make use of existing transliterations, a sign-by-sign representation of the tablet content in Latin script. Since these do not provide sign localization, we propose a weakly supervised approach: We align tablet images with their corresponding transliterations to localize the transliterated signs in the tablet image, before using these localized signs in place of annotations to re-train the sign detector. A better sign detector in turn boosts the quality of the alignments. We combine these steps in an iterative process that enables training a cuneiform sign detector from transliterations only. While our method works weakly supervised, a small number of annotations further boost the performance of the cuneiform sign detector which we evaluate on a large collection of clay tablets from the Neo-Assyrian period. To enable experts to directly apply the sign detector in their study of cuneiform texts, we additionally provide a web application for the analysis of clay tablets with a trained cuneiform sign detector. Used in most of the Ancient Near East for a period of over three thousand years until the beginning of the Current Era, the cuneiform script is the oldest known writing system in the world, providing us with invaluable records of early human history across all spheres of life.cunei in Latin, hence the name cuneiform) formed cuneiform signs, of which several hundred have been documented in cuneiform sign lists [Most cuneiform texts were written on palm-sized clay tablets by impressing an angular stylus that left a wedge-shaped mark. Groups of wedges  is recorded in Latin script. Due to the special design of the transliteration system, it is possible to retrieve the original sign code class of each sign from its reading. If we mention transliterations in the remainder of this article, we will refer to this sign-by-sign representation in terms of sign code classes rather than readings. In the last step of the analysis, a translation of the readings is created.Even for experts, the process of reading and analyzing clay tablets is difficult and time-consuming –4. In ancuneiform sign detector that outputs for a tablet image where a sign is located (bounding box enclosing the sign) and what sign code class it belongs to  as showWhile in many writing systems the recognition of individual characters is not an issue, detecting cuneiform signs is difficult for several reasons. In many scripts whitespace between characters simplifies detection significantly, because it allows us to separate localization and classification in two consecutive steps. However, cuneiform signs are often inscribed without space between neighboring signs making their localization and classification interdependent . Sign siCuneiform tablets have been digitized in various forms that strongly differ in their availability and production cost. Cuneiform tablets are best studied in their original form as 3D objects: signs are often found not only on front and back but also along edges, and their visibility depends on lighting and viewpoint. Thus working on 3D scans of tablets is desirable –10. FromThere are three categories of computer vision approaches for text or handwriting recognition: Character-based –23, wordIdeally, we would follow a standard machine-learning approach and train a sign detector from thousands of annotated examples of cuneiform signs (supervised learning) –21, 25. While the transliteration provides a sign-by-sign representation of the tablet content, it does not explicitly localize each sign in the 2D tablet image. If we want to learn how to detect cuneiform signs from tablet images and corresponding transliterations (weakly supervised learning), we need to localize the transliterated signs for each 2D image, i.e. solving the inverse problem with respect to sign detection as shown in weak supervision, in contrast to the fully supervised setting with available bounding box annotations. Character-based methods [From a machine-learning perspective, the transliteration provides  methods , 23 have methods , 27. Rec methods , but the methods  uses a p methods  proposesWeakly supervised learning is an important research area as it is one of the most common learning scenarios found in the wild. Learning to detect cuneiform script challenges us to find new ways to bridge the gap between weak and full supervision, enabling state-of-the-art cuneiform sign detection for over a hundred sign code classes without requiring manual annotations. While our proposed solution deals with cuneiform sign detection, similar problems  occur in other ancient scripts that might profit from our weakly supervised approach.Our main contributions are summarized as follows: (i) Since reading cuneiform script is difficult and time-consuming even for experts, we propose to train a deep neural network-based sign detector that can localize and classify cuneiform signs directly in 2D images of clay tablets. To this end, (ii) this article describes a novel method to supervise the sign detector training with weak supervision provided by existing transliterations—instead of requiring extra manual annotation of ten thousands of cuneiform signs. (iii) To the best of our knowledge, we are the first to demonstrate a cuneiform sign detector that performs well on a large and diverse dataset and detects over a hundred different sign code classes. (iv) We release the first large-scale dataset for the challenging problem of cuneiform sign detection in 2D images with several thousand signs annotated by Assyriologists. (v) The approach is made available with code, web application and trained models, and it is applicable to cuneiform scripts of different periods paving the way for large-scale digital analysis in the field of Assyriology.In the following we describe our approach in detail, evaluate our approach and its components thoroughly in a number of experiments, and finish with a discussion of our approach and its implications for computer vision and Assyriology.iterative learning procedure that alternates between generating sign annotations and training the sign detector. We model the sign detector as a convolutional neural network (CNN) whose representation of cuneiform signs is updated in each iteration of iterative training.Training a cuneiform sign detector requires thousands of sign annotations. Instead of requiring manual annotations, our weakly supervised approach generates sign annotations by automatically aligning hundreds of tablet images with their transliterations in parallel. We propose a placed detections). To keep improving the sign detector, it is necessary to increase the quality and quantity of generated sign annotations from iteration to iteration. When applying the trained sign detector on tablet images (of the training set), this produces raw detections with few true positive (TP) and many false positive (FP) sign detections. By aligning transliterated signs with raw detections in a tablet image, our method identifies a reliable subset of raw detections  that are most likely TPs and can serve as sign annotations for the next training iteration. When aligned detections become available after the first iteration, the task of sign placement shifts to localizing the unaligned signs left in the gaps between aligned detections. As summarized in To start iterative training, an initial set of sign annotations is required to train a first sign detector. Since the transliteration only provides the relative positions of cuneiform signs, we propose a sign placement method that relies on line detections to turn the relative positions of the transliterated signs into actual bounding boxes in the tablet image (sign placement).Localize transliterated signs in the tablet image using detected lines and aligned detections as reference points (sign detector training).Train a sign detector using the generated aligned & placed detections as sign annotations .After applying the sign detector, refine the raw detections by optimizing the alignment between transliteration and tablet image . In contrast, the alignment method converts weak supervision from transliterations into high-quality aligned detections (exploitation). The ability to explore new sign code classes is of particular importance due to the problem of sign code class imbalance: Many sign code classes are rare in cuneiform script because their occurrence follows a discrete Pareto distribution as shown in Fig B in Before iterative learning, line detection is performed as a pre-processing step on all tablet images. Cuneiform text is commonly inscribed along lines. Since these lines are easy to detect, we can simplify the alignment between tablet image and transliteration. Given the lines in a tablet image, the full alignment problem is decomposed into a line-level alignment (that matches detected with transliterated lines) and for each line a sign-level alignment (that matches detected with transliterated signs). Knowing the position of each line can effectively reduce sign localization in a 2D tablet image to an 1D search along a line, significantly constraining the number of possible solutions.We propose a line detection method for cuneiform script that benefits the three steps of our learning method described in the following paragraphs. As shown in Transliterations only provide a relative placement of some signs to another, but not the exact locations of individual cuneiform signs in the tablet images (bounding boxes), essential for training a sign detector. In the first iteration of iterative training, the sign placement method combines the relative sign positions from the transliteration with line detections in the tablet image in order to generate an initial set of sign annotations as shown in In later iterations of iterative learning, the sign placement additionally leverages the aligned sign detections in order to localize the remaining unaligned signs from the transliteration. The aligned detections serve as additional reference points throughout the tablet image that complement the reference provided by the detected lines. In particular, the localization of signs close to aligned detections is improved. Therefore, the more aligned detections become available during iterative training, the better the remaining unaligned signs can be localized. Also the line-level alignment is now adopted from the previous image-transliteration alignment step. More details on the implementation of sign placement are in Sect. A3 of Besides providing an initialization for our learning method, in later iterations the sign placement step drives the learning of sign code classes not yet learned by the sign detector. Placed detections correspond to transliterated signs that have either not been detected or not been aligned successfully, and thus have the potential to be valuable training data for the next round of detector training. Through iterative learning with placed detections, the sign detector gradually learns to distinguish new sign code classes.The CNN of the sign detector is based on the Single Shot Multi-Box Detector (SSD) architecture  for geneAs backbone architecture of the sign detector, we use a MobileNet-v02  with theWhen we train a cuneiform sign detector, we improve its internal representation of cuneiform signs. Different cuneiform signs share the same representation that captures the commonalities between signs. Since cuneiform signs are all constructed from very similar parts (wedges), success in the distinction of some sign code classes already lays the foundation for the distinction of yet unlearned sign code classes. Erroneous and ambiguous training samples are difficult to integrate into the learned representation and tend to be ignored. Thus the sign detector training provides in itself an critical regularization that filters out the noise in the generated sign annotations.In each iteration of iterative training, the sign detector is trained on the aligned & placed detections as shown in semi-supervised learning because sign annotations are only available for a small subset of the training data. The rest of the training data remains weakly supervised. During our experiments, we evaluate the sign detector training in both cases, purely weakly supervised and semi-supervised. In the Sect. A4 & A7 of Our approach allows the integration of expert knowledge in the form of manual annotations, e.g. correct some of the generated sign detections. While our learning approach works weakly supervised (without full supervision), we find that complementing the weak supervision (i.e. transliterations) with a small number of sign annotations is beneficial in such a fine-grained detection setting. For this purpose, we extend the sign detector training with an optional fine-tuning step that trains the sign detector with a reduced learning rate on training samples annotated by experts. This form of training is referred to as There are many causes like damaged signs or wedge-shaped cracks that can fool a cuneiform sign detector to produce FP sign detections. We close the iterative training loop of our approach by including an image-transliteration alignment step that serves as a filter for the raw detections of the sign detector. By selecting only sign detections that are successfully aligned with transliterated signs, we obtain a set of reliable detections for the next iteration of iterative training.By extracting reliable aligned detections from the raw output of the sign detector, the image-transliteration alignment addresses two problems caused by an inherent discrepancy between tablet image and its transliteration: First, the transliteration does not record every visual detail found in the tablet image like writing style, gaps in the lines, damage to the clay tablet. Second, the transliteration often goes beyond what is actually visible in a tablet image. An Assyriologist may infer additional cuneiform signs due to context knowledge like multiple text sources, language understanding etc. While broken and damaged parts of the script are often documented, the level of detail varies between transliterations.The optimization of the image-transliteration alignment yields a set of aligned detections that is consistent with the top-down information from transliteration and line geometry as well as the bottom-up information from line and sign detections. Due to line detection, we can decompose the problem of aligning transliterated signs of the transliteration with raw detections in the tablet image into two individual alignment problems as shown in The line-level alignment is modeled as a path search problem through the matrix of all possible alignments where the shortest path represents the best line alignment , due to the number of texts readily available and the standardized form of the cuneiform writing by that time. The dataset of clay tablet images with their transliterations mostly originates from two different sources:State Archives of Assyria online (SAAo) [Transliterations of Neo-Assyrian tablets found in the e (SAAo) , 43, as e (SAAo) .Cuneiform Digital Library Initiative (cdli) [Clay-tablet images made available through the e (cdli) .For the Neo-Assyrian period, the SAAo series are invaluable, delivering a diverse corpus of texts, including royal correspondence, divination, and literary texts or international treaties, among other genres. We distilled our dataset by first extracting the usable transliterations from SAAo and then collating them with the available images in cdli. Only tablets with an available transliteration and image were included in our corpus. Clay tablets were often inscribed on both sides and even on the edges. Thus images in cdli are composites of different views (inscribed sides of a clay tablet). We segment those composite images in order to separate the different views into individual images and then associate the segmented views with their corresponding transliteration.Out of the c. 900 different cuneiform sign code classes catalogued in Borger’s sign list , we restFor evaluation, a sign detection is considered a TP, if its bounding box and a ground truth box overlap more than 50% (intersection-over-union) and their labels match, otherwise it is considered an FP. The quality of the generated sign detections  are evaluated in terms of precision, recall and F2-score, each of which is averaged across the 186 sign code classes. We emphasize the recall of the generated sign annotations since exploring examples, that are difficult-to-learn or belong to rare sign code classes, is essential during iterative training, and even more so due to the natural sign code class imbalance in the dataset. The performance of the sign detector on an individual sign code class is measured in terms of average precision (AP) which is the standard metric for object detection . The oveIn our first experiment, we analyze the impact of the alignment and placement methods on the quality of sign detections. For this purpose, we track the change in precision, recall and F2-score from raw detections to aligned detections and eventually to the union of aligned & placed detections. The experiment is conducted on the test set, starting from the raw detections of a sign detector obtained after three rounds of iterative training. Then the alignment and placement methods are applied consecutively.In drift [Our second experiment investigates how iterative training gradually improves the sign detector in order to eventually detect all signs in a tablet image. To understand the effect of iterative training, we report for each iteration the composition of the aligned & placed detections in drift , that reThe first and second training iterations of this experiment are weakly supervised without any manual sign annotations. In the first iteration, only placed detections are available for detector training of which less than twelve percent are TPs when evaluated on the test set. Despite the low precision of the placed detections, the sign detector training produces a first detector with 20.7 mAP. By aligning more than 80k detections, our weakly supervised approach increases the sign detector performance significantly (45.3 mAP) in the second iteration. An additional third iteration of purely weakly supervised training fails to improve performance. In particular, we find that sign localization of aligned & placed detections worsens due to poorly placed bounding boxes and this drift cancels out the positive effects of iterative training , 463 (B), 745 (C), 1472 (D), 2910 (E) or 4663 (F) manual sign annotations respectively. For our iterative learning approach, configuration A corresponds to weakly supervised training and configuration B–F correspond to semi-supervised training. Similar to In our final experiment, we analyze individual sign detections and gain insight into the detector’s decision making. Finally, we analyze which visual features are captured by the learned representation of the sign detector when it decides on the sign code class of cuneiform signs. We employ a technique called grad-CAM  that mapIn this article we have investigated how to train a cuneiform sign detector with minimal supervision. Instead of requiring manual annotations, our approach generates sign annotations for sign detector training by leveraging existing transliterations that are part of the Assyriologist’s workflow. In each iteration our iterative learning method alternates between training a sign detector and generating sign annotations by solving the alignment problem between tablet image and transliteration across hundreds of clay tablets in parallel. To improve the sign detector, our approach focuses on increasing the quality and quantity of generated sign annotations. To deal with the fine-grained nature of cuneiform sign detection, the strong imbalance of sign code class frequency and the difficulty of the transliteration alignment, we split the sign annotation generation into two distinct steps: sign placement and image-transliteration alignment. In this way we balance between learning from placed sign detections with sign code classes that are hard-to-predict or even unknown to the detector (exploration) and learning from aligned detections that are reliable (exploitation). The exploration part of our approach injects sign annotations with new sign code classes into the training of the sign detector by systematically placing signs from the transliteration in the gaps left after the alignment step. The exploitation part of our approach produces very reliable sign annotations that are consistent with the available bottom-up information (line and sign detections in tablet image) and top-down information (transliteration and line-geometry prior).The performance analysis of the trained sign detector uncovers some of its limitations. The sign detector struggles with some rare sign code classes Click here for additional data file.S1 VideoThe purpose of this demonstration is to illustrate how a sign detector could be made available to Assyriologists. Through a web interface, the sign detector is applied to a tablet image. The detection results are immediately available for analysis by the user. Additional details regarding the demo application can be found in Sect. C8 of (MP4)Click here for additional data file.


The techniques for noninvasive measurement of brain function such as electroencephalography (EEG), magnetoencephalography (MEG), functional magnetic resonance imaging (fMRI), and functional near-infrared spectroscopy (fNIRS) have been used in diagnosing brain conditions. However, the conventional techniques have critical limitations of spatial or temporal resolution. Here, we developed a novel technique which enables the precise measurement of dynamic brain signals and localized identification of active brain regions. In this technique, termed as magnetically biased field (MBF), human brain signal is measured as the fluctuation of a transcranial static magnetic field emitted by a coil placed on the scalp. The validity of MBF was confirmed by the measurement of somatosensory evoked signals. Fast somatosensory evoked signals were successfully observed. Localized maximum positive and negative deflections appeared at the region which represents the right primary somatosensory area contralateral to the stimulated hand. The ability of MBF to detect dynamic brain activity precisely can have numerous applications such as diagnosing brain diseases and brain-machine interfaces. I.Noninvasive methods for the measurement of brain activity have been utilized in diagnosing brain conditions such as seizure, epilepsy, head injuries, dizziness, headache, brain tumors, and sleeping disorders. However, the conventional techniques including electroencephalography (EEG), magnetoencephalography (MEG), functional magnetic resonance imaging (fMRI), and functional near-infrared spectroscopy (fNIRS) have not achieved high resolution in both spatial and temporal domains with one modality. While EEG and MEG can measure fast brain signals in the order of milliseconds, localizing those electromagnetic sources is an ill-posed inverse problem that, in the absence of constraints, does not admit a unique solution because a measured electromagnetic field pattern can be generated by an infinite number of current distributions in the brain To overcome the limitations of the conventional noninvasive methods for measuring brain function, here, we developed magnetically biased field (MBF) as a technique for the precise, localized detection of dynamic brain activity. Further, we verified the validity of MBF by measuring the somatosensory evoked signals in human subjects.II.A.In MBF, a static magnetic field is emitted into the head from a coil placed on the scalp, and the magnetic field returned to the coil is measured with a magnetic sensor placed at the top of the coil . As the To measure human brain signals with MBF, we made a coil producing a static magnetic field; a 28-American wire gauge  enameled copper wire was wound densely in 2 layers around an acetal resin cylinder with a 6-mm diameter and 15-mm height. The cylinder had a screw-hole situated along the central axis. We adopted a highly sensitive sensor  that can measure magnetic field changes at the order of nanotesla in the geomagnetic environment. A polycarbonate screw was attached to the edge of the magnetic sensor along the sensor axis. The magnetic sensor and coil were connected by rigidly tightening the screw into the screw-hole of the coil cylinder .Fig. 2.We manufactured 16 sets of the magnetic sensors and coils as shown in B.We verified the validity of MBF by measuring the somatosensory evoked signals in human subjects. The experiment was performed with five healthy volunteers . The study was approved by the ethical committee of Hiroshima City University, Hiroshima, Japan, and written informed consent was obtained from all subjects. Experiments were conducted in a magnetically shielded room. Median nerve electrical stimulation was applied to the left wrist while the subject sat comfortably in a chair with a mounted headrest. The electric current stimulation consisted of a monophasic square wave pulse with duration of 0.3 ms applied just above the motor threshold to elicit a slight twitch of the thumb, following the recommended standard of International Federation of Clinical Neurophysiology (IFCN) III.Somatosensory evoked MBF signals were thus successfully recorded as shown in IV.−4 of that in tSMS, so the modulation of the cortex observed in the tSMS is improbable in MBF. This study is the first trial showing the validity of MBF with a measurement of somatosensory evoked signals. It is expected that MBF can be applied to clinical diagnoses by measurements of other functional brain signals such as visual evoked signals, auditory evoked signals and event related signals.In this study, we achieved the measurement of dynamic brain signals and the localized identification of active brain regions by using transcranial static magnetic fields emitted by coils placed on the scalp, a technique that we call MBF. In the somatosensory evoked MBF signals, main peaks appeared with latencies of about 80 ms, 120 ms, and 160 ms. There have been studies of somatosensory evoked potentials (SEPs) and somatosensory evoked magnetic fields (SEFs) following median nerve stimulation. It is known that large peaks at latencies of about 20 ms and 30 ms in SEPs V.We successfully developed a technique, termed as MBF, for the precise measurement of dynamic brain signals. The ability of MBF to detect dynamic brain activity precisely can aid numerous applications, including cases in which the limitations of conventional noninvasive techniques of brain function render them inadequate in diagnosing brain conditions. MBF can also potentially be applied to brain-machine interfaces (BMI): systems that allow for the direct communication between the brain and external devices


Colorectal cancer is the second most common cancer diagnosed in men and the third most commonly occurring in women worldwide. Interactions between cells and the surrounding extracellular matrix (ECM) are involved in tumor development and progression of many types of cancer. The organization of the ECM molecules provides not only physical scaffoldings and dynamic network into which cells are embedded but also allows the control of many cellular behaviors including proliferation, migration, differentiation, and survival leading to homeostasis and morphogenesis regulation. Modifications of ECM composition and mechanical properties during carcinogenesis are critical for tumor initiation and progression. The core matrisome consists of five classes of macromolecules, which are collagens, laminins, fibronectin, proteoglycans, and hyaluronans. In most tissues, fibrillar collagen is the major component of ECM. Cells embedded into fibrillar collagen interact with it through their surface receptors, such as integrins and discoidin domain receptors (DDRs). On the one hand, cells incorporate signals from ECM that modify their functionalities and behaviors. On the other hand, all cells within tumor environment  synthesize and secrete matrix macromolecules under the control of multiple extracellular signals. This cell-ECM dialog participates in a dynamic way in ECM formation and its biophysical and biochemical properties. Here, we will review the functional interplay between cells and collagen network within the tumor microenvironment during colorectal cancer progression. In recent decades, several works have underlined the importance of the microenvironment in colon cancer progression . In the In vitro, β1 integrin expression is down-regulated in response to 3D type I collagen  has been reported to upregulate the expression of ABCB1/gene and consequently P-glycoprotein in highly resistant colon carcinoma to chemotherapy  are the most abundant cell type in TME; they are an activated type of fibroblast that plays a major role in tumorigenesis and metastatic processes . CAFs deIn vivo, targeting of FAP-α into an immune-competent murine model of colon cancer decreased blood vessel density and induced fibrillar collagen accumulation  collagen-coated systems' routine use has largely shown their limitations to summarize the complexity of tumor initiation and progression processes. It is absolutely necessary to include some major extracellular components to mimic properties of the TME such as the spatial configuration  and the collagen , substancollagen . New 3D collagen .in situ (in vivo restrictions. In this model, human colonic microvascular endothelial cells cultivated in a 3D vessel-mimetic device are attached to the wall of the lateral channels of the microfluidic chip whereas HCT-116 cells are embedded in collagen IV-enriched Matrigel in the central chamber (Pape and colleagues developed a CRC model using high-density type I monomeric collagen, termed tumoroids . This moin situ . The str chamber .in vivo models (Considering the feature of tumor heterogeneity, the main limitation of these models is the presence of a single CRC cell type exhibiting a unique genetic pattern. The development of more realistic preclinical models is absolutely required and is a major challenge for the coming years, especially for improving drug screening. The use of patient-derived 3D tumor models may provide a solution to overcome the oversimplified 2D cell cultures and the limitations of o models . These nAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Ventricular premature beats originating from the right ventricular outflow tract can have myocardial extensions to the pulmonary valve and pulmonary artery. Treatment may consist of catheter ablation combined with the use of three-dimensional mapping to determine the exact location of ectopy. The location of ectopy relative to the pulmonary valve may be hard to ascertain. Intracardiac echocardiography (ICE) is a noninvasive approach by which one can determine the relationship of the pulmonary valve relative to the ablation catheter prior to ablation. ICE has achieved increasing popularity during the ablation of other arrhythmias such as tricuspid valve arrhythmias and has been shown to be helpful in guiding catheter placement prior to ablation. The additional information gained from deploying ICE may ensure more precise ablation, prevent theoretical damage to the pulmonary valve, and alleviate the need for a repeat procedure. Here, we present a case involving the use of ICE during a pediatric patient’s second ablation procedure to precisely determine the location of ectopy of nonsustained ventricular tachycardia originating from the distal pulmonary valve. Intracardiac echocardiography (ICE) is a noninvasive way to determine the relationship of the pulmonary valve relative to the RF catheter prior to ablation in real time without leaving the electrophysiology (EP) laboratory. ICE has experienced increasing popularity in the ablation of other arrhythmias, like the tricuspid valve arrhythmias, and has been shown to be helpful in guiding catheter placement prior to ablation.4 ICE also has a role in enhancing the safety of the ablation of RVOT arrhythmias near the pulmonary valve to prevent pulmonary valve dysfunction. Although not previously reported, inadvertent ablation energy applied to the pulmonary valve may impact its function. The additional information gained from using ICE may prevent the need for a repeat procedure. We herein present a case that incorporated ICE in a pediatric patient’s second RF ablation procedure to determine the precise location of ectopy of nonsustained ventricular tachycardia (NSVT) originating from the distal pulmonary valve.Ventricular premature beats (VPBs) originating from the right ventricular outflow tract (RVOT) can have myocardial extensions to the pulmonary valve and pulmonary artery.A 15-year-old female arrived at the Children’s Hospital of Orange County with exertional chest discomfort and palpitations. She already had undergone an EP study and RF ablation in the RVOT at another center. Although this prior ablation was acutely successful, she showed a very early recurrence of VPBs and rare symptoms of dizziness and shortness of breath. Her workup revealed ventricular bigeminy that suggested an RVOT etiology. Despite taking atenolol, she remained symptomatic. Her echocardiogram indicated normal cardiac function. Holter monitoring was performed twice, with resulting rates of monomorphic VPBs of 20.7% and 26.8%, respectively. The patient also had experienced a symptomatic event of syncope immediately after sprinting at basketball practice and was referred for exercise testing. During exercise testing, she showed frequent monomorphic VPBs that were suppressed with exercise. During recovery, she presented an abrupt onset of VPBs with the same morphology and symptomatic NSVT with dizziness and near-syncope. The decision was made to proceed with another EP study based on her persistent symptoms and a second possible RF ablation.® 3; Biosense Webster, Diamond Bar, CA, USA) localized the VPBs to the RVOT . The earliest bipolar activation in the RVOT was 20 ms presystolic, but unipolar electrograms from these locations had persistent R-waves. An 8-French (Fr) ICE catheter  was advanced to the proximal RVOT to visualize the location of the ablation catheter relative to the pulmonary valve . The ablation catheter was then advanced across the pulmonary valve into an area within the pulmonary valve cusp in the left posterior aspect of the proximal pulmonary artery . Presystolic activation was recorded at 37 ms earlier than the surface QRS with a pure Q-wave on the unipolar tracing . RF ablation with an irrigated-tip catheter  was performed with real-time visualization of the ablation catheter and its relationship to the pulmonary valve on ICE, which produced an acceleration of ventricular ectopy followed by the cessation of ventricular ectopic beats. The patient was asymptomatic during early follow-up, and repeat Holter monitoring revealed only six ectopic ventricular beats. One year after the procedure, she remained asymptomatic, with no VBPs observed during ambulatory monitoring.During the EP study, three-dimensional electroanatomical mapping (CARTO1 even though the RVOT interdigitates with the same myocardial extensions that surround the aortic root and aortic cusp, which are common sites of ablation of left ventricular outflow tract tachycardias. Advancing the ablation catheter into the pulmonary cusp resulted in a dramatic improvement in bipolar and unipolar activation times, with a pure Q unipolar electrogram, and ablation at the site of these electrograms resulted in complete and long-lasting success for this patient.Prior to the introduction of 8-Fr ICE catheters, ICE was not technically feasible in the majority of pediatric patients. The sizeable bore sheaths needed to introduce 10-, 12-, or 14-Fr ICE catheters were prohibitively too large for pediatric patients. However, in this case, the use of an 8-Fr ICE catheter advanced into the proximal RVOT successfully resulted in a real-time evaluation of the ablation catheter and its relationship to the pulmonary valve leaflets. Although the RVOT is a common origin for idiopathic VT and VPBs, the pulmonary cusp remains a somewhat rare site of origin7; however, very few pediatric patients were included in these studies. Further, complication rates published from these investigations focused on acute complications like acute cardiac events or those related to vascular access. To our knowledge, there has been no study that assessed the long-term outcomes of RF ablation of VPBs from the RVOT. Although injury to the pulmonary valve has not been reported, direct visualization of the ablation catheter and its proximity to the pulmonary valve was not routinely conducted or documented. Thus, it is our recommendation to use ICE in conjunction with RF ablation to better visualize the pulmonary valve to avoid causing potential damage to the valve. In our patient, the ectopic focus was located in the pulmonary cusp and was successfully ablated without signs of pulmonary valve dysfunction during her immediate postoperative course. In addition, the use of ICE initially may have prevented the need to repeat the procedure, which carries a number of concerns including those associated with sedation, thus making the cost–risk ratio more favorable.Published success rates of RF ablation for VPBs from the RVOT have been excellent and range from 93% to 97.1%We report on the use of an 8-Fr ICE catheter positioned in the RVOT to identify and successfully ablate a ventricular tachycardia originating from the pulmonary cusp in a pediatric patient with symptomatic ventricular tachycardia. The availability of smaller ICE catheters can help to expand the utility of ICE for pediatric patients through enhancing the safety of the procedure by minimizing the impact of vascular access.


Traumatic bone cyst (TBC), a “pseudocyst” that usually affects long bones, is a rare lesion among cystic lesions in the jaws. The most commonly affected site is the posterior mandible. Most of the time, TBC is asymptomatic and discovered during routine radiographic examination. The treatment recommended for TBC is surgical exploration followed by curettage of the bony walls, which also serves as a diagnostic procedure. A 27-year-old Caucasian male with a noncontributory medical history was referred to our department for the endodontic evaluation of the mandibular right first and second molars, which were connected to an extensive asymptomatic osteolytic lesion. A multimodular diagnostic assessment involving CBCT imaging, ultrasound, and histopathologic examination led to a definite diagnosis of a TBC overlapping with apical periodontitis (AP). Subsequently, a multidisciplinary treatment approach was performed, including surgical excision and biopsy of the lesion, endodontic retreatment of the right mandibular first molar, and postsurgical root canal treatment of the second molar. During the follow-up period of five years, the patient was reassessed periodically once a year and showed, in the absence of signs and symptoms, progressive healing of the affected area. The present article reports a case following the CARE guidelines of a TBC combined with AP where a multimodular diagnostic assessment was performed and discusses the possible pathogenetic mechanisms involved in its generation. Although the majority of osteolytic lesions in the periradicular area of teeth are inflammatory in origin, some may not be inflammatory. The assessment of osteolytic lesions in the maxillary bones should always involve an exhaustive medical history report and a careful clinical examination comprising diagnostic tests and radiographic examinations that can be crucial in the differential diagnosis between apical periodontitis (AP) and nonendodontic lesions . Three-dA 27-year-old Caucasian male with a noncontributory medical history and no previous trauma was referred from the maxillofacial department of the hospital for the endodontic evaluation of the mandibular right first and second molars, which were connected to an extensive asymptomatic osteolytic lesion incidentally discovered on a routine panoramic radiograph and scheduled to be treated surgically under general anesthesia. The patient reported that he had experienced pain and swelling in the right mandible months before, while the first molar had a history of caries, extensive amalgam restoration, and incongruous endodontic treatment performed ten years earlier. The clinical examination showed no sign of buccal or lingual bone expansion, no lymph node involvement, and intact overlaying mucosa. The first mandibular molar was asymptomatic. The right second mandibular molar was asymptomatic with an intact crown, and it responded normally to the sensitivity tests at the time of our examination. The panoramic radiograph showed a well-defined unilocular osteolytic lesion with sclerotic margins located between the two molar teeth and superimposed on the alveolar inferior nerve with a slight displacement of the second molar. The first molar showed inadequate root canal treatment with signs of resorption in the apical third of the distal root involved in the osteolytic lesion. A preoperative periapical radiograph taken using the paralleling technique confirmed these findings . Cone beThe present report documents a case of a mandibular lesion diagnosed as TBC accompanied by complications, such as involvement in the field of a tooth affected by AP and an inflammatory granuloma-like histological pattern. TBC is described with a variety of names , suggesting a lack of complete understanding of its nature . Indeed,The clinical significance of this case report is the presence of two lesions, AP and TBC, combined in the same anatomical site, and such presentation has not been described before in the literature. The management of this pathological entity possibly was due to a multimodular assessment. In addition, this is the first report to describe the ultrasound examination of a combined lesion.


This special issue about selected diseases of nonhuman primates was createdin honor of Franz-Josef Kaup, who worked as a primate pathologist atthe German Primate Center (DPZ) for 25 years. In 1992, Franz-Josef Kaupstarted his career at the DPZ as head of the working groupExperimental Pathology. Prior to that he worked as a research assistantin the division Electron Microscopy at the Institute of Pathology of theUniversity of Veterinary Medicine in Hanover. He was very experienced in thefield of electron microscopy and used this expertise to establish a centralelectron microscopy laboratory at the DPZ. In the beginning, research of theworking group Experimental Pathology was focused on gastrointestinal andrespiratory infections and was closely related to projects of the Departmentof Virology. At that time, experimental infections of rhesus macaques withsimian immunodeficiency virus (SIV) and associated opportunistic infectionsbecame the main subject of his research. The contribution of ChristianeStahl-Hennig and coauthors about SIV-induced cardiovascular diseasesreflects the still ongoing collaboration in this research field. Aftermerging the Experimental Pathology and Primate Husbandry in 1996,Franz-Josef Kaup headed the newly created Department of Veterinary Medicineand Primate Husbandry. This department became the central service unit ofthe DPZ in 1999 and offered a broad spectrum of servicesin veterinary diagnostics, primate husbandry, and animal welfare, which wasintensively used by many internal and external scientists. In 2001, WalterBodemer joined the group and the scientific contents expanded with a newfocus on the pathogenesis of prion diseases. Some important aspects of thisera are summarized in the work of Walter Bodemer. Helicobacter pylori infections. Currently, themain research focus is on the pathogenesis of orthopoxvirus infections.Kerstin Mätz-Rensing and colleagues established a new animal model fororthopox virus infections, which is based on a natural outbreak of thedisease in a private New World monkey husbandry. During this outbreak, a neworthopox virus was discovered, which was named calpox after its hostspecies. This animal model was used for pathogenetic and vaccination studiesin orthopox virus research. Over the years, a close cooperation with severalworking groups working in this important field of virus research arose. Thecontribution of Kerstin Mätz-Rensing gives an example of theexperimental work with the newly discovered calpox virus in closecollaboration with colleagues at the Robert Koch Institute in Berlin.Several animal models were successfully established under the leadership ofFranz-Josef Kaup, including an animal model for The Department of Veterinary Medicine and Primate Husbandry wasreorganized into thePathology Unit and the Cost Center Primate Husbandry, both headed byFranz-Josef Kaup. Since 2004, the Pathology Unit has been composed of the Primate PathologyGroup headed by Kerstin Mätz-Rensing, the Dermatopathology Group headedby Bärbel Löblich-Beardi and the Herpes Virus Group headed by DieterJentsch. The research spectrum broadened with the dermatopathology- andherpes-virus-related research. As head of the Primate Husbandry Franz-JosefKaup focused on the herpes B problematic in macaques and supported theestablishment of herpes B diagnostics at the DPZ. Herpes B is of specialinterest when handling macaques in research projects and breeding colonies.The development of a valuable herpes B screening test and the current stateof art at the DPZ is described in the contribution of Stefan Pöhlmannand colleagues.Another important disease that can cause health problems in breedingcolonies is endometriosis. The contributions of Eva Gruber-Dujardin andIvanela Kondova address this disease and its related research and lead overto spontaneous diseases of nonhuman primates, which have been in the focusof the Pathology Group for many years.Over the years, several important cases of emerging diseases, rarelyoccurring neoplasia, and unique disease entities in nonhuman primates weredescribed by this group. The work by Karen Lampe about a unique T-celllymphoma in a patas monkey and by Nicole Cichon about a unique granulomatousarteritis are examples of those spontaneous diseases observed during routinepathomorphologic diagnostics. The opportunity to work on those extraordinarycases emerged from close contact with several German zoos that sought theexpertise of Franz-Josef Kaup's group in the field of primate diseases andpathology. Other interesting case reports resulted from the routine clinicaland diagnostic work such as the contribution of Tamara Becker aboutGuillain–Barré syndrome in a rhesus monkey and Roland Plesker, a closecolleague from Paul Ehrlich Institute in Frankfurt, about a gallstoneproblematic.Over the years, Franz-Josef Kaup supported the work of colleagues from theDepartment of Behavioral Ecology and Sociobiology and other colleaguespredominantly working in the field in the natural habitats of nonhumanprimates. One of the biggest health problems among natural primate coloniesis parasites, and the articles by Andrea Springer, Peter Kappeler, FabianLeendertz reflect this situation.A cooperation with the working group of the Fraunhofer Institute forToxicology and ExperimentalMedicine (ITEM) in Hanover headed by Franziska Dahlmann was established in2010. The ITEM group worked on primate models for obstructive lung diseasesand asthma and was supported by the working group Anatomy/Pathology of theRespiratory Tract headed by Martina Bleyer. The contributions of MartinaBleyer and Franziska Dahlmann in this issue will highlight aspects of theirwork. Over the years, Franz-Josef Kaup's main research focuses were lungdiseases, starting with the work in Hanover on chronic obstructive pulmonary disease in horses. With the newproject on an asthma model in nonhuman primates, the circle of his lifeworkis complete.


Staphylococcus aureus but orthologs of Bap in other staphylococcal species belong to the core genome. When present, Bap promotes adhesion to abiotic surfaces and induces strong intercellular adhesion by self-assembling into amyloid like aggregates in response to the levels of calcium and the pH in the environment. During infection, Bap enhances the adhesion to epithelial cells where it binds directly to the host receptor Gp96 and inhibits the entry of the bacteria into the cells. To perform such diverse range of functions, Bap comprises several domains, and some of them include several motifs associated to distinct functions. Based on the knowledge accumulated with the Bap protein of S. aureus, this review aims to summarize the current knowledge of the structure and properties of each domain of Bap and their contribution to Bap functionality.One of the major components of the staphylococcal biofilm is surface proteins that assemble as scaffold components of the biofilm matrix. Among the different surface proteins able to contribute to biofilm formation, this review is dedicated to the Biofilm Associated Protein (Bap). Bap is part of the accessory genome of  Staphylococcus aureus V329  of SaPIbov2 in S. aureus V329 carried two-point mutations that abrogated the integrase functionality. As a consequence, SaPIbov2 remained stable in the bacterial chromosome. If the integrase would have been functional, most of the biofilm deficient mutants had been due to the loss of the SaPI element and not to genetic inactivation caused by transposon insertion. The presence of Bap in a pathogenicity island was anticipating that the fitness cost imposed by SaPIbov2 carriage was compensated by the benefit that the SaPI cargo (bap gene and the corresponding ABC transporter) conferred during the intramammary gland infection. Initial searches for Bap orthologs revealed the presence of Bap orthologs in many different bacterial species  was identified during the analysis of biofilm defective transposon insertion mutants in the bovine mastitis isolate, eus V329 . S. aure species . The rec species . Very ofing unit ; Table 1Listeria monocytogenes, bacilli, clostridia, or nocardia , Spa, fibronectin-binding protein B (FnbpB), serine-aspartate repeat protein C (SdrC) and D  following the signal peptide . Sequencity 10%; . Region  warneri ,B. Secon warneri . Severalproteins . Intuitiproteins . A S. auunctions . Domain tor Gp96 . The intEnterococcus faecalis (S. aureus contains two sequences with high similarity to the consensus EF-hand motif (amino acids 729–741 and amino acids 752–764). The EF-hand motif consists of a 12-residue loop flanked on both sides by a 12-residue alpha-helical domain and is involved in binding intracellular calcium . Thus, increasing number of evidence suggest that amyloid-like conformation is a general mechanism to mediate biofilm formation of the Bap_like proteins (This strategy to mediate multicellular behavior seems to be conserved among the Bap orthologs. Using the curli-dependent amyloid generator (C-DAG) system to detect amyloid aggregates , it was operties . Interesproteins .S. aureus, region C is comprised of a core of 14 tandem repeats of 86 amino acids (C-repeats), which are identical even at the nucleotide level  comprises three repeats of 18 amino acids and a cell-wall-anchoring region consisting of an LPXTG motif and hydrophobic amino acid segments characteristic of surface proteins covalently anchored to peptidoglycan. Region D repeats are present in many of the staphylococcal Bap proteins . For calcium to serve as a regulator of Bap function, the fluctuations in the local calcium concentration should be higher than the binding affinity of the protein for the cation. Otherwise, Bap-mediated biofilm development will be irreversible, and bacterial propagation from the site of infection will be seriously compromised. It is very likely that only in the mammary gland environment the concentration reaches the high values needed to inhibit the function of Bap. It will be important to determine whether Bap-mediated biofilm is a system specialized for the conditions present in the mammary gland. If so, it will represent an excellent model to explore the real contribution of adhesion and biofilm development during the course of the infection process.A second intriguing question is related with the presence of Bap in bovine mastitis isolates of IL and JV conceptualized the content of the article. IL, JV, and XF contributed to writing and revision of the work. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.