Pseudomyxoma peritonei (PMP) is an uncommon pathology, and its rarity causes a lack of scientific evidence, precluding the design of a prospective trial. A diagnostic and therapeutic algorithm (DTA) is necessary in order to standardize disease treatment while balancing optimal patient management and the correct use of resources. The Consensus of the Italian Society of Surgical Oncology (SICO) Oncoteam aims at defining a diagnostic and therapeutic pathway for PMP and appendiceal primary tumors applicable in Italian healthcare.Aim: Pseudomyxoma peritonei (PMP) is an uncommon pathology, and its rarity causes a lack of scientific evidence, precluding the design of a prospective trial. A diagnostic and therapeutic algorithm (DTA) is necessary in order to standardize the disease treatment while balancing optimal patient management and the correct use of resources. The Consensus of the Italian Society of Surgical Oncology (SICO) Oncoteam aims at defining a diagnostic and therapeutic pathway for PMP and appendiceal primary tumors applicable in Italian healthcare. Method: The consensus panel included 10 delegated representatives of oncological referral centers for Peritoneal Surface Malignancies (PSM) affiliated to the SICO PSM Oncoteam. A list of statements regarding the DTA of patients with PMP was prepared according to recommendations based on the review of the literature and expert opinion. Results: A consensus was obtained on 33 of the 34 statements linked to the DTA; two flowcharts regarding the management of primary appendiceal cancer and peritoneal disease were approved. Conclusion: Currently, consensus has been reached on pathological classification, preoperative evaluation, cytoreductive surgery technical detail, and systemic treatment; some controversies still exist regarding the exclusion criteria for HIPEC treatment. A shared Italian model of DTA is an essential tool to ensure the appropriateness and equity of treatment for these patients. Pseudomyxoma peritonei (PMP) is a rare peritoneal malignancy characterized by an effusion of mucinous or viscous ascites in the peritoneal cavity, associated or not with the presence of epithelial cells, whose degree of malignancy is variable. The incidence of PMP is estimated at 1–3 per million people annually [The symptoms are heterogenous: often appendiceal cancers are found incidentally at radiological exam or laparoscopy/laparotomy for appendicitis. The most common symptoms are pain and abdominal distension; over time, this syndrome results in massive abdominal bloating and associated mechanical and functional gastrointestinal obstruction .Although this peritoneal malignancy is minimally invasive and rarely causes hematogenous or lymphatic metastases, conventional surgical management of repeated interval debulking for symptomatic relief resulted in a low long-term survival expectation ,4. In thGiven its rarity, randomized controlled trials on its management are lacking; in this scenario, diagnostic and therapeutic algorithms (DTA) are mandatory for several reasons. CRS and HIPEC are available in a limited number of specialized centers; moreover, most PMPs are diagnosed incidentally, often in an emergency setting. A guideline can help follow a correct diagnostic-therapeutic path and direct patients to referral centers.The consensus panel included 10 delegated members of oncological referral centers affiliated with the Peritoneal Surface Malignancies Group of the Italian Society of Surgical Oncology (SICO). The recommendations are based on a review of the literature and expert opinion, as well as evidence synthesis. The statements covered the entire path from diagnosis through the decision-making process to treatment with curative and/or palliative intent for patients with appendiceal cancer and pseudomyxoma peritonei.The topics of the statements were evaluated and modified during a first online meeting of the expert panel. The panel then divided the indications into two rounds using the RAND/UCLA Appropriateness Method (RAM) . In the In the second round, the panel members met on the web; each panelist received before the meeting a document showing the distribution of all the experts’ first round ratings. During the discussion, panelists debated the ratings, focusing on areas of disagreement; then the panel rerated each indication individually and anonymously. The same method was used for the two-round rating of the two flowcharts.The statements were related to different question points regarding the management of appendiceal tumors and pseudomyxoma peritonei, from diagnosis to treatment. All the statements were considered appropriate, with an AMS ranging between 7 and 9, and all the propositions were considered valid. Statement 26, although scored as appropriate (AMS 8), did not reach consensus with an IPR lower than the limit (6.7–8)—The two flowcharts about PMP management  and primThe DTA represents a systematic process, specific for disease and stage, that leads each specialist along the diagnostic-therapeutic path of the disease. The purpose of the DTAs is to increase the quality of assistance, equity in terms of access to care, and availability while improving outcomes and promoting patient safety through the use of the right resources.The rarity of the pathology precluded the design of prospective trials. This consensus tried to define the best diagnostic and therapeutic algorithm for pseudomyxoma peritonei and appendiceal primary tumors. The vast majority of these statements are based on data obtained in clinical studies and experts’ recommendations on disease management.There was widespread agreement that patients diagnosed with PMP should be evaluated at a peritoneal surface malignancy referral center. Most patients are referred from other surgical/gynecological, or emergency units. Referring teams should perform the minimal surgical procedures required to obtain a histopathological diagnosis or solve the emergency condition; extensive previous attempts to reduce tumor load were shown to have a negative impact on survival .There has been considerable debate in the literature about the site of origin and pathological classification of PMP. These difficulties in the pathological classification of the clinical entity of PMP have led to ongoing confusion concerning the appropriate treatment.In 1995, Carr et al. proposed a classification of appendicular mucinous tumors based on their review of 184 tumors into adenoma, mucinous tumors of uncertain malignant potential, and adenocarcinoma . In the In 2003, Misdraji et al. subsequently proposed a two-tiered system using “low-grade appendiceal mucinous neoplasm” (LAMN) for all low-grade mucinous tumors of the appendix that do not demonstrate invasion of the appendiceal wall, either confined to the appendix or that have spread to the peritoneum; adenocarcinoma was reserved for tumors with either high-grade cytology or destructive invasion .Other classifications of primary pathology and peritoneal diffusion have emerged over time ,11.At the PSOGI meeting in 2012 in Berlin, a generalized inhomogeneity was still present, and consequently, in 2016, a consensus was organized in order to standardize diagnostic terminology for appendiceal mucinous tumors with or without peritoneal disease; according to the panelists’ ratings, the PSOGI 2016 Consensus for histopathological classification should be adopted [A preoperative work-up including serum markers , a CT scan, and a colonoscopy was rated as fully appropriate by the majority of the panelists (80%); in some studies, preoperative elevation of tumor markers was reported to be linked to the probability of complete cytoreduction  and striLaparoscopy in order to obtain a histopathologic diagnosis and evaluate resectability may be considered ,27,28. SAppendectomy is curative in cases of incidental adenoma, hyperplastic polyp, or LAMN in the appendectomy specimen ,30. In cIn the case of a neuroendocrine tumor, a right-sided hemicolectomy should be considered if unfavorable prognostic factors are present . The litThere was complete agreement in considering CRS + HIPEC as the first therapeutic option in patients with PMP ,38,39. AThe main determinant of the outcome, beside histology, is the completeness of the cytoreduction ; howeverThe role of systemic treatment in the management of PMP is still poorly investigated: the small amount of available evidence shows no benefit from neoadjuvant chemotherapy neither in low-grade nor in high-grade PMP ,52,53,54Palliative systemic chemotherapy can be considered when surgery is not feasible for unresectable disease or poor general conditions ,60: desp2) and MMC (40 mg) in closed HIPEC, evaluating toxicity, quality of life, and survival [According to literature results, the mitomycin C (MMC) regimen is recommended in patients with PMP eligible for CRS + HIPEC ,69, althsurvival : no signAnalogous recommendations were reported in a recently published consensus by members of the PSOGI Executive Committee on the management of appendiceal cancer and PMP; recommendations were provided based on three Delphi voting rounds with GRADE-based questions amongst a panel of 80 worldwide PMP experts .The increasing network of PSM-specialized centers may help to consolidate the available data about this rare pathology, compensating for the lack of hard scientific evidence in PMP treatment. This DTA for the management of patients with appendiceal cancer and PMP is an important tool for healthcare providers to ensure the appropriateness and equity of treatment for these patients.


Arthropods are characterized by having an exoskeleton, paired jointed appendages and segmented body. The number and shape of those segments vary dramatically and unravelling the evolution of segmentation is fundamental to our understanding of arthropod diversification. Because trilobites added segments to the body post-hatching which were expressed and preserved in biomineralized exoskeletal sclerites, their fossil record provides an excellent system for understanding the early evolution of segmentation in arthropods. Over the last 200 years, palaeontologists have hypothesized trends in segment number and allocation in the trilobite body, but they have never been rigorously tested. We tabulated the number of segments in the post-cephalic body for over 1500 species, selected to maximize taxonomic, geographical and temporal representation. Analysis reveals long-term shifts in segment number and allocation over the 250-million-year evolutionary history of the clade. For most of the Palaeozoic, the median number of segments in the body did not change. Instead, the total range decreased over time and there was long-term increase in the proportion of segments allocated to the fused terminal sclerite relative to the articulated thoracic region. There was also increased conservation of thoracic segment number within families. Neither taxonomic turnover nor trends in functionally relevant defensive behaviour sufficiently explain these patterns. The final segmental composition of the body in many arthropods is attained during post-embryonic development through a series of moults. Hemianamorphic arthropods are characterized by undergoing a phase of moulting (ecdysis) during which new segments are added to the body followed by a phase during which ecdysis and growth continues even though no new segments are added to the body. Arthropods with this mode of segmentation occur across the phylum, including some crustaceans, some myriapods and some extinct arthropods like trilobites . TrilobiThe mature trilobite exoskeleton consisted of an anterior cephalic shield comprised of fused segments, and a trunk consisting of a thorax with narrow, similarly shaped articulated tergitesA 1920 compilation based on a small number of specimens reported a decrease in the average number of thoracic tergites from the earliest Cambrian and more protracted increase in the number of pygidial segments across the Palaeozoic . Changes. 2N > 22 000, [We tabulated the number of segments in the trunk for 1589 trilobite species from images sourced from primary and secondary literature and museum catalogues . We limited our search to complete, well-preserved, articulated specimens, necessarily excluding the vast majority of named trilobite species  for whi 22 000, –15; see p-values, but not enough to change the interpreted significance of the results. The number of permutations for all applications was 10 000.Because the distributions of segment numbers in different time intervals show skewed distributions with heavy tails and different sample sizes , common approaches for testing for differences in means may be inappropriate. Instead we test for location shifts in the median among multiple groups using the single-step procedure of Richter & McCann . The proIn order to determine if the median number of segments changed significantly through time, we applied the Richter & McCann  single-sAll data analysis and visualization were done in the statistical programming language R v4.2.2  using th. 3a, figure 1a). Subsampling indicates that the contraction in range is not an artefact of differences in sample size across time intervals . This contraction is consistent with an increase in taxonomic conservation in the number of segments in the thorax within subclades , with the largest and most significant increases occurring in the late Palaeozoic .As a result of the above changes, the median number of segments in the trunk remained essentially constant until the late Palaeozoic but the range in segment number decreased considerably (figure 1The lack of taxonomic consensus among trilobite systematists and a paucity of robust clade-wide trees ,29,30, s. SimilarA candidate ecological explanation lies in long-term changes that occurred in enrolment behaviour in trilobites. Enrolment is a posture seen in trilobite specimens whereby the pygidium and cephalon were brought in close proximity. Frequently, the cephalon and pygidium are in complete alignment and the exoskeleton would have completely enclosed the ventral side of the body including appendages. By analogy to modern arthropods, like terrestrial isopods, enrolment is interpreted to have been a defensive behaviour. Evidence of the long-term adaptive value of this behaviour comes from the appearance of features on the margins of the cephalon and pygidium, such as grooves, that facilitated a tight fit devoid of gaps –37. SeveIn 1839, Hermanus Emmrich observed that trilobites with large numbers of thoracic tergites often had small numbers of pygidial segments, and vice versa, and proposed a ‘law’ of a constant 21 segments in the trilobite body (, origina


Many metagenomic studies have linked the imbalance in microbial abundance profiles to a wide range of diseases. These studies suggest utilizing the microbial abundance profiles as potential markers for metagenomic-associated conditions. Due to the inevitable importance of biomarkers in understanding the disease progression and the development of possible therapies, various computational tools have been proposed for metagenomic biomarker detection. However, most existing tools require prior scripting knowledge and lack user friendly interfaces, causing considerable time and effort to install, configure, and run these tools. Besides, there is no available all-in-one solution for running and comparing various metagenomic biomarker detection simultaneously. In addition, most of these tools just present the suggested biomarkers without any statistical evaluation for their quality.To overcome these limitations, this work presents MetaAnalyst, a software package with a simple graphical user interface (GUI) that (i) automates the installation and configuration of 28 state-of-the-art tools, (ii) supports flexible study design to enable studying the dataset under different scenarios smoothly, iii) runs and evaluates several algorithms simultaneously iv) supports different input formats and provides the user with several preprocessing capabilities, v) provides a variety of metrics to evaluate the quality of the suggested markers, and vi) presents the outcomes in the form of publication quality plots with various formatting capabilities as well as Excel sheets.https://github.com/mshawaqfeh/MetaAnalyst.The utility of this tool has been verified through studying a metagenomic dataset under four scenarios. The executable file for MetaAnalyst along with its user manual are made available at The online version contains supplementary material available at 10.1186/s12874-022-01812-5. In contrast to the conventional cultivation-based approaches, metagenomics enables the characterization of compositional and functional profiles of microbial colonies directly from environmental samples. Increasing number of metagenomic studies have revealed strong associations between the imbalance in microbial abundance profiles and a wide range of diseases such as obesity , detected markers by each algorithm [see Additional file 3], and the overlapped set of markers [see Additional file 4] as excel sheets.To shed insights on the utility of the multi-level labeling feature of MetaAnalyst in enabling the study of the dataset from different perspectives, this section demonstrates how to extend the previous scenario to study the impact of obesity and gender. To illustrate, assume that the researcher is interested in excluding the impact of obesity from the previous study  automatically installs and handles all package dependencies-related issues of 28 state-of-the-art biomarker detection algorithms and 4 classification models with several data preprocessing capabilities, (ii) provides a simple graphical user interface that naturally guides the user through the analysis pipeline, (iii) accepts input datasets in several files with flexible data formats, (iv) supports multi-level labeling feature to flexibly cluster the positive and negative cohorts and to study a given dataset under a multitude of scenarios, (v) runs several algorithms simultaneously and evaluates their performance according to three criteria , (vi) reports the results in publishing-quality plots as well as Excel sheets. Due to the similarity between metagenomic data and other omic data and the possibility of applying the packed algorithms in MetaAnalyst to other omic data, we believe that MetaAnalyst will become a popular tool for metagenomics applications and other studies. The executable file for MetaAnalyst along with a detailed user manual are made available at Additional file 1. The complete set of plots that are generated by the MetaAnalyst software for scenario 1.Additional file 2. An Excel sheet that is generated by the MetaAnalyst software that contains the obtained classification performance  by the five algorithms included in the study  over Scenario 1 for various number of top features .Additional file 3. An Excel sheet that is generated by the MetaAnalyst software that contains the top 20 detected metagenomic markers by the five algorithms included in the study  over Scenario 1.Additional file 4. An Excel sheet that is generated by the MetaAnalyst software that contains the overlapped set of metagenomic markers by the five algorithms included in the study  over Scenario 1.


Using simulators in high education enables practical training by repetition in circumstances close to reality reducing the stress of both animal and operator. The limited resources of veterinary schools, the increase in the number of students in lecture halls, and the low availability of animals for teaching due to welfare regulations, reduce teaching opportunities with live animals being simulator as the better alternative. This study aimed to assess the efficacy of a low-cost handmade simulator (SIMCA-COW) in eight veterinary students inexperienced in palpation, ultrasonography evaluation, and artificial insemination in cows.Two sets of exercises were carried out: structure localization by rectal palpation and ultrasonography were evaluated by the inexpert veterinary students in the SIMCA-COW simulator. Also, evaluated the length of time to insert the insemination catheter through the cervix in the inert simulator during four sessions.All the students were able to palpate both structures and to locate the body and both uterine horns by ultrasonography. Cervix and follicles were located by 5/8 (62.5%) students and 3/8 (37.5%) students found the corpus luteum by ultrasonography. A reduction in time span between the first and fourth intrauterine insemination attempts was observed .The simulator validated in this study (SIMCA-COW) allows training and learning by repetition, saving the limitations found in live animal practice. Bovine rectal palpation is commonly used for reproductive tract evaluation and the most popular among large animal veterinarians . Rectal Training and teaching programs are fundamental for the acquisition of skills with direct application of this technique . Animal This study aimed to assess the usefulness of a low-cost handmade simulator called SIMCA-COW as a model for structure recognition training through rectal palpation, ultrasound evaluation, and intrauterine insemination by inexperienced veterinary students.The nature of the study did not require ethical approval because slaughterhouse viscera was used to develop the simulator.The study was conducted from June 2022 to July 2022 in the Agrarian School of Elvas from Polytechnic Institute of Portalegre . Inexperienced veterinary volunteer students were from different Veterinary Universities in Portugal.in vivo  In the first exercise, inexperienced students with interest in the bovine species were given some basic theoretical knowledge and afterward performed a simulator test to recognize the structures. The theoretical training was based on reviewing the anatomy of the reproductive system of cows, the estrus cycle, physiological alterations, and ultrasound images. For the practical simulator test, the initially stood at the exposed side of the simulator and guided each student in recognition of the reproductive structures. Subsequently, the students practiced the acquired knowledge by themselves in the same reproductive organ and an individual exam was made to assess structure identification by each student. Afterward, an ultrasonograph was provided to each individual without prior practical training in order to analyze the skills acquired by structure recognition made in the previous exercise . To incrThe data were analyzed using the statistical software package Sigma Plot Version 12.3 for Windows . The means of the values were represented with standard error (mean ± standard error of the mean). The groups were compared with a one-way analysis of variance to check whether they followed a Gaussian distribution. Differences between values were considered significant when p < 0.05 according to Tukey´s honestly significant difference test.In the first exercise, all the students managed to find the cervix, uterine body, both uterine horns, and ovaries through rectal palpation in the simulator after training with the teacher . Using tOver the four attempts of the second exercise, a decrease was observed in the time spent by all individuals in performing the intrauterine artificial insemination technique . Signifiin vivo [This study aimed to test the efficacy of a handmade simulator (SIMCA-COW) made at a low-cost. Simulation in the practice of veterinary medicine represents a safe environment where students’ errors can be quickly corrected . Moreovein vivo . The lowin vivo , teachinin vivo .There is controversy among authors about how rectal palpation affects pregnant cows. Some studies suggest that rectal palpation in early stages may be a major cause of pregnancy loss , 21, whiThe eight students who participated in this study were able to locate by palpation all the reproductive structures with the SIMCA-COW model. The use of abattoir viscera is a procedure widely used in veterinary practices and their use progressively reduces the amount of time needed for the students to find the structures . The devet al. [The majority of large animal simulators are focused on bovine rectal palpation and/or pregnancy diagnosis , while iet al.  found thet al. , improviRecently, simulator use in veterinary education has increased significantly, allowing consistent, practical teaching and reducing the number of live animals used . The lowin vivo practicing.The SIMCA-COW low-cost handmade simulator, aimed at safe student practices in the area of veterinary medicine, seems to be an alternative to simulators of different materials available on the market at higher costs, allowing for repetition training and solving limitations of EMP: Conceived the idea and built the simulator. EMP and CBS: Collected the data, performed the computations, verified the analytical methods and prepared the manuscript. Both authors have read and approved the final manuscript.


There are critical periods of mortality risk at onset and cessation of opioid agonist treatment. We aim to determine whether non-fatal overdose followed the same pattern as fatal overdose, comparing the first 4 weeks of treatment and treatment cessation and the remainder time off treatment, with the remainder treatment time, to determine intervention markers.Retrospective cohort study of people with a history of opioid agonist treatment using linked New South Wales data. The incidence of non-fatal overdose hospitalization; emergency department presentation; and fatal overdose from national death records were compared. Rates were calculated using generalized estimating equations adjusting for demographics, year, and recent health and incarceration events.The rate of an emergency department drug overdose presentation was highest. It was more than three-fold the rate of opioid non-fatal overdose hospitalisation and 14 times higher than fatal opioid overdose. It was also twice the rate of non-opioid non-fatal overdose hospitalisation.Fatal overdose was lowest while in treatment. This differed from the measures of non-fatal overdose, the overdose rate was elevated in the first four weeks in treatment as well as the first four weeks post treatment.Retention on opioid agonist treatment is protective against drug related overdose. There is elevated risk of non-fatal overdose at treatment initiation that is not evident for fatal overdose, however the first month of treatment cessation is a critical period for both non-fatal and fatal overdose. These findings emphasize the importance of treatment retention and interventions for polysubstance overdose at cessation.


The COVID-19 pandemic brought unprecedented disruptions in the ways we lived and interacted with one another. Research studies done in the immediate aftermath suggested that the COVID-19 pandemic and associated lockdown restrictions may have increased feelings of isolation and loneliness, which together with disruptions in services may have precipitated psychological distress and mental health deterioration, particularly among persons with pre-existing mental health conditions. Following the introduction of first national lockdown in late March 2020, all visits to the hospital by family and friends were ceased. VTC became one of the rapid interventions implemented across several NHS Hospitals to promote continued patient contact with carers. In October 2021, we set out to undertake an evaluation project to determine the level of patient satisfaction with the use of Skype for social visits, to understand patient and staff perspectives on its pros and cons, and to understand patient preference post-COVID-19 pandemic.All ward-based staff who had ever facilitated Skype social visits and all patients who had had at least one social visit facilitated by Skype were approached to participate in the project. Data were collected using anonymous questionnaires with both quantitative and qualitative items.A total of twenty-nine patients and thirty-nine nursing staff participated in the study.Sixty-two per cent of patient-participants reported being satisfied with the Skype social visits and over half (52%) rated the Skype social visits as ‘the same’ as face-to-face visits. All participants reported patient-satisfaction with the process and speed of setting up a Skype visit, the benefits of visual contact and the reduction of travel costs. A few patient-participants noted that they relished the opportunity of seeing their home environment. Issues regarding increased demands on staffing resources, privacy, IT skills, and hardware and software glitches were identified.Overall, Skype social visits have been a positive experience for the patients and have not resulted in any significant risk concerns. Most patients (90%) indicated that they would like Skype social visits to continue post-COVID-19 pandemic.The average length of stay (LOS) of patients is often longer in forensic compared to general adult mental health units and about 4.5 years at the study site. This evaluation found that the introduction of Skype for the purposes of social visits was considered a useful development by both patients and staff. The study findings were fed back to all stakeholders and certain changes have been implemented as a result.


Preeclampsia, a human pregnancy syndrome, is characterized by elevated blood pressure and proteinuria after the 20th week of gestation. Its etiology remains unknown, and its pathophysiological mechanisms are related to placental hypoperfusion, endothelial dysfunction, inflammation, and coagulation cascade activation. Recently, the role of the complement system has been considered. This syndrome is one of the main causes of maternal and fetal mortality and morbidity. This article discusses the hypothesis of preeclampsia being triggered by the occurrence of inadequate implantation of the syncytiotrophoblast, associated with bleeding during the first stage of pregnancy and with augmented thrombin generation. Thrombin activates platelets, increasing the release of antiangiogenic factors and activating the complement system, inducing the membrane attack complex (C5b9). Immature platelet fraction and thrombin generation may be possible blood biomarkers to help the early diagnosis of preeclampsia. Hypertensive disorders are very frequent complications in pregnancy. It is one of the main causes of maternal and fetal morbidity and mortality.Defective implantation of the syncytiotrophoblast and bleeding in the first trimester of pregnancy contribute to increased thrombin generation, causing increased platelet activation and release of antiangiogenic factors in the maternal circulation (such as sFLT-1). The activation of platelets also triggers the complement system, membrane attack complex (C5b9) .Hemostatic changes occur during pregnancy, shifting the balance in favor of hypercoagulability with an increased thrombosis risk.Platelets play an important role in the pathophysiology of PE, being responsible for coagulation and participating as an important inflammatory mediator. There is evidence of PE with platelet activation and increased platelet surface markers (CD62P) when comparing women with PE to healthy women.Platelet activation may be due to increased thrombin generation. Thrombin is a multifunctional protease, responsible for coagulation cascade and one of the most potent platelet activators. Activation through thrombin generation causes degranulation and platelet activation, which displaces adhesion receptors to the cell surface and releases hemostatic and inflammatory mediators in the bloodstream, facilitating cell adhesion.There are some studies showing association between thrombin generation increase and the pathogenesis of PE.There is evidence shown by the increased generation of thrombin in pregnant women with PE.Thus, thrombin increases the secretion of sFlt-1. Soluble feline McDonough sarcoma-like tyrosine kinase-1is a receptor protein produced by syncytiotrophoblast, and its concentration in normal pregnancies is only a few times higher than that of placental growth factor (PlGF). It is related to the maternal endothelial dysfunction, a PE feature.Increased SFlt-1 in maternal circulation is one of the elements that determines the PE maternal multisystemic syndrome. These changes in sFlt-1 concentration precede the onset of clinical and laboratory symptoms in preeclamptic women by ∼ 5 to 6 weeks.In addition, evidence brought by few studies shows the involvement of the excessive increase in tissue factor (TF) with the activation of proteins C3 and C5 of the complement system. This activation is probably due to the stress generated by the syncytiotrophoblast. Although TF is important for placental development, its increase during trophoblast implantation and tissue hemorrhage exarcebates the activation of coagulation cascade, which has been the first hypothesis of abnormal implantation of trophoblast.The activated platelets trigger the alternative complement pathway, especially the membrane attack complex (C5b9). And the activation of complement proteins may help to trigger PE and hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome. Burwick et al.Platelets play a fundamental role in the pathophysiology of PE. We suggest that platelet activation in preeclamptic pregnancy is caused by the excess generation of thrombin associated with bleeding in the first trimester, increasing the release of antiangiogenic factors and activating the complement system before the onset of the clinical symptoms of the syndrome. Although platelet activation and increased IPF is confirmed in pregnant women who develop PE, these tests are not routinely performed for diagnosis. Laboratory essays for measuring IPF and thrombin generation are simple and easily accessible in laboratories that use advanced technology to perform them. They may be useful for the early diagnosis of this syndrome and the management of patients. Therefore, we believe further studies focused on these laboratory tests are required to enable early diagnosis and treatment of the disease.


Instrumented ultrasonic tracking provides needle localisation during ultrasound-guided minimally invasive percutaneous procedures. Here, a post-processing framework based on a convolutional neural network (CNN) is proposed to improve the spatial resolution of ultrasonic tracking images.in vivo. The axial and lateral spatial resolution of the tracking images were used as performance metrics of the trained network.The custom ultrasonic tracking system comprised a needle with an integrated fibre-optic ultrasound (US) transmitter and a clinical US probe for receiving those transmissions and for acquiring B-mode US images. For post-processing of tracking images reconstructed from the received fibre-optic US transmissions, a recently-developed framework based on ResNet architecture, trained with a purely synthetic dataset, was employed. A preliminary evaluation of this framework was performed with data acquired from needle insertions in the heart of a fetal sheep Application of the CNN yielded improvements in the spatial resolution of the tracking images. In three needle insertions, in which the tip depth ranged from 23.9 to 38.4 mm, the lateral resolution improved from 2.11 to 1.58 mm, and the axial resolution improved from 1.29 to 0.46 mm.The results provide strong indications of the potential of CNNs to improve the spatial resolution of ultrasonic tracking images and thereby to increase the accuracy of needle tip localisation. These improvements could have broad applicability and impact across multiple clinical fields, which could lead to improvements in procedural efficiency and reductions in risk of complications. Ultrasound-guided needle insertions are widely performed in many clinical contexts . A key cin vivo transmission-mode tracking images. Additionally, we investigate the impact on CNN performance by comparing different parameters with which to generate ground truth images for CNN training. This preliminary evaluation was performed using data acquired from a preclinical fetal sheep model.With ultrasonic tracking, the resolution at which the needle tip can be resolved is of critical importance. Recently, a framework based on a convolutional neural network (CNN) was proposed to enhance the image quality of instrumented reception-mode ultrasonic tracking images that were acquired with ultrasound reception from the needle tip . Here, wThe instrumented ultrasonic tracking system  compriseZ and X are the axial and lateral dimensions, respectively) were used to train three CNNs and their performance was compared. The choice of anisotropic kernels elongated in the axial dimension was made to compensate for the difference in axial and lateral sampling rates in the channel data.Post-processing of tracking images was performed using a framework  based onThe CNN framework comprised a modified residual neural network with 16 residual blocks . Each blin vivo, as part of a broader set of preclinical experiments. The procedure was conducted in accordance with the U.K. Home Office regulations and the Guidance for the Operation of Animals (Scientific Procedures) Act (1986). Ethics approval was provided by the joint animal studies committee of the Royal Veterinary College and University College London (UCL), U.K.To evaluate the performance of the trained network, three needle insertions into the heart of a fetal sheep were performed Reconstructed tracking images were evaluated in terms of the axial and lateral spatial resolution of the needle tip. For resolution measurements, a An example of a needle insertion is shown in Fig. Additionally, the impact of the dimensions of the Gaussian kernel used to obtain ground truth images was investigated Fig. . The useIn ultrasonic tracking, obtaining large training sets for training neural networks accurate estimation of ground truth is often challenging . Manual in vivo dataset, which the framework handled well. Fourth, explorations of the performance of the CNN with far fewer simultaneously-received A-lines used to generate the tracking images would be of interest in terms of limiting system complexity and cost. Finally, in order to remove the image reconstruction step, end-to-end network approaches that use A-lines acquired directly from the ultrasound imaging probe as inputs [Several topics could be addressed in order to improve upon the results presented here. First, further optimisation of the dimensions of the kernels used to generate ground truth images could be performed. This might lead to the use of kernel dimensions that vary with the ground truth needle tip position, perhaps mirroring spatial variations in the point spread function of needle tips in reconstructed US tracking images. Second, a Kalman filtering approach could be used to improve needle tip position estimates by incorporating data from multiple ultrasonic tracking frames , therebys inputs , 17 coulin vivo. These results provide strong indications of the potential to improve the spatial resolution in ultrasonic tracking and thereby to increase the accuracy with which the needle tip is localised, with the aim of improving the efficiency and safety of ultrasound-guided needle insertions.This study demonstrated for the first time that a CNN-based framework trained only on synthetic data can be used to improve the spatial resolution of transmission-mode ultrasonic tracking images acquired


Shear-induced platelet activation (SIPAct) is an important mechanism of thrombosis initiation under high blood flow. This mechanism relies on the interaction of platelets with the von Willebrand factor (VWF) capable of unfolding under high shear stress. High shear stress occurs in the arteriovenous fistula (AVF) commonly used for haemodialysis. A novel patient-specific approach for the modelling of SIPAct in the AVF was proposed. This enabled us to estimate the SIPAct level via computational fluid dynamics. The suggested approach was applied for the SIPAct analysis in AVF geometries reconstructed from medical images. The approach facilitates the determination of the SIPAct level dependence on both biomechanical (AVF flow rate) and biochemical factors (VWF multimer size). It was found that the dependence of the SIPAct level on the AVF flow rate can be approximated by a power law. The critical flow rate was a decreasing function of the VWF multimer size. Moreover, the critical AVF flow rate highly depended on patient-specific factors, e.g., the vessel geometry. This indicates that the approach may be adopted to elucidate patient-specific thrombosis risk factors in haemodialysis patients. One of the main functions of platelets is their participation in haemostatic reactions preventing excessive blood loss in case of injury ,2. In thDuring the recent years substantial efforts have been made to understand shear-induced platelet activation (SIPAct) and its impact on thrombus formation ,14. BothThe AVF is a surgically created connection between an artery and a vein, widely applied in long-term haemodialysis ,32. ClinIt is generally accepted that both the magnitude and duration of the shear stress determine whether platelets are activated ,38,39. TIn the current study, we have combined computational reconstruction of patient-specific vessel geometry and haemodynamics with a recent mathematical model describing VWF-mediated platelet activation . As a reWe hope that the developed approach may find its further application for the assessment of patient-specific thrombotic risk factors in haemodialysis patients with AVFs. Also the approach might be extended to several other clinically valid settings with increased risk of thrombosis  ,42.The approach is aimed at evaluating the SIPAct level in the AVF considering patient-specific data. The evaluation is performed via computational fluid dynamics (CFD) methods. Information on the AVF vessel anatomy, blood flow intensity (time-dependent flow waveforms), and VWF multimer size was considered in the calculations . In the Analysis of SIPAct was performed in two mature patient-specific AVFs. The AVF of the first patient (P1) was formed in the forearm of the non-dominant upper extremity from the radial artery and cephalic vein . The AVF of the second patient (P2) was created at the elbow of the non-dominant arm from the brachial artery and cephalic vein . The patients were subjected to non-contrast enhanced magnetic resonance angiography (MRA) of the non-dominant arm vessels. The scan was performed three months postoperatively. MRA images of the arm were acquired with a voxel size of 0.6×0.9×1.4 mm for both AVFs with a 1.5 T scanner .The haematocrit was equal to 33% in both patients. Standard coagulogical parameters and additional clinical characteristics of patients are presented at The study was approved by the Ethics Committee of the National Research Center for Hematology. Serial MRA data of arteriovenous fistulas from 2 patients were acquired at MRI and US diagnostic department of National Research Center for Hematology using protocols approved by the Review Board of National Research Center for Hematology. Written informed consent was obtained from all patients of this study in accordance with the Declaration of Helsinki.Patient-specific geometries of the AVFs were reconstructed from MRA data via methods described elsewhere  43]. St. St43]. This work is aimed at the analysis of platelet activation initiated by the unfolding of VWF multimers on platelet surfaces ,26. VWF The calculation of the SIPAct level was performed in several steps. First, unsteady Navier-Stokes equations were solved . As a reCSS in the AVFs was obtained. For this purpose, components of the viscous shear stress tensor in the AVF were determined via the calculated velocity distribution and patient dynamic viscosity . Th. ThCSS iet Γina, . A zero-t = mΔt0, m denotes the number of cardiac cycles, Δt0 denotes the duration of a cardiac cycle, Ja is the convective flux of the priming platelets, and JΣ is the total convective platelet flux expressed as:P0 was introduced previously (Eq (The variable of the platelet activation level (PAL) was considered a characteristic of the SIPAct level in the fistulas:usly (Eq ).The values of the parameters are given in The aim of the study was to calculate the dependence of the SIPAct level (Eq ) on the The influence of the first factor was investigated by varying the average volumetric flow rate et Γina, . Accordilic AVFs ,59. In tlic AVFs ,59. In tt Γouta,  was set  of Qina . The aveThe time-dependent volumetric flow rate waveforms are given in N) in the VWF multimers ranges from 2 to 80 under physiological conditions . These approaches were focused on the investigation of biomechanical factors influencing the initiation of thrombus formation. In particular, the presence of overcritical shear stress zones was explored.In the current work, the SIPAct level dependence on both biomechanical factors  and the The obtained results vary for different patients. Thus, patient-specific factors such as the anatomical structure of the AVF vessel and emerging flow abnormalities might be considered as a source of additional risk of thrombotic complications in haemodialysis patients. Moreover, the approach developed in the current paper allows to quantitatively characterize these individual factors from the point of view of potential platelet activation risk. Further studies on sufficiently large cohorts of patients will be necessary to determine clinical prognostic value of the developed approach ,81. AlsoIt was shown that the shift in the VWF size distribution towards smaller multimers may lead to an increase in the SIPAct level at sufficiently high AVF flow rates . It may The SIPAct level should initiate thrombus formation in cases when the level exceeds a certain individual value. It seems promising to conduct experiments aimed at the systematic investigation of the interpatient threshold variability in haemodialysis patients ,88.We suppose that the SIPAct level in the AVF is one of the risk factors for thromboembolic complications in haemodialysis patients . PlateleAcoustic diagnostic methods are of great interest to reduce the level of thrombotic complications in haemodialysis patients. To date, ultrasound methods have been applied not only for the acquisition of information on biomechanical AVF features (vessel geometry and flow waveforms)  but alsoArterial pressure rise leads to an increase in the AVF flow rate and consequently in the value of cumulative shear stress. In accordance with the current work, these changes should lead to an increase in the SIPAct level in a fistula. In contrast, a decrease in blood flow should reduce the cumulative shear stress. Moreover, a decrease in the blood flow rate below the threshold level should lead to the absence of SIPAct. From this point of view, even short-term physical activity or severe emotional stress could be additional risk factors for thrombotic complications in haemodialysis patients. The relationship of these factors with a thrombotic complication risk increase has been established for the general population ,92. It iThe current approach enables us to estimate the critical flow rate in patient-specific AVFs at the given VWF multimer size . Thus, ain silico approach may be applied for the determination of specific ways of thrombotic complication reduction in haemodialysis patients considering their individual features.In this paper, a patient-specific approach for the estimation of the SIPAct level in AVFs was developed. This approach is based on a combination of modern medical imaging technologies, CFD methods, and the mathematical model of platelet activation induced by unfolding of the VWF multimers ,26. The S1 Text(PDF)Click here for additional data file.S2 Text(PDF)Click here for additional data file.S3 Text(PDF)Click here for additional data file.S4 Text(PDF)Click here for additional data file.S5 Text(PDF)Click here for additional data file.S6 Text(PDF)Click here for additional data file.


In this manuscript, we discuss our approach to developing novel patient-specific total TMJ prostheses. Our unique patient-fitted designs based on medical images of the patient’s TMJ offer accurate anatomical fit, and better fixation to host bone. Special features of the prostheses have potential to offer improved osseo-integration and durability of the devices. The design process is based on surgeon’s requirements, feedback, and pre-surgical planning to ensure anatomically accurate and clinically viable device design. We use the validated methodology of FE modeling and analysis to evaluate the device design by investigating stress and strain profiles under functional/normal and para-functional/worst-case TMJ loading scenarios. In treating the TMJ dysfunction, all nonsurgical approaches should be exhausted. In some select patients, the end-stage TMJ pathology resulting in distortion of anatomical architectural form and physiological dysfunction dictates the need for total joint replacement (TJR) ,2,3,4. TTMJ resections have been carried out for about 150 years ,9,10. BeTMJ implants can be differentiated into fossa-eminence prostheses, ramus prostheses and condylar reconstruction plates, and total joint prostheses. Although singular replacement of the fossa or condyle is preferred as a temporary solution, the partial TMJ reconstruction finds comparatively declining usage by surgeons for clinical reasons. Total TMJ implants are recommended when the glenoid fossa is exposed due to excessive stress in conditions such as degenerative disorders, arthritis ankylosis, and multiply operated pain patients ,4,5,6,7.Relative contraindications to the use of alloplast in reconstruction of the TMJ are age of the patient, mental status of the patient, uncontrolled systemic disease such as diabetes mellitus or myelodysplasia, active or chronic infection at the implantation site, and allergy to materials that are used in the devices to be implanted ,3,4. TheWe performed a comprehensive review of published literature ,34,35,36The history of alloplastic TMJ reconstruction has, unfortunately, been characterized by multiple highly publicized failures based on inappropriate design, lack of attention to biomechanical principles, and ignorance of what already had been documented in the orthopedic literature ,4,12,14.van Loon, et al.  indicateMost patients requiring TMJ replacement have deformed local bony anatomy. During implantation of the stock TMJ prosthesis, the surgeon confronts with a difficult challenge of making ‘off-the-shelf’ components fit and remain stable, and often the precious host bone needs to be sacrificed to make the stock TMJ components to create stable component-to-host-bone contact . SurgeonIn this section, we discuss the methodology of designing condylar and fossa components of the custom-designed total TMJ prostheses. Also discussed, are unique design features such as accurate fit of the prosthetic surface to the host bone in contact, perforated notches of implant which protrude and fit into the custom-cut slots in native bone, customized surgical guides, and screws with locking mechanism.The schematic in Subject-specific 3D anatomical reconstruction of the patient’s mandible and skull/fossa/articular eminence is performed using commercial software Mimics v14.12  from computed tomography (CT) scans see . Upon imClose collaboration between device designer and surgeon (treating the given TMJ patient) is an important aspect of the proposed design and development approach. Mutual sharing of knowledge and expertise, clinical and design requirements and constraints is vital in ensuring the optimal design and performance of TMJ devices. We utilize the computerized anatomical model and its 3D printed equivalent to acquire surgeon’s design requirements such as location of the facial nerve (to keep it from any damage or injury during surgery), location of the condylar osteotomy , outline of shape for the planned condylar and fossa prostheses, location of screws to secure the condylar and fossa components to host bone, number and dimension of screws, etc.To help the surgeon accurately remove the damaged part of condylar neck/head, a surgical guide is custom designed for each reconstruction case as shown in Our design approach and pre-surgical planning enables appropriate design of screws and pre-drilled screw holes in implants to avoid unintentional injury to facial nerve, soft tissue, and other delicate structures in the vicinity of the complex surgical site. Following the similar design approach used for osteotomy guide, the screw-drill-guide is custom designed each for the condylar/ramus component and the fossa-eminence part of the TMJ prostheses. These drill guides are intended to create a hole of preferred dimension (diameter and depth) at the accurate location and orientation for each screw as prescribed by the surgeon. For a given screw, a drill of smaller diameter than that of the particular screw is selected so ensure less bone damage, optimal purchase, and rigid interface between the screw and host bone during and after implantation.Based on a surgeon’s initial design requirements, the prostheses, drill guides, osteotomy guide, and templates are designed. In response to surgeon’s feedback about the initial designs, suggested changes are incorporated to improve the device design. This feedback loop is kept open, and the designs are fine-tuned, till the surgeon approves the designs. In-vitro biomechanical assessment of patient’s host bone and TMJ prostheses is incorporated in the design validation and improvement loop as described later in this paper. After sufficiently improving the designs, the prostheses graduate to the next stage where finished implants and accessories are ready for prototyping and pre-surgical simulation of the operating procedure using anatomical models and finished prototypes. In real-world scenario, before applying our methodology to actual clinical application, it has to be verified and validated through cadaver studies.Anatomically accurate fit of TMJ prosthesis to the host bone is essential for stable fixation leading to efficacy and longevity of the device. Our custom-designed condylar components follow the anatomical geometry and contours on the lateral surface of ramus and condylar part of host anatomy to which the prosthesis is to be fixated. Custom shape of the prosthesis maximizes the possibility of precise fit and secure fixation. Different shapes of the condylar and ramal parts can be designed per surgeon’s recommendations to conform to the patient’s unique/complex anatomical situation. An important advantage of our patient-specific design approach is that the components can be precisely designed to withstand the loads encountered by unique anatomic condition. For the custom-designed condylar/ramus component, the center of rotation of its head can be moved vertically to correct the open bite deformity. The prosthetic condylar head can be placed such that its center of location in located inferior to that of the natural condyle it replaced, thereby allowing low-wear articulation of the reconstructed total TMJ and natural movements of the non-replaced contra-lateral TMJ. Ramal component can be shaped to accommodate the amount of available mandibular host bone. The condylar heads can be designed in different shapes to offer larger articulating surface area to avoid stress concentration in small area of the articulating condylar head and fossa as illustrated in One novel feature of our TMJ prostheses is the perforated notches protruding into the host bone. Fitting the skull is a major problem in TMJ reconstruction patients because of the irregular shape of their TMJs ,15 The pUnlike hip or knee joints, the bony anatomy of mandibular ramus and temporal glenoid fossa do not afford the use of modular stock components for TMJ TJR that can be stabilized initially with press-fitting or cementation . TherefoMotion of implanted TMJ prosthesis under load can cause degeneration of the surrounding bone, which may lead to further device loosening and possible failure . Screws Using advantageous physical characteristics of biocompatible materials is an essential aspect in the design and manufacture of a successful prosthetic device. Some of the important characteristics of materials used to manufacture the TMJ prostheses from are biocompatibility, mechanical strength, low wear-rate, and harmless wear particles. Advancement in materials research has led to materials  such as Wrought Co-Cr-Mo is reported to have excellent wear resistance when articulated against UHMWPE in the non-movable articulating surface of most orthopaedic TJR devices . HoweverTitanium alloy (Ti-6Al-4V) for condylar/ramus component and bone screws, and UHMPE for fossa component is based on their favorable characteristics and successful long-term applications reported in scientific and clinical literature. Unalloyed titanium reacts rapidly with oxygen in the air to form a thin (<10 μm) layer of chemically inert titanium oxide which provides a favorable surface for biointegration of prosthesis with bone . In addiMethods for biomechanical assessment of prosthetic TMJ must be developed to make the implantation outcomes more predictable and reliable, and to evaluate the methods of device fixation to minimize or eliminate implant loosening and joint failure . We perfSubject-specific 3D anatomical reconstruction of patient’s mandible and skull/articular eminence was performed using commercial software Mimics v14.12  from computed tomography (CT) scans of patient’s TMJ. Upon importing the patients CT images in Mimics, anatomical model comprising of patient’s mandible and fossa eminence was developed from the CT scan by performing a series of operations such as image processing, segmentation, mask formation for bone and teeth, region growing, and calculation of 3D equivalent similar to the 3D reconstruction method described elsewhere . Using tAs illustrated in The interface between prosthetic condylar head and articulating surface of fossa prosthesis was modeled as sliding contact with a coefficient of friction of 0.3. The interface between the prostheses and bone in contact was modeled with contact elements having a coefficient of friction of 0.42 as reported in literature . The scrYoung’s modulus and Poissson’s ratio of anatomical components (fossa and mandible bone with teeth), titanium alloy , and UHMWPE (for fossa component) were selected as listed in The von Mises stress and micro-strain in the TMJ prostheses (fossa and condylar), screws, and native bone in regions adjacent to screws were measured. Small difference in the stress and micro-strain occurred in the host bone adjacent to screws in condylar and fossa components of both total TMJ prosthesis systems. For both types of implant designs, von Mises stress in the bone surrounding fixation screws was in the range of 3.2–4.7 MPa and 7.1–13.6 MPa under normal loading and over–loading, respectively see . These rFE simulations resulted in lower stress in anterior part of the condylar and fossa prostheses see  similar Other than where the actual loads and constraints were applied, the stress concentration was highest around the inserted screw and the screw holes in the host bone. The medial notches in the condylar and fossa prostheses are designed to provide improved stability by promoting post-implantation bone growth into the perforated surfaces of the notches. Von Mises stress in the notch regions of the condylar and fossa implants were less than that in the screw regions, indicating that the notches may not act as stress risers in the device. Stress profile in the host bone portion where the medical notches of the implant are inserted show stresses lower than that at the screw holes, but higher than those in other parts of the host bone. This indicates that the stress developed in the notches under functional loading may augment bone growth into the perforated notches, thereby maximizing the opportunity for improved stability of the prostheses. Also, in all simulations, the peak von Mises stresses in the condylar component were higher than those in the fossa component of the total TMJ prostheses see . This maPeak stress and strain the implant fixation screws are summarized in Among the screws, the highest stresses occurred in the neck portion of two condylar screws—one placed most inferiorly, and another placed most posteriorly and at the curvature of the ramal part of the implant. This is contradictory to what found in ,33 reporScrews used for both condylar and fossa components showed von Mises stresses of higher order at their interfaces with prostheses, especially in the region of screw neck and at the site of prosthesis-bone junction. This may have happened as the screws carried more load when they served as a medium of load-sharing between the prosthesis and host bone. As listed in In view of scarcity of published literature about design methods and biomechanical analysis of total TMJ implants, the present study provides good reference work for patient-specific design and biomechanical evaluation of such designs through FE simulations. Few published studies have investigated biomechanics of the artificial TMJ implants. In our knowledge, no study has reported FE analysis of total TMJ prostheses. The present study can serve as a reference for the clinicians regarding advantageous features of the patient-specific total TMJ implants. Moreover, design methodology and FE findings of this study can provide industrial designers with reference data for improving their products, especially the custom-designed products intended for patients with complex and challenging anatomic situations.Limitations of this study must be considered when reviewing implant designs and evaluating FE results. The main focus of this study was the patient-specific design and biomechanical analysis of the total TMJ prostheses. The skill of the surgical approach (preauricular incision or retromandibular incision) and patient-related issues such as long-term effects were not considered. Therefore, the surgeons should be careful when applying the findings from this study to clinical situation. The present study used only one set of material properties for patient’s host bone. Future investigations should assess effect of altered bone quality on the performance of total TMJ replacement. Also, material properties of bone were assumed to be homogeneous and isotropic. Although this represents a major simplification, other studies have demonstrated that this is acceptable ,26,34. OIn summary, this study demonstrates that our custom-design approach offers potential for stable and durable total TMJ reconstruction, and that the FE models can reproduce information useful in design and assessment of total TMJ prostheses. Findings of this study provide a good basis for future work focusing on developing a more refined and standardized method for custom design of total TMJ prostheses, and pre-clinical FE tests for design verification and validation.


An 80-year-old male patient was referred to the neuro-ophthalmology clinic with a history of sudden vision loss in the right eye one week earlier and vision loss in the left eye four days after that. The vision assessment was no light perception in both eyes at the time of the initial examination. Both eyes were pseudophakic and anterior segment examination was unremarkable. Funduscopic examination revealed a swollen optic disc in the right eye and a diffuse retinal whitening with a cherry-red spot, arterial attenuation, and a chalky-white blurred-margin optic disc in the left eye . Fluorescein angiography (FA) disclosed a diffuse choroidal filling delay with leakage from the optic nerve head in the venous phase in the right eye and nasal choroidal filling delay and diffuse delay in the retinal arterial filling in the left eye [Figure 2]. The erythrocyte sedimentation rate was 98 mm/hr, and the level of C-reactive protein was 76 mg/L. The patient was admitted and pulse corticosteroid therapy was commenced with the diagnosis of giant cell arteritis (GCA). The diagnosis was later confirmed with a histopathologic evaluation of the left side temporal artery biopsy specimen [Figure 1C]. Unfortunately, even though treatment was started immediately, it failed to improve the patient's vision. The main goal of corticosteroid therapy in GCA is to prevent the occurrence or progression of visual loss. Bilateral ocular involvement is another concern in these patients. Hayreh et al reported that in all GCA patients with bilateral vision impairment, older changes could be found in one eye, suggesting that the patients were unaware of vision loss in one eye until the second eye was affected giving the erroneous interpretation of simultaneous bilateral ocular involvement. Thus, the estimations of the prevalence of simultaneous bilateral GCA ocular involvement suffer from the inaccuracy in the timing of the examination and perhaps were mostly imprecise and possibly preventable.Giant cell arteritis (GCA) is a granulomatous vasculitis that involves large- and medium-sized vessels. Anterior ischemic optic neuropathy (AION), central retinal artery occlusion (CRAO), and posterior ischemic optic neuropathy (PION) are the most reported ophthalmic presentations of GCA. CRAO in these patients is almost invariably associated with AION, and posterior ciliary artery occlusion  is highly suggestive of the arteritic nature of the occlusion. There has been only one report of a similar presentation of GCA in literature. Although we cannot confirm the similarity of the extent of bilateral involvement between these two cases due to the lack of sufficient angiographic data, both reports have one thing in common, which is neither of these patients has enjoyed vision improvement after pulse corticosteroid therapy. Overall, this report presents an extreme manifestation of GCA with detailed illustrations to emphasize the importance of timely diagnosis and urgent treatment in these patients.CRAO is a rare but well-known disaster that has been reported in 4% of GCA patients.Informed consent including publication of photographs in medical journals was obtained from the participant of this study.The authors did not receive any financial support or funding for this work.The authors have no conflicts of interest to declare.


A challenge facing researchers conducting mobile health  research is the amount of resources required to develop mobile apps. This can be a barrier to generating relevant knowledge in a timely manner. The recent rise of “no-code” software development platforms may overcome this challenge and enable researchers to decrease the cost and time required to develop mHealth research apps.We aimed to describe the development process and the lessons learned to build Pathverse, a no-code mHealth app design platform.The study took place between November 2019 and December 2021. We used a participatory research framework to develop the mHealth app design platform. In phase 1, we worked with researchers to gather key platform feature requirements and conducted an exploratory literature search to determine needs related to this platform. In phase 2, we used an agile software framework (Scrum) to develop the platform. Each development sprint cycle was 4 weeks in length. We created a minimum viable product at the end of 7 sprint cycles. In phase 3, we used a convenience sample of adults (n=5) to gather user feedback through usability and acceptability testing. In phase 4, we further developed the platform based on user feedback, following the V-model software development process.Our team consulted end users  and utilized behavior change technique taxonomy and behavior change models  to guide the development of features. The first version of the Pathverse platform included features that allowed researchers to (1) design customized multimedia app content , (2) set content delivery logic , (3) implement customized participant surveys, (4) provide self-monitoring tools, (5) set personalized goals, and (6) customize app notifications. Usability and acceptability testing revealed that researchers found the platform easy to navigate and that the features were intuitive to use. Potential improvements include the ability to deliver adaptive interventions and add features such as community group chat.To our knowledge, Pathverse is the first no-code mHealth app design platform for developing mHealth interventions for behavior. We successfully used behavior change models and the behavior change technique taxonomy to inform the feature requirements of Pathverse. Overall, the use of a participatory framework, combined with the agile and hybrid-agile software development process, enabled our team to successfully develop the Pathverse platform. Advancements in internet-enabled digital devices  and improved access to these devices have led to the rapid growth of mobile health  research . Due to One of the challenges facing researchers conducting mHealth intervention research is the cost and time required to develop and maintain mobile apps . The cosAn innovative solution to overcome these mHealth app development challenges facing researchers has recently arisen: “no-code” development platforms . A no-coWe used a participatory research framework to develop a no-code mHealth app design platform called Pathverse . A partino-code mHealth app builders to determine whether such mHealth app builders existed. In addition, we performed a literature search to determine mHealth apps features that were associated with intervention effectiveness. Specifically, MEDLINE, PubMed, EMBASE, and PsycINFO were searched for articles published from January 2009 to December 2019 with the following key words:  AND (effectiveness OR efficacy) AND (features OR characteristics OR behaviour change techniques OR theories) AND . Our interdisciplinary team met regularly throughout this phase to brainstorm features  required to build mHealth apps. In order to ensure that these features met the researchers’ requirements for building mHealth apps, our team used the multi-process action control framework (M-PAC) as a theoretical template model and used physical activity change as the template outcome behavior. The M-PAC framework has been shown to be effective in promoting physical activity [mHealth researchers (n=13) with various levels of research experience  and software developers (n=4) were involved in identifying key software features for the no-code app design platform, Pathverse. The team members’ demographics are presented in activity -24. M-PAactivity . One advactivity ,25,26. Factivity , which gWe used the Scrum framework to develop the Pathverse platform . This agWe used a 4-week sprint cycle in this project. We aimed to produce a working version of the platform in about 7 months . The key members in the Scrum team were an mHealth researcher , the Scrum master (HL), and the software development team. End users with various levels of mHealth research experience  were involved during each sprint. The Scrum team presented the completed platform features and discussed goals for the next sprint with the team at the end of each sprint.Similarly to our previous studies ,29, we gBased on user feedback, our team planned for an additional phase of development. During this phase, we used the V-model software development process. This method combines traditional sequential development methodology  with feedback mechanisms in the agile development process  to ensure that the new features added work appropriately . The V-mInformed consent was obtained from participants completing the usability and acceptability testing. This study was approved (17361) by the Human Research Ethics Board at the University of Victoria.Our multidisciplinary team of researchers and software developers met regularly to determine requirements and features for the Pathverse platform. A summary of the activities conducted at each meeting is shown in Our team generated a list of potential Pathverse features by building a mock-up app using the M-PAC framework as a template theoretical framework and physical activity as the behavior change outcome. Similarly to our previous study, our team then matched the BCTs required to implement the physical activity app using the M-PAC framework .The final platform features included the ability to (1) design customized and interactive multimedia content in the app; (2) set flexible content delivery logic ; (3) deploy customized surveys to the participants; (4) provide personalized self-monitoring trackers ; (5) enable participants to set goals; (6) implement customized app notifications to remind participants of any new mHealth intervention content; (7) provide gamified points and badges; and (8) enable participants to share progress made on their social media accounts . The Scrum team met with researchers throughout the sprint cycles to gather user feedback and plan the tasks to be completed by the end of the next phase. A summary of the activities completed in each Scrum phase is described below. The commit history of the software development process can be found in The first sprint started with determining the Pathverse platform architecture required to implement the key features identified in phase 1. The platform consisted of 3 main components: the Pathverse researcher web portal, the Pathverse participant app (available in both the iOS and Android app stores), and the backend application program interface (API) server and databases . The resThe programming team simultaneously coded the components of the Pathverse platform. At the end of this sprint, the programing team developed a prototype version of the dashboard of the Pathverse researcher web portal using React.js, a JavaScript library licensed from the Massachusetts Institute of Technology . The logThe main priorities for this sprint were to finish developing the feature that enabled researchers to upload customized multimedia content for an mHealth intervention and set the delivery logic for the intervention. This was the first time the integrated platform was tested collectively. After sharing a working prototype at the end of this phase, researchers tested the prototype and provided feedback on system bugs and design issues, and they also suggested other features that would improve their experience. The top-priority suggestions included the need to optimize multimedia content  for various screen sizes, organize the order of the intervention content delivery using drag and drop, and provide real-time visualization of the multimedia content added to the Pathverse participant app in the research portal.The programming team attempted to implement the suggestions made by the end users from the previous sprint. Additionally, the programing team completed the customized survey feature. This feature enabled the researchers to collect various types of survey responses . These features were tested, and various system bugs, UI design issues, and additional features were discussed. Specific main feature modification requests included providing options to enable participants to complete the survey multiple times and randomize the order of the questions. Due to the large quantity of feedback received (for UI and feature requests) and the slower than expected feedback implementation, our team decided not to develop 2 features: gamified points and social sharing. This was to ensure that a working prototype of the Pathverse platform could be delivered on time.The programming team developed and implemented the self-monitoring tool for step tracking in the participant app. This allowed the Pathverse app to connect to Apple or Google Health wearable devices and display a user’s daily step data. The end users worked with the development team to provide feedback on how the wearable data were displayed in the app. The end users provided the feedback that participants should also be able to display other health metrics, including blood pressure, weight, and daily active minutes.The programming team completed the development of goal setting and customized app notification features during this sprint. The goal-setting features enabled the participants to set customized personal goals and customized reminders for goal due dates. The customized app notification enabled researchers to set personalized app reminders whenever new app content became available to the participants. At the end of this phase, the programing team presented the first beta version of the platform to the end users. Due to time constraints, the programming team could not implement the feature that allowed the participant app to display all the health metrics requested, such as blood pressure and weight. A prototype of the daily active minutes feature was added. Our team decided that the next sprint would focus on conducting quality assurance (QA) testing.The primary goal of this sprint was to conduct QA testing prior to launching the Pathverse platform and submitting the app to the Apple App Store and Google Play Store. The end users and programming team generated a list of system bugs while testing the various features that were developed . The programming team and the end users met weekly during this sprint to discuss solutions to resolve known system bugs. The app (version 1.0) was officially submitted to the iOS and Android app stores at the end of this sprint. We invited 5 participants to provide feedback on the Pathverse platform. The demographic characteristics of the researchers are shown in The most helpful features identified by the users included easy navigation for both the research portal and participant app and the ability to download app usage and survey data. Potential improvements included the ability to deliver multiple surveys throughout the day, add the ability to deliver adaptive interventions, and add features such as community group chat. A summary of the feedback received is shown in We applied the V-method of software development. The requirement analysis phase occurred in September 2021. Based on the user feedback from the previous phase, our team determined three main requirements that we would implement given the availability of resources: (1) expand survey functionalities so that multiple surveys could be delivered throughout the day, (2) improve the data download format  for easier analysis and postprocessing, and (3) provide the ability to customize whether to use the self-monitoring features, as not all mHealth studies require this feature. The system and architecture design and the module design phase took place during the last week of September 2021. The programming team determined the main modules to be developed to meet the program requirements. These modules included customized survey release times in the researcher web portal, a display of the various surveys in the participant Pathverse app, the ability to download survey data in .csv format, the ability for researchers to choose whether to collect wearable and survey data in the researcher web portal, and revision of the UI design for the participant app to not display self-monitoring tools. Based on these module designs, the software team initiated the coding phases from October to November 2021. The validation testing to resolve system bugs took place in December 2021. Pathverse (version 1.5) was released to the app stores at the end of this phase. Video demonstrations of the functionality of the platform were made available online .This study describes the development process of a no-code mHealth app design platform for researchers. To our knowledge, this platform (Pathverse) is the first no-code mHealth app design platform for developing mHealth behavior interventions. This platform has the potential to enable researchers with no previous software programming skills to design mHealth intervention apps. Consequently, this should help reduce the time and cost required to develop mHealth interventions. Our team used a behavior theory framework (M-PAC) and the BCT taxonomy to inform the design of the various software features in the first version of the Pathverse platform. These features can offer researchers the flexibility to design mHealth interventions with various BCTs, depending on the behavior theory or the mechanisms of action. The participatory development methods used in this project allowed our team to ensure that feedback from end users (researchers) was incorporated throughout the development phases. Despite receiving helpful feedback  from the researchers, our team could only address the most important issues given resource availability. However, we plan to address all the feedback received in future development.Similarly to previous mHealth software development studies ,29, our The software development methods  used in this study were effective in delivering the product on time. However, our team found that the Scrum method easily led to scope creep, resulting in a buildup of backlog tasks and feature cancellation. For example, after completing the customized survey feature, the research team requested additional survey functionality  in sprint 4. Similarly, they requested additional self-monitoring trackers  in sprint 6. We also spent a significant amount of time optimizing and making changes to the app UI throughout the Scrum cycles. Future development should set a limit on the number of UI changes that can be made after the initial designs have been approved. Scope creep is a known challenge in agile development environments . There aFinally, we learned the need to implement QA protocols throughout the software development phases. We did not designate a specific QA analyst role during the rapid sprint cycles. Thus, some QA issues were not discovered until the product was launched. Adopting QA testing early in the development cycle could help avoid users experiencing software bugs following deployment. An advantage of using the V-model was the systematic approach to QA testing throughout the development stages. Thus, future Scrum software development might consider incorporating a dedicated QA analyst as part of the team.The end users identified several useful features  that could be implemented in the future to further expand the capabilities of the no-code mHealth app builder tool for researchers. A strength of the study was using the participatory framework throughout the development of the Pathverse platform. This process enabled our team to gather valuable insights into ways to improve the platform. A limitation of the study is that the end users who were involved in designing and testing the platform were mHealth researchers; this may limit the generalizability of our findings beyond this population. Furthermore, the end users provided feedback about platform feature development throughout the development phases. Due to our limited sample size during usability testing, it remains unclear how these features would be used in a larger group of users. Future studies are warranted.In summary, this study describes the development process of Pathverse, a no-code mHealth app design platform. The process reinforced the importance of involving end users  and demonstrated the use of agile and hybrid-agile software development methods to develop mHealth research tools. Our participatory research approach enabled our team to clarify the feature requirements of the Pathverse platform. Overall, we believe that our no-code mHealth app design platform will help researchers decrease the resources required to leverage mHealth technology.


There are still numerous problems with modern joint replacement prostheses, which negatively influence patient health and recovery. For example, it is especially important to avoid failures and complications following hip arthroplasty because the loss of hip joint function is commonly associated with increased demand on the healthcare system, reoperation, loss of independence, physical disability, and death. The current study uses hip arthroplasty as a model system to present a new strategy of computationally generating patient-specific statistical reconstructions of complete healthy anatomical structures from computed tomography (CT) scans of damaged anatomical structures. The 3D model morphological data were evaluated from damaged femurs repaired with prosthetic devices and the respective damaged femurs that had been restored using statistical reconstruction. The results from all morphological measurements  indicated that the values of femurs repaired with traditional prostheses did not fall within the +/−3 standard deviations of the respective patient-specific healthy anatomical structures. These results demonstrate that there are quantitative differences in the morphology of femurs repaired with traditional prostheses and the morphology of patient-specific statistical reconstructions. This approach of generating patient-specific statistical reconstructions of healthy anatomical structures might help to inform prosthetic designs so that new prostheses more closely resemble natural healthy morphology and preserve biomechanical function. Additionally, the patient-specific statistical reconstructions of healthy anatomical structures might be valuable for surgeons in that prosthetic devices could be selected and positioned to more accurately restore natural biomechanical function. All in all, this contribution establishes the novel approach of generating patient-specific statistical reconstructions of healthy anatomical structures from the CT scans of individuals’ damaged anatomical structures to improve treatments and patient outcomes. Each year, there are over 1 million hip arthroplasties completed around the world, a number that is expected to double within two decades because of the aging global population . AlthougHip arthroplasty is carried out primarily to address pain and loss of function due to osteoarthritis, but patients also undergo hip joint replacement to treat fractures, avascular necrosis, dysplasia, Paget’s disease, and rheumatoid arthritis ,8. Hip jThe earliest hip arthroplasty methods tended to be effective for short periods of time in terms of pain relief and function, but as time passed, they frequently resulted in negative outcomes due to chronic infections ,13,14,15Unfortunately, there are still numerous problems with hip arthroplasty, including infection, degradation, failure of the prosthesis, and various fractures ,11. SuccIn addition to these negative outcomes for hip replacements, fractures can occur either in the bone or in the prosthesis. Fractures of the bone usually occur in the form of periprosthetic fractures along the femoral component of the prosthesis, rather than in the os coxae surrounding the acetabular cup ,11. ProsSelecting the best possible treatment for hip fracture and pathology is essential to avoid increased demand on the healthcare system, reoperation, loss of independence, physical disability, and death of the patient . PreviouThe current study uses the hip prosthesis as a model system for demonstrating a new approach to generating patient-specific statistical reconstructions of the missing portions of damaged anatomical structures. It is hypothesized that morphological disparities will be evident between femurs with prostheses and the patient-specific statistical reconstructions of the healthy structure of those same femurs. Specifically, the current study establishes a novel computational approach to generating patient-specific statistical reconstructions of healthy anatomical structures from computed tomography (CT) scans of individuals’ damaged anatomical structures.In order to be able to statistically reconstruct the missing portions of anatomy on a damaged structure , it was n = 35). The donor cadavers were imaged prior to dissection using a GE Discovery 690 helical CT, which was carried out at the UB Clinical and Translational Research Center (CTRC).For the healthy sample, cadaveric donors with joint replacements and surgical pins were excluded because of the artificial morphology of these structures and their associated CT data artifacts. In addition, individuals with pathologies such as osteoarthritis and osteoporosis were excluded from the sample used to generate the SSM of the healthy anatomical structure  with a symmetric Gaussian kernel, which is a procedure that improves the SSM by making it more capable of capturing all the shape variations in the healthy structure. Furthermore, this process was carried out because augmentation helps any given SSM to be resistant to any potential remaining noise or errors in the dataset. This enhanced SSM of the healthy femur structure was then used to statistically reconstruct the damaged femur structures.Patient-specific statistical reconstructions were obtained for each of the damaged femurs. This was carried out using the damaged femur structure without the metallic prosthesis, enhanced SSM, and GP regression for model fitting. For a particular specimen, this process yielded a complete healthy femur structure that maintained the morphology of the part of the anatomy that was still intact and the corresponding statistical reconstruction of the healthy anatomy that had been absent.Moreover, the statistical reconstruction process was applied to obtain the different statistically determined variations of the restored healthy anatomical structure. For each damaged specimen, 7 statistically reconstructed 3D anatomical model variants were generated for the quantitative evaluation of morphology. These variants based on the SSM of the healthy population included the statistical reconstruction mean anatomical structure, +1 standard deviation (SD) statistical reconstruction anatomical structure, −1 SD statistical reconstruction anatomical structure, +2 SD statistical reconstruction anatomical structure, −2 SD statistical reconstruction anatomical structure, +3 SD statistical reconstruction anatomical structure, and −3 SD statistical reconstruction anatomical structure.To evaluate how the traditional femur prosthetic compares with the patient-specific statistically reconstructed healthy anatomy, quantitative morphological data were collected from the traditional prosthesis plus the damaged femur 3D anatomical model as well as the 7 statistically reconstructed 3D anatomical models. Morphological data consisted of commonly used anatomical measurements for the femur . These dFive types of quantitative data were collected including the maximum femoral length, the Hausdorff distance, the femoral neck anteversion, the length of the rotational center divergence, and the angle of inclination. The maximum femoral length was defined as the maximum length between the femoral head and the farthest femoral condyle ,50. The The maximum femoral length data showed clear differences between the femurs with traditional prostheses and the statistically reconstructed femurs. The traditionally repaired femurs had maximum femoral lengths that were more than 22 mm smaller than the respective patient-specific statistical reconstruction mean structures . The femAmong the statistical reconstructions of the healthy anatomy, the +/−1 SD statistical reconstructions had Hausdorff distances of approximately 2.9 mm. Considerable differences were evident between the Hausdorff distances of the statistically reconstructed anatomical structures and the femur structures with traditional prostheses . The femThe femoral neck anteversion data of femur structures with traditional prostheses displayed femoral neck anteversion values that were much greater than values of all the statistical reconstructions of the healthy structures . In partThe data from the length of the rotational center divergence had values for femur structures with traditional prostheses that were considerably greater than those of all the statistical reconstructions of the healthy anatomy . The +/−The angle of inclination data also indicated clear differences between the femur with traditional hip prosthesis structures and the statistical reconstructions of healthy femur structures . The valIn addition to the marked differences displayed in these quantitative measurements of morphology between the femur structure after traditional hip arthroplasty and the statistical reconstructions of healthy femur structure, the 3D anatomical models revealed some valuable qualitative insights. The surface boundary of the traditional prosthetic extended beyond the surface of the mean statistical reconstruction of the healthy anatomy. This disparity occurred at the inferior surface of the femoral head and near the base of the femoral neck . AdditioOverall, the results support the hypothesis that femurs with statistical reconstructions of the healthy structure are morphologically distinct from the respective femurs with traditional prostheses . The difRegardless of the influence of the femoral head diameter on the wear rate of the prosthesis, there are other functional considerations related to the femoral head diameter. A reduction in the femoral head diameter decreases the femoral head-to-neck ratio, decreases the range of motion in all directions, and increases the chance of impingement, which ultimately increases the likelihood of dislocation ,52,53. MUnlike the maximum femoral length and the Hausdorff distance, the other measurements  are independent of the femoral head diameter. These three types of data should have no difference between the femurs with prostheses and the statistically reconstructed healthy femurs, if the hip arthroplasties accurately recreated these anatomical attributes of healthy femurs. Interestingly, the results from the femoral neck anteversion, the length of the rotational center divergence, and the angle of inclination indicate substantial differences between the femurs with prostheses and the statistical reconstructions of the healthy anatomy. The values from femurs with prostheses did not fall within the values of the +/−3 standard deviation statistical reconstructions.The disparities in the lengths of the rotational center divergence of the femurs with hip prostheses and the statistical reconstructions are especially intriguing and not without consequence. During hip arthroplasty, it is crucial to accurately restore the center of rotation in order to preserve biomechanical function . The incSimilarly, the 3D anatomical models of the statistical reconstructions revealed additional information indicative of the incorrect positioning of the prostheses on these damaged femurs. Each of the prostheses exhibited a slight tilt on the longitudinal axis that contributed to an anterior projection of the prosthetic femoral head and neck relative to the femoral head and neck of the healthy structure. Furthermore, the femoral stem of each prosthesis was not centered on the longitudinal axis of the femoral shaft . The corThe successful treatment of hip fracture and pathology is critical for avoiding increased demands on the healthcare system, reoperation, loss of independence, development of physical disability, and death of patients . The quaThe present study has the limitation that it only demonstrates this new approach using the model system of hip prostheses. Quantitative morphological differences were evident between the femurs repaired with traditional hip prostheses and the patient-specific statistical reconstructions of the healthy femur structure, but morphological differences may not be as significant between other anatomical structures repaired with prostheses and statistical reconstructions of those respective healthy structures. Therefore, although patient-specific statistical reconstructions have the potential to improve many prosthesis designs and surgical procedures, the results of the current study only suggest that hip prostheses are in need of further improvement.Extensive study of the modern hip joint prosthesis showed that there is a critical need for subject-specific data to inform medical implant development so that implant failure is reduced ,37. The A CT scan of the patient’s damaged anatomy in combination with a SSM generated from the particular healthy anatomical structure could be used to create a patient-specific statistical reconstruction of the missing healthy structure, which has many positive potential applications. Generating patient-specific statistical reconstructions of the healthy structure might be helpful for informing prosthetic design so that the prostheses more closely resemble natural anatomical structures. Furthermore, someday, this concept could be used to generate 3D-printed custom prostheses for patients. These new prostheses could potentially reduce recovery time, have lower risks of failure, and more effectively restore natural biomechanical function for the patient.This approach could also be applied in the surgical setting by using diagnostic CT data to rapidly provide surgeons with a visual guide. The statistical reconstructions of a patient’s anatomy could inform prosthetic device selection and support more accurate positioning of the prosthesis. All in all, the statistical reconstruction of patient-specific anatomy has the potential to augment prosthetic device design and aid surgical procedures, thereby decreasing the likelihood of prosthetic implant failure, decreasing recovery time, and more effectively restoring a patient’s natural biomechanical capabilities.