Randomized trials provide the most valid evidence of effectiveness of interventions. The study aims to determine the primary study question for randomized controlled trials; to evaluate the study questions in trials on effectiveness of arthroscopic meniscectomy for meniscal rupture of the knee; and to explore the clinical and research implications.Previous studies on benchmarking controlled trials were utilized. A literature search was undertaken to find the trials on arthroscopic surgery for meniscal rupture of the knee, data was extracted, and checked for accuracy twice.The first question in RCTs is whether to assess the pure intervention effect, or intervention effect in routine health care circumstances. The former necessitates a double blinded design and the latter a non-blind design. The trials on arthroscopic meniscectomy of the knee showed considerable differences in study characteristics.The study question in RCTs on pure intervention effect dictates use of blinded design, while question of intervention effect in routine health care dictates use of non-blinded design. Blinding should not be considered a validity criterion when study question is on effectiveness in routine health care. When informing patients, the potential for other effects besides the pure intervention effect should be considered.The online version of this article (10.1186/s12874-018-0549-z) contains supplementary material, which is available to authorized users. The experimental studies, particularly randomized controlled trials (RCTs) provide the least biased information on effectiveness of medical interventions and create the basis for systematic reviews on effectiveness of interventions . BlindinThe aims of this study were to find and operationalize the study question to be considered first in randomized controlled trials (RCTs); to assess consequences of this operationalization both conceptually and by using empirical data on effectiveness of arthroscopic meniscectomy for meniscal rupture of the knee; and to explore the consequent clinical and research implications.The present study utilized the methods for observational effectiveness studies, the benchmarking controlled trials (BCTs), where there is a need for a very detailed description of the study questions, selection of patients, characteristics of patients, interventions, and outcomes . In BCTsLiterature search was undertaken to find all randomized controlled trials published in peer-reviewed journals assessing effectiveness of arthroscopic partial meniscectomy of the knee in comparison to any other non-pharmacological treatment, including sham surgery, among patients having knee pain, with at least one-year follow-up. Trials focusing on knee osteoarthrosis were excluded. The following key words were used: arthroscopic partial meniscectomy, randomized controlled trial, systematic review. Cochrane CENTRAL, Ovid MEDLINE, and Web of Science databases till October 2017 were used to find the eligible articles by the author, who checked the search findings to exclude misclassifications. The search strategy is described in Additional file The descriptive information in each trial concerning blinded vs non-blinded study design, selection of patients, and characteristics of patients, interventions and outcomes were extracted by the author, who rechecked twice the accuracy of the data. The study question characteristics were also depicted in a flow chart to show the similarities and differences between the studies.Characteristics of RCTs assessing pure intervention effect or effectiveness in real-world health care are shown in Table When the study question is to assess the pure intervention effect the answer can be obtained only by a double blinded design Table . The comIn routine health care patients and their health care providers are always aware of the treatment options and to concord with this a non-blinded RCT is necessary Table . When thThe primary literature search of the three databases found altogether 2375 abstracts of articles. Based on data in abstracts altogether 6 randomized controlled trials (RCTs) assessing effectiveness of arthroscopic partial meniscectomy and fulfilling the inclusion criteria where found  as their primary outcome; one study used WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index), one study used visual analogue scale for pain and the Lysholm Knee Scoring Scale. Only one study used the meniscal lesion specific WOMET  as the primary outcome Table . In one Figure the study question of assessing pure intervention effect dictates use of a double blinded design, and the study question of assessing effectiveness of intervention in routine health care settings dictates use of non-blinded RCT  of an intervention, but ideal circumstances  can be designed equally well also for the non-blinded, routine health care experiments. Double blinded randomized trials are often conducted in optimal circumstances, and in these cases may reveal the best attainable effectiveness estimates, but they may also be conducted - as pragmatic trials - in routine health care contexts. Consequently, the idea of categorically denoting efficacy to double blind RCTs and effectiveness to non-blinded RCTs may not be justifiable.The extent of the placebo effects and non-specific effects in routine health care may be dependent on the individual patient, and on the health care provider, and how well they are able to communicate between each other. Additional potential modifying factors may be e.g. competence of staff, structures of the health care system and cultural features . There iblinding is not justified. Hitherto, the instructions for assessment of risk of bias in RCTs consider success of blinding in all RCT designs an important validity criterion [The assessment of risk of bias  of the two study designs differs. When the study question is on intervention effectiveness per se, the success of double blinding and concealment of treatment allocation are of outmost importance. But, when the study aims to quantify the effectiveness of an intervention in routine health care circumstances, where both patients and health care staff are aware of the interventions chosen, riterion . The preThe study question analysis on arthroscopic meniscectomy of the knee shows major differences in the characteristics of the six trials, and all the trials are clinically heterogeneous. Therefore comparison of the double blinded vs non-blinded trials is not appropriate. The trial by Gauffin et al., which found effectiveness in routine health care, might be reproduced in a double blinded design with a sham surgery comparison to quantify the pure intervention effect in this representative patient population. In the four other non-blinded RCTs no treatment effectiveness was found, and considering the invasive nature of the intervention, with potential harms there may not be an indication to repeat these experiments in a double blinded design. In the only double blinded trial by Sihvonen et al. no benefits of surgery were found. As the surgery involves potential risks, there is no justification to proceed into non-blinded study design using same patient, intervention and outcome characteristics.The study question analysis can be applied for planning and assessing of future RCTs, and for assessment of clinical homogeneity in systematic reviews.When the aim is to assess pure intervention effect, a double blinded RCT is indicated, and when the intention is to assess effectiveness of an intervention in routine health care circumstances, a non-blinded RCT is required. Appropriate blinding of patients and therapists is an essential validity criterion when assessing pure intervention effect, but blinding is contraindicated, when assessing effectiveness of interventions in routine health care. There is a need for non-blinded trials assessing effectiveness and cost-effectiveness in different patient groups and health care settings. When informing patients, the potential for additional effects besides the pure intervention effect should be considered. The study question analysis of the RCTs on arthroscopic meniscectomy of the knee showed that all the trials are clinically heterogeneous, and do not allow a meta-analysis or a comparison of the double blinded vs non-blinded trials.Additional file 1:Literature search strategy. (DOC 40 kb)


Prolonged grief disorder (PGD) is included as a new mental health disorder in the 11th edition of the International Classification of Diseases (ICD-11). Understandably, this has boosted research efforts to investigate this newcomer to psychopathology. However, the use of different diagnostic algorithms has resulted in substantially different prevalence rates both within and across cultural groups. Furthermore, global applicability of the new criteria outside of the Global North has not been yet been established. This perspective presents key findings from Asian research groups and discusses the roadblocks to unified PGD research, including the heterogeneric use of diagnostic algorithms and the lack of cultural compatibility of ICD-11 items. The authors discuss the key issues and address implications for practice. For the first time, prolonged grief disorder (PGD) is included as a new mental health disorder in the World Health Organization’s (WHO) 11th edition of the International Classification of Diseases (ICD-11) . This prAround the world, prevalence rates for PGD have been examined using several different sets of diagnostic algorithms. Most predominantly the PGDPlos criteria , ICD-11 A similar variation can be found for research conducted in the Global North . For insIn addition, it is unclear if the prevalence rates indicate the most valid symptom expression. Although in both Chinese individuals and samples from the Global North, yearning or longing for the deceased, indicative of separation-related distress, constitute the hallmark symptom for disordered grief , there mAdditionally, features of the ICD-11 PGD criteria may be more or less common for certain cultural subgroups and thus should be weighted accordingly. We explored the cross-cultural utility and applicability of the ICD-11 PGD criteria among Chinese and German-speaking health-care providers . While hexpression of grief varies by culture, despite the universal experience of grief, it is vitally important that we detect these variations early as we apply diagnostic criteria. In recent years, an increasing number of empirical studies (of Chinese origin in particular) have explored grief responses in samples beyond the Global North and added to a growing body of knowledge regarding prevalence rates of pathological grief. But despite these efforts from researchers and WHO stakeholders, we are far from establishing global applicability of PGD. The heterogeneity of diagnostic algorithms used by researchers and clinicians resulting in different prevalence rates within and across cultural groups constitutes one of the major challenges of cultural compatibility. If researchers keep using different diagnostic approaches to assess cases of PGD, conclusions and comparisons regarding prevalence rates and cross-cultural applicability are hampered.Many cultural factors, working invisibly in the background, affect the way symptoms are expressed, perceived, assessed, interpreted, and documented. Religious beliefs and practices, for instance, are strongly related to culture and may account for some of the variations in grieving processes . InfluenWe therefore recommend that expert researchers and clinicians in the field come together to decide on a consensus PGD algorithm that can be used across research groups and countries. The new wave of research emerging from Asian countries should stimulate collaboration to explore cross-cultural similarities and differences in the presentation of grief. With the novum of having disordered grief included in classification systems for mental health disorders, it is critical to no longer presume a universality of grief responses but instead move toward a culturally integrated grief framework. Further research can examine this by collecting open-ended written responses to questions or interviews about grief reactions in a culture and generating culture-specific grief items . AdditioAlthough there is no gold standard procedure for cross-cultural measurement of PGD and it is currently unknown how feasible such an assessment might be for grief, several researchers have confirmed that culturally informed mental health assessment is feasible, useful, and improves the validity of mental health diagnosis . MethodoE-MS constructed the structure of the perspective and wrote most of it. NZ searched the articles conducted in China and reviewed the results of the Chinese studies. CK proposed the idea and directed the whole process of the writing. AM and M-FO’C read and revised the manuscript in detail.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Emergency Department (ED) crowding is a global public health phenomenon affecting access and quality of care. In this study, we seek to conduct a systematic review concerning the challenges and outcomes of ED crowding. This systematic review utilized original research articles published from 1st January 2007, to 1st January 2019. Relevant articles from the PubMed (MEDLINE), EMBASE, and Google scholar databases were extracted using predesigned keywords. Following the PRISMA guidelines, two reviewers independently evaluated the quality of the studies using Critical Appraisal Skills Programme for cohort studies and qualitative studies, and Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument for studies. Out of the total of 73 articles in the final record, we excluded 15 of them because of poor quality. This systematic review synthesized the reports of 58 original articles. The outcomes of multiple individual patients and healthcare-related challenges are comprehensively assessed. ED crowding affects individual patients, healthcare systems and communities at large. The negative influences of crowding on healthcare service delivery result in delayed service delivery, poor quality care, and inefficiency; all negatively affecting the emergency patients' healthcare outcomes, in turn.  The requirement of emergency healthcare service is an ongoing issue . The emeEvidence shows an increase in emergency healthcare service utilization because of the increased rates of accidental injuries. However, the capacity of the emergency healthcare systems has not been well developed to respond to such high demand because creating a balance between emergency services and the required resources is challenging, especially in under-resourced countries -5. This Crowding of the ED leads to adverse outcomes for the patients, providers, the healthcare system and the community. Delay in service provision to patients not only can compromise the quality of the emergency services but can also worsen their consequences. Crowding of the ED might also lead to the violations of the norms and the service provision standards, which in turn might result in patients leaving the facilities without getting the required services. Thus, this systematic review aims to describe the consequences of ED crowding for emergency patients, emergency care providers, and healthcare systems. The findings are anticipated to provide inputs to decision-makers for a better understanding of the effects of ED crowding and to contextualize practical solutions to improve the quality of medical emergency services.Search StrategyIn this review, we adopted the definition for “crowding” from the American College of Emergency Physicians which states “Crowding occurs when the identified need for emergency services exceeds available resources for patient care in the emergency department, hospital, or both.” Then, we searched for articles related to crowding in EDs and its major outcomes published in English between January 1, 2007, and January 1, 2019, in PubMed (MEDLINE) and Embase electronic databases. We applied search terms based on common keywords in the literature concerning the consequences of emergency department crowding . We usedData collection and quality assessmentTwo reviewers (HR.R. & A.AE.), independently screened the titles, abstracts and the methodological validity of the records using data extraction format before their inclusion in the final review. Discussions with the senior author (M.E) were used to resolve any disagreements among the reviewers during the assessment phase. The inclusion criterion was: All studies evaluating the effects and consequences of ED crowding. However, a study was excluded if it only reported the outcomes of a case report or systematic review investigations.A total of 73 articles were eligible for the review . We furtEthics approval and consent: The research protocol was approved by the review committee of the Baqiyatallah University of Medical Sciences.Our search initially retrieved 158 studies. However, 132 papers were excluded by reviewing title and abstract and assessing full-text due to non-relevance. Then, 15 studies were excluded after final quality measurement and scoring for primary screening due to receiving below 0.33 points (<33%). Finally, 58 eligible peer-reviewed original articles were included in the final review .The consequences of patient crowding in hospitals are multifaceted involving effects related to patient health outcomes, healthcare delivery system and the community at large. The response to emergency and non-emergency patients influences the quality of services provided, patients’ outcomes and the healthcare system. Discharge of patients even with high-risk clinical features  and diveThe crowding of the EDs negatively influences both the healthcare delivery process and the outcomes. The high workload  results This systematic review synthesized the outcomes related to ED crowding in hospitals. Crowding of ED can result in consequences for emergency patients’ health outcomes, the healthcare delivery system, and the community at large. The high inflow of emergency patients to ED leads to crowding of the ED, which can in turn negatively affect the healthcare delivery process and outcomes. Delayed emergency healthcare service provision and patients leaving without being seen (LWBS) -14 have The increase in the workload of emergency healthcare staff due to the high patient flow results in delayed clinical decision making and emergency healthcare service provision and increased ED LOS of patients , 61, 62.ED crowding can negatively affect the quality of emergency healthcare. The higher the number of emergency patients, the longer the time it takes to investigate their conditions and to take supportive actions . These cStrengths and Limitation This systematic review synthesized original articles related to outcomes of the emergency department crowding in hospitals globally. Several studies identified complex issues related to emergency department crowding. Our review identified several crowding-related challenges and consequences including patient and staff reactions. The relevant original articles on ED crowding were accessed from the PubMed, Embase, and google scholar databases using comprehensive search keywords. The qualities of the records have been assessed using relevant checklists and those with low quality have been excluded. Our review also adds to the comprehensiveness of the view about the issues. The more explicit schematization of our synthesis compared to other existing reviews can facilitate a better understanding of the complex phenomenon. However, this review has certain limitations. It used study reports published only in English retrieved from the two mentioned sources. Moreover, the reviewed studies did not have a shared definition of crowding.ED crowding affects individual patients, healthcare systems and communities at large. The negative influences of crowding on healthcare service delivery result in delayed service delivery, poor quality care, and inefficiency; all negatively affecting the emergency patients' healthcare outcomes, in turn. This review highlights the importance of response to emergencies and emergency-related crowding and preventing the consequences to better address the healthcare needs of emergency patients and increase the effectiveness of healthcare service delivery centers.ED: Emergency DepartmentMeSH: Medical Subject Headings CASP: Critical Appraisal Skills ProgrammeJBI-MAStARI: Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review InstrumentLWBS: Left Without Being SeenLOS: Length of StayThe datasets used and analyzed during the current study are available from the corresponding author on request.No conflicts of interestNot applicableAll the authors have contributed to development of the concept and production of the final manuscript.


Controlling and preventing infections require deep understanding of the complex interplay that occurs between the host and pathogen following infection. In essence, immunomodulation is any process leading to an immune response that can be altered to a desired level. In mammals, the immune system has developed an extensive array of cells and immunomodulators to recognize, identify, and eliminate foreign invaders. On the other hand, pathogens have evolved multiple mechanisms to combat the host immune system as they establish infections. In this context and under certain circumstances, an infection may result in a subverted immune system, which may lead to an exacerbated illness. Recent advances in biotechnology have enhanced our knowledge of the complex interplay that occurs between the host and invading pathogens following infection, through understanding of the microbial virulence strategies as well as the host's approaches to combat the infection.This special issue collects six high-quality papers, four research articles and two reviews, related to understanding immunomodulation in the context of viral and parasitic infections.Taenia crassiceps-Excreted/Secreted Products Induce a Defined MicroRNA Profile that Modulates Inflammatory Properties of Macrophages” by D. Martínez-Saucedo et al., the authors described how Taenia crassiceps-excreted/secreted antigens (TcES) can modulate proinflammatory responses in macrophages by inducing regulatory posttranscriptional mechanisms and, hence, reduce detrimental outcomes in hosts running with inflammatory diseases. In summary, their study demonstrates a role for TcES in regulating the production of key inflammatory cytokines, “possibly by inducing microRNAs that target inflammatory transcripts and promoting the release of IL-10 in macrophages.” This phenomenon shapes the transcriptomic profile of macrophages and consequently the outcome of the immune response. These findings increase the basic understanding of how the released molecules from helminths would regulate inflammation and, thus, may offer new approaches for the treatment of autoimmune and inflammatory diseases.In the article titled “The remaining three research articles focused on viral infections of three different families, namely, the lymphocytic choriomeningitis virus (LCMV), human papillomavirus type 16, and MERS-coronavirus. The first of these studies was titled “Lymphocytic Choriomeningitis Virus Infection Demonstrates Higher Replicative Capacity and Decreased Antiviral Response in the First-Trimester Placenta” by E. A. L. Enninga and R. N. Theiler from the University of Texas Medical Branch. LCMV is a zoonotic pathogen, of which rodents are the natural reservoir. Although the majority of persons infected with LCMV show relatively minor illness, nonetheless, the virus can cross the placental barrier during pregnancy and cause congenital defects in fetuses. In this study, differences in immunomodulation between the first- and third-trimester placental explants infected with LCMV were evaluated. Generated data suggested that the innate immune response to LCMV infection of the human placenta is more vigorous in the third trimester compared to the first trimester. The authors attributed the absence of viral replication in term placental explants to the robust innate antiviral response in this tissue. These findings are in agreement with clinical observations of decreased transplacental transmission and less severe fetal phenotypes of viral pathogens acquired in later gestation.In the other study titled “Human Papillomavirus Type 16 Disables the Increased Natural Killer Cells in Early Lesions of the Cervix,” J. Zhang et al. retrospectively analyzed the histologic pathology results of 245 women with HPV type 16 only (HPV16+) or type 18 only (HPV18+). The study was the first on emphasizing the unique immune profiles of the cervical microenvironment between two high-risk HPV types. In summary, the authors indicated that more severe lesions are found in the cervix of HPV16+ women compared with those in HPV18+ women. Briefly, their data demonstrated that the number of NK cells was increased but their cytotoxic function was abnormal in an HPV16-infected cervix. The involved mechanisms may partially explain why HPV16 is the most likely to cause cervical cancer and may provide new potential strategies for its clinical management.Several serological studies indicated that the Middle East respiratory syndrome coronavirus (MERS-CoV) has been circulating in camels in the Arabian Peninsula for more than two decades. However, it is still intriguing why the virus was first detected in humans in 2012. It is worth noting that infection with MERS-CoV could be asymptomatic or cause mild influenza-like illness. This may suggest that the prevalence of MERS-CoV infections in the general population is underestimated. The aim of the study by R. A. Al Kahlout et al. was to evaluate the performance of various serological assays and to estimate the seroprevalence of anti-MERS-CoV antibodies in high- and low-risk groups in Qatar. The paper reported low prevalence of anti-MERS antibodies in the general population, which coincides with the low number of all reported cases by the time of their study. Importantly, serological analysis indicated high cross-reactivity between MERS-CoV and other coronaviruses, which necessities more detailed investigation of the immune responses to coronavirus infections.One of the two reviews in this issue by W. Zeng et al. examined the transplantation of probiotics and fecal microbiota on immunomodulation. Probiotics or microbiota are commensal/nonpathogenic microbes that provide beneficial effects to the host through several mechanisms, including but not limited to competitive exclusion of pathogenic bacteria and modulation of immune responses. The aim of this review was to follow through the recent literature on immunomodulatory effects and mechanisms of probiotics and fecal microbiota transplantation (FMT) and also the efficacy and safety of probiotics and FMT in clinical trials and applications. The authors concluded that the immunomodulation induced by probiotics is a complex interplay between different hosts and microorganisms, and hence, the immunomodulatory characteristics of specific probiotics cannot be generalized. Accordingly, “personalized probiotics intervention and standardized fecal bacteria transplantation should be challenges and prospects for future research on the intervention model of intestinal flora.”Macrophages are indispensable modulators of the innate immune system because they maintain a delicate balance between immunity against pathogenic bacteria and tolerance of commensals in the intestine. In their review titled “Functions of Macrophages in the Maintenance of Intestinal Homeostasis,” S. Wang et al. focused their attention on intestinal macrophages, “describing the recent insights into the role of intestinal macrophages in maintaining gut homeostasis and managing gut inflammation.” They also discussed the nutritional modulation of intestinal macrophage functions and the potential of nutritional strategies to manipulate intestinal macrophages and ameliorate inflammatory bowel disorders. They concluded that “a better understanding of mechanisms employed by intestinal macrophages in maintaining intestinal homeostasis and the action of enteral nutrients in the regulation of intestinal macrophages will facilitate the development of nutritional strategies in gut health improvement as well as prevention and control of inflammatory bowel disorders.”This special issue provides original research and review articles that would be helpful to experts and broad audience alike in enhancing their understanding of the complex host-pathogen interactions.


At present, a number of computer vision-based crack detection techniques have been developed to efficiently inspect and manage a large number of structures. However, these techniques have not replaced visual inspection, as they have been developed under near-ideal conditions and not in an on-site environment. This article proposes an automated detection technique for crack morphology on concrete surface under an on-site environment based on convolutional neural networks (CNNs). A well-known CNN, AlexNet is trained for crack detection with images scraped from the Internet. The training set is divided into five classes involving cracks, intact surfaces, two types of similar patterns of cracks, and plants. A comparative study evaluates the successfulness of the detailed surface categorization. A probability map is developed using a softmax layer value to add robustness to sliding window detection and a parametric study was carried out to determine its threshold. The applicability of the proposed method is evaluated on images taken from the field and real-time video frames taken using an unmanned aerial vehicle. The evaluation results confirm the high adoptability of the proposed method for crack inspection in an on-site environment. Civil infrastructures are aging in most of the industrialized countries, which is associated with significant social issues. In the case of the United States, the condition of their infrastructure is graded as D+ on average, and the rehabilitation cost for bridges in the USA is expected to be $123 billion . As shown in the video, the developed method successfully detected 15 out of 16 cracks, missing only a very small crack whose width was approximately 0.05 mm. For all images used in the detection, the precision and recall in the pixel level were calculated as 88% and 81%, respectively. Considering that the video frames taken by the moving UAV are quite blurred, the result shows that the proposed method is at the edge of practice for a UAV-based structure inspection.The real-time detection is demonstrated in the video [Link: This paper proposed an automated crack detection method based on deep learning to detect cracks on a large set of images taken on real structures. The entire procedure of the proposed method consists of fine-tuning AlexNet with Internet-based training images and crack detecting based on the probability map. The training and validation images covering diverse environments of on-site concrete structures were collected from the Internet using a web scraper. Data augmentation skills such as rotation, blurring, and color adjustment were implemented to enhance the diversity and quantity of the thousands of training and validation images. AlexNet was fine-tuned for five categories, Crack, Joint/Edge (ML), Joint/Edge (SL), Intact Surface, and Plant on 42,000 augmented images with 227 × 227 pixel resolutions. The probability map is suggested to strengthen the robustness of the sliding windows detection method. To construct the probability map, pixels accumulate the softmax layer value of the Crack class regardless of the highest detection result during the specified number of detections. After scanning all pixels, pixels with a larger value than a specified threshold are determined as cracks.The comparative and parametric study examined the two main skills for increasing detectability of the CNN classifier, detailed categorization of the concrete surfaces and probability map. The comparative study was conducted to confirm how five categories increase the adoptability of the proposed CNN classifier for on-site inspection. The proposed CNN classifier was compared with a crack detection method based on a subtraction process and another CNN classifier having two classes: crack and intact surface. The proposed CNN classifier succeeded to extract the crack parts out of intact surfaces and objects having similar patterns to cracks while other methods determined the objects as cracks. An optimized threshold for the probability map was chosen through the parametric study. According to the result of the parametric study, the threshold is determined as 35% where both precision and recall are higher than 90%.The performance of the proposed detection method using a CNN classifier was evaluated on 40 images representing on-site environments and a real-time video of a concrete wall taken using a UAV. Despite the existence of the concrete mold marks, pipes, and tie holes around cracks, the proposed CNN classifier successfully detected cracks against intact surfaces and similar objects. The average precision and recall for the images were 92.35% and 89.28% on the pixel level, respectively. The CNN classifier also succeeded in detecting cracks from the real-time video taken by the UAV at 3 frames per s with a recall of 81% recall and precision of 88%. The evaluation of results confirmed the applicability of the proposed method to on-site crack inspection.This research confirmed that the CNN-based method shows a high degree of applicability for crack detection when proper skills are applied. The feature-extracting capability of CNN carries a huge advantage for computer vision-based inspection in civil and infrastructural engineering. The proposed method is beneficial in analyzing the crack morphology by eliminating the interrupting objects in an image in prior. Thus, the CNN-based method is expected to replace current visual inspection in the near future because of its automated feature-extracting capabilities and objective assessment of cracks.


The eponymous term 'Girdlestone situation' originally referred to an excision of the femoral head in case of an acute pyogenic infection of the hip, described by Gathorne Robert Girdlestone in 1945. Over time the procedure and the indication to perform it have significantly changed. This article presents a short biography of Girdlestone with a concomitant report on investigating the evolution of the indication and technique of the Girdlestone situation from the first description up to contemporary literature. Before the introduction of antibiotics and arthroplasty the treatment options for infectious or post-traumatic lesions of the hip were limited. One common option, when surgery was possible, was to resect the femoral head to relieve the painful or infected joint. An early example of head and neck resection of the femur was performed in 1818 by Anthony White on a 9-year-old child with septic non-union of a fracture of the hip.In 1928 Gathorne Robert Girdlestone, an English orthopaedic surgeon, described excision arthroplasty of the hip as a salvage procedure for septic arthritis Eponymous terms are easy shorthand but are subject to interpretation, and the supposed meaning of an eponymous term might differ between professionals By using the original publication we retrieved the original description of the femoral head resection. We also conducted biographical research on Girdlestone. Finally, a literature review was conducted into the eponymous procedure.A literature search in PubMed was conducted on 30 October 2018 on the Girdlestone procedure. The electronic databases Embase, Pubmed, Cochrane Register of Clinical Trials, and Google scholar were used to identify relevant studies up to 30 October 2018. The following search strategy was used in Embase:  NEAR/6 (arthroplast* OR hemiarthroplast* OR hemiarthroplast* OR prosthe* OR replacement*) NEAR/6 (excision OR resection*)) OR ((thr OR tha) NEAR/6 (excision OR resection*))):ab,ti) AND [english]/lim NOT . A similar search strategy was applied in the other databases listed above. References in reviews and full-text articles were screened to retrieve more studies that could be eligible for this literature study.We analysed the articles and in chronological fashion are presenting the changes that occurred over time. We added 'historical' papers that were missing from our search strategy. The article results are presented in a table and flow diagram according to the Prisma guidelines Figure . We corrOur PubMed/Medline search identified 1441 articles. After excluding articles that were not relevant to Girdlestone resection arthroplasty and any duplicates, 15 articles remained. By checking the references manually and finding historical papers, an additional 12 articles were identified  was born in Oxford. After attending the Charterhouse School from 1896, he started clinical training in 1905 at St Thomas Hospital in London. In 1909 he married Ina Mabel Chatterton - the marriage would remain childless. When he started practicing surgery he met Sir Robert Jones, who would become a close friend and stimulated an interest in orthopaedic surgery. Gathorne became a Fellow of the Royal College of Surgeons on 1 December 1911 , as described above, is probably no longer performed. Nowadays the eponymous term is linked to PJI treatment with a radical procedure where the hip prosthesis is completely removed, leaving only a crude articulation between femur and acetabulum Figure . The proIn most cases, GRA is part of two-stage revision arthroplasty in the treatment of PJI. However, single-stage revision has become more popular in recent years to treat PJI Currently the average age for performing Girdlestone resection arthroplasty is 72 years In non-ambulatory cerebral palsy patients with persistent pain, chronic hip dislocation and subluxation, proximal femoral resection arthroplasty is performed as a salvage procedure for pain relief, improvement of sitting balance and perineal care Procedures eponymously named GRA started with the second article published by Girdlestone in 1943 in the Lancet. The article describes a related and perhaps even more radical operation for pyogenic infections In 1928-1950, the Girdlestone resection arthroplasty was originally indicated for pyogenic infection of the hip. These infections could be caused by fractures or gunshot wounds, or were of haematogenous origin Total hip arthroplasty (THA) gained success in the early 1960s when it was developed by the orthopaedic surgeon Sir John Charnley. He referred to his implant as 'low-friction arthroplasty'. Charnley is considered the father of the modern THA, which uses a straight lateral approach Patterson, (1973) Haw (1976) and Bittar (1982) were the first to link prosthetic joint infection to the Girdlestone resection arthroplasty on paper Reported results are conflicting. In 1980 Petty had poor results for infection control and pain relief Nowadays various approaches are used, under spinal or general anaesthesia This paper provides an overview of the historical changes of the original Girdlestone resection arthroplasty. The first procedure was described in 1928 by GRG. Almost a century has gone by, and the procedure has changed. The eponym is nonetheless still being used. Currently the broad definition of a Girdlestone resection arthroplasty is removal of the head and neck of the femur without replacing anything that fills the gap, leaving a crude articulation between the proximal femur and the acetabulum.The eponym “Girdlestone” nowadays attributed different procedures when we refer to him. This may lead to confusion in daily practice. Historically speaking, the original definition of the Girdlestone resection arthroplasty has been exposed to changes over time. This makes the eponymous term multi-interpretable and questions its correct use - which is a disadvantage when using the eponym. And yet, in contrast to most medical terms, this eponymous term is known all over the world and needs no translation.Our study shows that since Girdlestone's first description of removal of the femoral head, the eponym is being used to describe different situations: for removal of a hip prosthesis and in femoral head ostectomy in cerebral palsy patients. Use of the Girdlestone resection arthroplasty fits both procedures well, yet we should be aware of the broad definition the eponym enjoys nowadays.We advocate in favour of keeping the eponymous term Girdlestone situation, with the addition that it refers to a situation where there remains no formal articulation because the femoral head is resected. Whether or not the resection is primary  or secondary to removal of an implant (e.g. because of infection) has no influence on the resulting situation.


While the incidence of cancer in children and adolescents has significantly increased over the last decades, improvements made in the field of cancer therapy have led to an increased life expectancy for childhood cancer survivors. However, the gonadotoxic effect of the treatments may lead to infertility. Although semen cryopreservation represents the most efficient and safe fertility preservation method for males producing sperm, it is not feasible for prepubertal boys. The development of an effective strategy based on the pharmacological protection of the germ cells and testicular function during gonadotoxic exposure is a non-invasive preventive approach that prepubertal boys could benefit from. However, the progress in this field is slow. Currently, cryopreservation of immature testicular tissue (ITT) containing spermatogonial stem cells is offered to prepubertal boys as an experimental fertility preservation strategy by a number of medical centers. Several in vitro and in vivo fertility restoration approaches based on the use of ITT have been developed so far with autotransplantation of ITT appearing more promising. In this review, we discuss the pharmacological approaches for fertility protection in prepubertal and adolescent boys and the fertility restoration approaches developed on the utilization of ITT. The prevalence of cancer in children and adolescents (0–19 years of age) has increased by 27% over the last decades, while the likelihood to be diagnosed with cancer is higher in boys than in girls ,4,5. NonOncofertility, a term introduced by Woodruff in 2007 , is an eAlthough cancer treatment protocols have been amended to promote health and minimize the side effects , there iIn the first part of this paper we review the current approaches on male gonadal protection and introduce a new promising approach based on the use of microRNAs (miRNAs), while in the second part we review the in vitro and in vivo experimental strategies developed based on the use of ITT.The testis is a unique specialized organ with two main functions: the production of gametes and androgens. Each testis contains a number of convoluted seminiferous tubules and it is structurally and functionally divided into the intratubular and the interstitial compartment. The first compartment consists of the germ cells, Sertoli cells (which are the nourishing cells in contact with germ cells and closely attached to the basement membrane) and peritubular myoid cells . The components of the second compartment are the Leydig cells (whose main function is to secrete androgens), blood vessels, immune cells and connective tissue. The continuous sperm production depends on the capacity of spermatogonial stem cells (SSCs), a subpopulation of spermatogonia, to self-renew and to differentiate into more advanced germ cell types under hormonal regulation ,16,17.dark spermatogonia which are proposed to be the “true” SSCs [The prepubertal testis differs from the adult testis as it goes through a number of cellular modifications driven by changes of the endocrine environment from birth through puberty  Figure . Just afue” SSCs ,20. SperAround puberty, the pulsatile secretion of gonadotrophin-releasing hormone (GnRH) stimulates a progressive surge in gonadotrophin release with FSH promoting the proliferation of immature Sertoli cells and LH inducing the maturation of Leydig cells (adult Leydig cells), which start to produce T again ,21. The In contrast to previous knowledge , the preThe exact cytotoxic effect of the different chemotherapeutic agents on the testicular germinal epithelium and the risk of impaired fertility cannot be easily assessed, as they are subject to the dose and duration of treatment, the age of the patient and his sensitivity ,29. ChemThe testis is also sensitive to radiation exposure and the potential damage depends on the total dose, treatment field and fractionation . Doses aIn the case of gonadotoxic (chemotherapy and radiation) exposure of the testes with ongoing spermatogenesis (adolescent or adult), a significant reduction of sperm concentration within 2 months is observed . SpontanThe first-line strategy in fertility preservation in males is sperm cryopreservation. For adolescent and adult males, sperm banking represents a relatively easy, safe and clinically approved option to safeguard fertility . Long-teThe pharmacological protection of the testis during oncological treatments is a new emerging field in male oncofertility and appears to be very attractive, especially for prepubertal boys who cannot benefit from standard semen cryopreservation. The administration of pharmacological agents concomitantly to chemotherapy in order to prevent damage of germ cells and testicular somatic cells and to maintain the testicular function could become a non-invasive preventive approach to preserve fertility.Currently, there is no clinically approved pharmacological option to protect spermatogenesis during gonadotoxic treatments, but studies are ongoing at the preclinical level. More specifically, the temporary suppression of gonadotrophins using GnRH agonists or antagonists (GnRHa) has been tested in adult rodents and non-human primates with controversial results. According to these studies, the direct or secondary hormonal suppression in rats exposed to chemotherapeutic agents like procarbazine or busulfan could restore fertility and promote the spermatogenic resumption ,47, whilThe granulocyte colony-stimulating factor (G-CSF) is administered to cancer patients in order to address neutropenia, a common hematopoietic side-effect during oncological treatments. However, preclinical studies in a mouse model revealed that G-CSF has a protective and restorative role on spermatogenesis after exposure to a high dose of alkylating agents through the stimulation of undifferentiated spermatogonia proliferation. Following G-CSF injections, mice exhibited better recovery of spermatogenesis after busulfan treatment compared to non-injected controls . The mecIt is well-known that chemotherapeutic drugs increase oxidative stress in the testis by generating free reactive oxygen species (ROS) which can negatively influence spermatogenesis and impair sperm function, leading to increased risk of male infertility . AccordiAccording to a study of Carmely et al., (2009) the immunomodulatory AS101 can offer protection against cyclophosphamide-induced testicular damage in a mouse model . NormallThe current preclinical approaches indicate that there is a fragile balance between ‘’killing’’ cancer cells and ‘’rescuing’’ germ cells which should be leaning towards the benefit of the patient. Therefore, better knowledge of the chemotherapy-induced testicular damage is critical to reveal the molecular mechanism of gonadotoxicity and design new fertility preservation strategies.Recently, an alternative therapeutic approach has been introduced based on miRNAs in the field of female fertility preservation, and which can be further developed to protect the testicular function from chemotherapy-induced toxicity ,66,67. ASeveral studies have proven that miRNAs play key roles in processes like growth, differentiation and cellular death, while their contribution in spermatogenesis and testicular function has been demonstrated  Figure . Today, Mage-a genes can be related to increased risk of impaired spermatogenesis after chemotherapy [Mage-a genes can be developed as biomarkers to predict the sensitivity of some patients to chemotherapeutic drugs, leading to a personalized counseling for fertility preservation before treatment initiation.Recently, a study revealed that the mammalian-specific melanoma-associated antigen (MAGE) gene family is expressed during spermatogenesis and has a critical role in male germline protection against environmental stress caused by the lack of nutrients or genotoxic stress associated with chemotherapy. According to the authors, Mage-a KO mice presented increased levels of p53 in the germline which may sensitize these cells to genotoxic stress indicating that polymorphisms in human otherapy . TherefoITT banking is an option currently offered by a number of specialized medical centers to boys facing SSC loss. Although the first specimens of ITT were cryopreserved in 2002, there has been an increasing interest over the last few years with more than 700 patients ,14 optinIn vitro spermatogenesis aims at culturing single cells isolated from ITT or intact ITT in order to obtain mature germ cells. In contrast to the in vivo approaches, this approach can be offered to all pediatric cancer survivors as it eliminates the risk of reintroducing malignant cells. The two-dimensional (2D) cell culture has been shown to support the differentiation of human meiotic germ cells into elongated spermatids and mature spermatozoa when co-cultured with Vero cells or Sertoli cells ,90,91. AThe three-dimensional (3D) cell culture combines the culture of germ cells and somatic cells within 3D supportive matrices. This system appears to be more efficient for the in vitro germ cell development as it provides similar conditions to the in vivo situation enabling the cell-to-cell communication. The use of a 3D semi-solid culture system has been reported to support the differentiation of rat germ cells up to the post-meiotic stage and the formation of elongated spermatids in mice ,96. The However, the most successful system of in vitro spermatogenesis described so far is the organotypic culture. Culture of mouse ITT for three weeks resulted in mature spermatozoa production and the generation of fertile offspring by intracytoplasmic sperm injection (ICSI) ,102,103.An interesting in vitro approach has been recently introduced by Baert et al., (2019) employing tissue engineering and 3D bioprinting . The groAutotransplantation of SSCs is a fertility restoration option that involves the injection of SSCs, isolated from cryopreserved ITT, into germ cell ablated testis. The technique was successfully introduced in 1994, when mouse testicular cells containing SSCs were injected into germ cell depleted seminiferous tubules resulting in the colonization of the recipient’s empty niches and establishment of donor-derived spermatogenesis ,109. TheThe technique is limited by the low number of SSCs in the germ cell population, estimated to represent only 0.02%–0.03% of germ cells in the mouse  and 3.5%A number of safety concerns arise with SSC transplantation from cryopreserved ITT. The epigenetic and genetic safety are essential; however, studies addressing these issues are currently limited in the field of reproductive medicine. In a study of Goossens et al., (2010) no alterations in the genome of mouse offspring born after SSC transplantation were observed  and normAdditionally, following SSC propagation and transplantation, the incidence of cancer and the life span of mice were similar between the transplanted and control groups . HoweverAutotransplantation of ITT, an alternative fertility restoration strategy, involves the transplantation of SSCs within their intact microenvironment. The feasibility of immature human gonadal tissue transplantation has already been proven by successful transplantation of cryopreserved ovarian tissue  and whilSuccessful restoration of ITT functionality following transplantation and establishment of spermatogenesis with generation of offspring has been reported in several species ,134,135.Autotransplantation of human ITT has not yet been reported. The studies conducted so far with human ITT involve the xenotransplantation of the tissue in immunodeficient nude mice ,145,146.Whilst planning the first clinical trial on human ITT transplantation a number of questions need to be addressed and taken into consideration. Initially, and in order to ensure its safety, ITT transplantation should be offered only to patients diagnosed with solid tumors, or non-malignant hematological conditions receiving preconditioning therapy. For patients with metastatic or hematological cancer, such as leukemia, it is however not recommended as the risk of the collected testicular tissue being contaminated with malignant cells causing a disease relapse cannot be discarded.In addition, defining the optimal time as well as the optimal site for ITT transplantation is critical. In the recent study of Fayomi et al., (2019) the tissue was transplanted back to the recipients during prepuberty which ensured the natural maturation of the tissue and establishment of spermatogenesis while the monkeys entered puberty . HoweverThe next step following ITT transplantation is the recovery of the transplants from the testicular parenchyma or scrotum to isolate spermatozoa which will be used for the generation of offspring through assisted reproduction techniques. Although the process of spermatogenesis under physiological conditions requires approximately 74 days , the timSince spermatozoa have not yet been obtained following human ITT transplantation, their fertilization capacity remains questionable. Nonetheless, Honaramooz et al. (2004) reported a 19% blastocyst rate with spermatozoa generated in ectopic xenotransplants from rhesus monkey . More reDespite the birth of offspring from transplant-derived sperm, studies assessing the genetic and epigenetic integrity of spermatozoa are lacking. Only one study from Goossens et al., (2011) designed to characterize epigenetic modifications following ITT transplantation, reported no differences in the expression levels of enzymes catalyzing DNA methylation, the DNA methylation status and stage-specific histone modifications . HoweverWith the growing population of childhood cancer survivors, there is an urgent need to develop strategies to safeguard the fertility of this group of patients. The aforementioned studies mostly describe experimental approaches that could become future routine strategies for male fertility management, aiming at preventing, protecting and restoring the testicular function against oncological treatments. In the first instance, the development of novel approaches protecting germ cells and somatic cells during treatment, regardless of the cancer diagnosis, would potentially diminish the need for the invasive ITT collection and cryopreservation. However, recent advances based on the use of ITT and mostly the in vivo approaches  are encouraging but limited to certain cancer patients. Additionally, before any clinical implementation, validation of the safety is essential for the decision-making process as well as adequate counseling of the patients.


Brucella genus and affects a wide variety of domestic and wildlife species and is also an important zoonosis. The global burden of disease is difficult to assess but Brucella spp. have a worldwide distribution and are endemic in the Middle East, Africa, South America, and Asia. The clinical signs of fever and malaise are non-specific, and the available serological diagnostic tests lack a high degree specificity in endemic regions compared to other important public health diseases such as malaria. A better understanding of the pathogenesis of brucellosis through discoveries in animal models could lead to improved diagnostics and potentially a vaccine for human use. Mouse models have played an important role in elucidating the pathogenesis but do not replicate key features of the disease such as fever. Guinea pigs were instrumental in exploring the pathogenesis of brucellosis in the early nineteenth century and could offer an improvement on the mouse model as a model for human brucellosis.Brucellosis is a bacterial disease caused by species of the  Brucella genus, which are gram negative, facultative intracellular organisms , rats, rabbits, and guinea pigs. Few studies have been conducted in rats and rabbits due to low disease susceptibility and transient nature of infection (Brucella infection and need higher doses (>104) when inoculated via aerosols or i.p. to demonstrate systemic disease  have been used as animal models for the study of brucellosis. In contrast to mice, NHPs share many aspects of the disease manifestation in humans including fever, reproductive failure, and colonization of the reticuloendothelial organs , lymph nodes, and reproductive organs of males and females  are caviomorph rodents that originated from the Andes of South America  and develop systemic disease  of B. suis i.p. identified lesions in the spleen that began as accumulations of polymorphonuclear cells (PMNs) with intracellular Brucella antigen as early as 24-h post inoculation and developed into foci of macrophage hyperplasia with occasional multinucleated giant cells by day seven. Splenic abscesses were commonly noted 100-days post inoculation and contained Brucella antigen within epithelioid macrophages  or histological structure into three types  . Humans,Treponema pallidum), chlamydia (Chlamydia trachomatis), gonorrhea (Neisseria gonorrhoeae), and more recently Zika virus  with many developmental processes occurring postnatally . GestatiBrucella on the gravid uterus -8 is a chemokine that recruits neutrophils to sites of inflammation and is upregulated during in vitro . Recombitivation . Neutroptivation . Guinea tivation . Mice doresearch .Brucella infection (Brucella pathogenesis is an area of active interest. Two functions are proposed: (1) stimulates the production of the cytokine IL-12, which promotes classical macrophage activation and (2) reduces or prevents Brucella intracellular replication (Interferon-gamma (IFN-γ) and IL-12 are important activators of macrophages and are upregulated in response to nfection . The rollication . The patlication .Brucella involves a variety of cell types including CD4+ and CD8+ lymphocytes and antigen-presenting cells such as macrophages (Cell-mediated immunity is crucial to infection clearance and if the response is ineffective, it can lead to chronic infection . The celrophages . The guirophages .Brucella due to similarities in disease development, placental homology, and immunological responses to infection. One of the factors that has hampered the control of neglected zoonoses such as Brucella spp. is the availability of biologically relevant models that can improve understanding of the pathogenesis. Similar to Brucella spp., the guinea pig has been a neglected model that has suffered from a lack of investment. Individual labs have made strides toward developing the guinea pig as a model for infectious diseases, and the sequencing of the guinea pig genome offers an exciting potential for development of new reagents. This review highlights the historical role the guinea pig has played in exploring the pathogenesis of brucellosis, and it is the authors’ opinion that guinea pigs could offer an improved model for the investigation of human brucellosis, especially of the reproductive tract.The guinea pig has the potential to be an improved model for human infection with MH wrote the paper and developed the figures. AA-G conceived the paper and provided critical revision. All authors gave final approval for the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Sneddon's syndrome (SS) is a rare non-inflammatory thrombotic vasculopathy characterized by the combination of cerebrovascular disease with livedo racemose (LR). It has been estimated that the incidence of SS is 4 per 1 million per annum in general population and generally occurs in women between the ages of 20 and 42 years. Approximately 80% of Sneddon's syndrome patients have an antiphospholipid antibody marker. LR may precede the onset of stroke by years and the trunk and/or buttocks are involved in nearly all patients. The cerebrovascular manifestations are mostly secondary to ischemia . Other neurological symptoms range from headache, cerebral hemorrhage, seizures, cognitive and psychiatric disturbances. The involved internal organs include heart, kidney, and eyes. Histological findings of skin are characteristic and the involved vessels are small to medium-sized arteries at the border of dermis to subcutis with a distinct histopathological time course. The main diagnostic criteria are general LR with typical histopathological findings on skin biopsy and focal neurological deficits. The pathogenesis is related to hypercoagulable state and intrinsic small-vessel vasculopathy. The optimal management remains an unsolved problem and long-term anticoagulation have been recommended for cerebral ischemic events based on the presumed pathogenesis. There are controversial results in treatment of SS with immunomodulatory agents. We reported a case of a 49-year old women patient with recurrent ischemic cerebrovascular accidents as the first manifestation, accompanied by livedo reticularis in trunk and limbs and mitral valvulopathy without antiphospholipid antibody.


Respiratory epithelial adenomatoid hamartoma is a relatively new diagnosis, only added to the World Health Organization classification of tumours in 2005. The lesion results from non-neoplastic overgrowth of glandular tissue in the nasal cavity and rarely in de sinus cavities and is often associated with nasal polyposis. The classical appearance of a bilateral mass in the olfactory cleft causing widening of the olfactory cleft allows the radiologist to suggest the diagnosis on computed tomography or magnetic resonance imaging. They described it as “a proliferation of glands lined by multi-layered ciliated respiratory epithelium, often with admixed mucocytes, arising in direct continuity with the surface epithelium, which invaginated downward into the submucosa” [The term A 49-year-old woman presented at the otorhinolaryngology department with symptoms of repeated upper airway infections for six months. She complained of nasal obstruction, headaches, sneezing, hyposmia, postnasal drip and coughing. Treatment with antibiotics and oral steroids had no effect. She had already undergone functional endoscopic sinus surgery with septal correction and partial reduction of a right-sided hypertrophic concha media bullosa in 2008. Endoscopic nasal examination showed a bilateral oedematous mass located medially and cranially in the nose, originating anteriorly of the attachment of the concha media. A computed tomography (CT) Figure  was perfSince the lesion was only added to the World Health Organization classification of tumours in 2005 REAH is still a relatively unknown and therefore underdiagnosed entity 2. Thus faThe lesion is encountered in the third to ninth decade of life and is most commonly diagnosed in the fifth decade. The site of origin is typically the olfactory cleft, which is the area between the superior turbinate, cribriform plate and septum, lined by specialized olfactory epithelium . REAHs cThe CT imaging findings are described in only a limited number of studies. Lima et al. (51 cases), Hawley et al. (29 cases) and Lee et al. (51 cases) all conclude that REAH causes widening of the olfactory cleft and generally does not cause bone erosion. Hawley et al. states that the sensitivity and specificity for the presence of REAH is 88% and 74% respectively if the width of the olfactory clefts measures 1 cm or more, yielding a positive predictive value of 72% and a negative predictive value of 89%.To our best knowledge, Braun et al. wrote the only report available on the MRI findings of REAH. In all six patients the lesions reside bilaterally in the olfactory cleft and there is associated nasal polyposis. Their appearance is described as cerebriform, iso-intense to cerebral parenchyma on T1- and T2-weighted images and homogeneously enhancing. The cribriform plate is generally preserved and intracranial extension absent .It is not always possible to distinguish REAH from nasal polyposis. The different predilection site can sometimes aid in the differential diagnosis as REAH originates in the anterior half of the olfactory cleft and nasal polyps in the ethmoidal labyrinth, protruding into the nasal cavity. The effect of oral steroid treatment can also help since sinonasal polyps generally respond to this treatment and REAHs persist . Other i45REAH is a relatively new, unknown and underdiagnosed lesion of the nasal cavity, classically originating in the olfactory cleft. On computed tomography and magnetic resonance imaging the diagnosis can be suggested if the olfactory clefts are opacified and the total width is greater than 1 cm. Differentiation from often concurring sinonasal polyposis is difficult clinically as well as on imaging. A trial treatment with oral steroids can be useful as polyps will regress and REAH will persist. Correct identification of this benign entity is important to avoid unnecessarily aggressive surgery.


The first review is about the procedures that are most commonly used for microbiome analysis and that are implemented in R packages. Recently, it has been well recognized that understanding the role of the microbiome and its modulation in human health is becoming increasingly relevant for preventive medicine and for the medical management of chronic diseases. The development of high-throughput sequencing technologies has made it possible to study microbial genomes and to perform a more precise quantification of microbiome abundances and function. In this review, Dr. Calle  provided a very excellent overview on the statistical methods of metagenomics data by placing particular emphasis on the compositional structure of microbiome data. Since microbiome data analysis involves high-dimensional structured multivariate sparse data due to its compositional nature, its analysis is very challenging. Dr. Calle presented the principles of compositional data analysis and distinguish between standard methods and those that fit into compositional data analysis.Taenia solium metacestode to the central nervous system. NC is an important neglected tropical disease and an emerging disease in industrialized countries due to immigration from endemic areas. Now, NC has a major global public health impact in terms of disability-adjusted life years. This review pointed out that modern imaging modalities have substantially improved the diagnostic accuracy of NC. Thus, NC is now controllable and manageable. However, the authors recommended further studies to investigate methods for controlling late-onset intractable seizures and for the serological diagnosis of NC patients infected with few worms.The second review article by Ahn et al.  overviewed diagnostic approaches and discusses current issues relating to neurocysticercosis (NC). NC is known to be caused by invasion of This issue contains six Original Articles. First, Ham et al.  introduces a new transcriptome analysis pipeline for chronic obstructive pulmonary disease (COPD). The new pipeline uses a deconvolution process to reduce the heterogeneity of the sample. The new pipeline is shown to clearly identify the transcriptome data originated from the mild or moderate stage of COPD patients. Thus, this extensive evaluation of COPD transcriptome data could provide guidelines for analyzing heterogeneous gene expression profiles and classifying potential candidate genes that are responsible for the pathogenesis of COPD.In the second article, Jo and Choi  investigated the notion of the functional relevance of the first intron sites by estimating amounts of rare alleles in the first intron. The proportions of rare single nucleotide polymorphisms of minor allele frequency in the first introns was estimated, and compared to those in other introns. The rare alleles were found to be significantly enriched in most of the regulatory marks locating in the first introns.In the third article, Hwang et al.  presented an interesting study of athletic performance which is a complex multifactorial trait involving genetic and environmental factors. In particular, they analyzed mitochondrial DNA haplogroups to assess their association with the physical performance of Korean population. They successfully demonstrated that haplogroup F may play a crucial role in the physical performance of Korean athletes.In the fourth article, Daoud  proposes a window-based mechanism approach measure the seriousness of the difference among data-insights extracted from a composite biodata point. His approach is based on two components: undirected graph and Mosaab-metric space. He presents examples of influenza and Ebola viruses to demonstrate the robustness of his approach and to conduct comparisons.Pygoscelis antarcticus) and gentoo (Pygoscelis papua) penguins from the South Shetland Islands, Antarctica. The high-quality de novo assemblies of blood transcriptomes from these penguins were generated. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses they successfully detected many essential genes involved in the major innate immunity pathways. Blood transcriptome studies may be useful for checking the immune and health status of penguins without sacrifice.The last two articles are about animal studies. Kim et al.  reported blood transcriptome resources of chinstrap  presented insights into the signal transduction pathways of mouse lung type II cells. Transcription factor profiling in microarray datasets revealed that several members of AP1, ATF, NF-κB, and C/EBP families involved in diverse responses were expressed in mouse lung type II cells.In Clinical Genomics section, there is one article by Cho . He identified an ERBB pathway–activated cells in triple-negative breast cancer by using single-cell RNA sequencing data from a public resource. He showed that only the single-cell transcriptomes showed intratumor heterogeneity in the expression of three subtyping marker genes . Thus, his results show that ERBB signaling is activated via an indirect route and its molecular subtype is changed on a single-cell level.In the Application Note section, one program HisCoM-mimi was introduced. HisCoM-mimi developed by Kim and Park  was mainly for miRNA-mRNA integration analysis for binary phenotypes. HisCoM-mimi performs hierarchical structural component analysis to identify the miRNA-mRNA pairs associated with binary phenotypes. HisCoM-mimi uses the known mRNA target information provided by targetscan or mirTarbase into the integration model. Compared to the individual analysis of miRNA and mRNA, the integrated analysis by HisCoM-mimi is expected to higher detection power. Thus, HisCoM-mimi is expected to provide advanced accessibility to researchers who want to find the miRNA-mRNA pairs related with binary phenotypes.


We found that layer III of the rat presubiculum comprised multiple types of neurons (n = 12) with characteristic patterns of axonal collateralization, including cortical projection neurons (n = 6) and several types of intrinsic connectional neurons (n = 6). Two of six cortical projection neurons provided two or three major axonal branches to the MEC and formed elaborate terminal arbors within the superficial layers of the MEC. The width and axis of the area of their terminal distribution resembled that of the band-like terminal field seen in our massive-scale observation. Two of the other four cortical projection neurons gave off axonal branches to the MEC and also to the subiculum, and each of the other two neurons sent axons to the subiculum or parasubiculum. Patterns of axonal arborization of six intrinsic connectional neurons were distinct from each other, with four neurons sending many axonal branches to both superficial and deep layers of the presubiculum and the other two neurons showing sparse axonal branches with terminations confined to layers III–V of the presubiculum. These data demonstrate that layer III of the rat presubiculum consists of multiple types of cortical projection neurons and interneurons, and also suggest that inputs from a single presubicular layer III neuron can directly affect a band-like zone of the MEC.The presubiculum plays a key role in processing and integrating spatial and head-directional information. Layer III neurons of the presubiculum provide strong projections to the superficial layers of the medial entorhinal cortex (MEC) in the rat. Our previous study revealed that the terminal distribution of efferents from layer III cells of the presubiculum was organized in a band-like fashion within the MEC, and the transverse axis of these zones ran parallel to the rhinal fissure. Identifying axonal branching patterns of layer III neurons of the presubiculum is important to further elucidate the functional roles of the presubiculum. In the present study, we visualized all axonal processes and terminal distributions of single presubicular layer III neurons in the rat, using  Sensory information converges on EC and is transmitted to the hippocampal formation. Signals are processed in the internal circuit, propagated to the cortical and subcortical structures, then return to EC. Back projections from the hippocampal formation to EC include two pathways: one a direct back pathway . We used eight adult male Wistar rats , with every effort made to minimize the number of animals used and the pain and distress of animals.The DNA construct containing the sequences for GFP tagged with a membrane-targeting palmitoylation site was inserted into the PmaCI site of pSinRep5  as fully described by Furuta et al. . The recRats were initially sedated with 5% isoflurane and a surgical level of anesthesia was maintained by intramuscular injection of a mixture of ketamine (60 mg/kg body weight) and xylazine (20 mg/kg body weight). Each animal was placed in a stereotaxic frame, and a hole was drilled in the skull at coordinates derived from the atlas of  and perfused transcardially with physiological saline followed by 4% formaldehyde in 0.1 M phosphate buffer , and the brains were removed. Brains were cut into several blocks and post-fixed with the same fixative for 4–5 h at 4°C. We created an “extended” hippocampal formation  for 30 min at room temperature. After several washes in Tris-buffered saline (TBS), all sections were serially mounted on gelatin-coated slides and counterstained with neutral red. Sections were then dehydrated in an ethanol series, cleared with xylene, and coverslipped.After confirming the presence of several GFP-expressing cells in sections containing PreS under a fluorescent microscope, all sections were immunostained with antibody against purified GFP. Sections were first incubated in PBS containing 0.1% hydrogen peroxide for 1 h at room temperature and washed in PBS. Sections were then incubated overnight at 4°C with anti-GFP antibody solution  attached with a camera lucida apparatus (at ×40 magnification). In the process of neuronal tracing, we labeled the axonal arbor by painting with several colors to identify each axonal branch originating from a single cell body. When there were any inexact points of joining and tracing fragments of axonal fibers, such as in cases where the target axonal branch was indistinguishable from other overlapping processes, we excluded these fibers from our dataset. Some neurons were also mapped and reconstructed using a computer-assisted microscope system and data analysis program . Shrinkage of section thicknesses was corrected along the z (depth) axis by Neurolucida™. In addition, two-dimensional unfolded maps were prepared as previously described  were visualized in all animals of Within the six cortical projection neurons, two sent fibers only to MEC ergic neuron cannot be denied , five of our six intrinsic connection neurons in our results seem to be classifiable as inhibitory interneurons, while only neuron #11, a small, spiny pyramidal-type neuron, can be excitatory. Within the five presumable inhibitory interneurons, three  showed densely spiny dendritic arbors. Some kinds of GABAergic interneurons in the rat neocortex are spiny .We divided layer III of PreS into multiple regions along the septotemporal, proximodistal and also superficial-to-deep axes, and demonstrated the locations of soma and terminations of axonal branches. In our study, as seen in In conclusion, we have demonstrated the morphological features of the 12 layer III neurons of PreS, including cortical and intrinsic projection neurons, and have indicated the existence of multiple types of MEC projection neurons with distinct patterns of axonal collateralization. Layer III of PreS also comprises a wide variety of intrinsic projection neurons, which may play a critical role in mechanisms underlying head-directional signaling.The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.The present experiments were approved by the Animal Care and Use Committee of Tokyo Women’s Medical University, and all conformed to the Guidelines for the Care and Use of Laboratory Animals . We used eight adult male Wistar rats , and every effort was made to minimize the number of animals used and the pain and distress of animals.All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. YH and TF: study concept, design, drafting of the manuscript, analysis and interpretation of data. YH: acquisition of data and obtained funding. TF: critical revision of the manuscript for important intellectual content.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Patients treated for head and neck cancer (HNC) often suffer from severe and visible loss of function as the cancer itself and the side effects of aggressive treatments have the potential to severely affect quality of life. Therefore, the aim of follow-up is not only the early detection of potentially curable recurrences and second primary tumors but also the diagnosis and rehabilitation of functional impairments. Clear guidelines determining the frequency of follow-up visits are missing, and the impact of follow-up visits on patient's prognosis is unclear. An intensive post-treatment follow-up is needed to detect functional impairments and to initiate their treatment. The aim is an optimal rehabilitation of the patients. This article focusses on goals of aftercare treatment and describes the spectrum of long-term sequelae, and the impact of Patient Reported Outcome (PRO) instruments of which three will be introduced. A systematic definition of the aftercare follow-up does not yet exist. Most head and neck oncologists perform the aftercare in an individual way. The goals in head and neck cancer aftercare are different from most other tumor entities. Orientating on the recommendations of the American Cancer Society  and the The first goal is surveillance for recurrence of the cancer and detection of second primary tumors. Until now it is unclear whether surveillance provides any survival advantage in HNC . The surDetection and treatment of therapy associated side-effects is another goal of follow-up in clinical routine setting. Early monitoring for treatment-related side-effects like acute complications of surgery and/or (chemo)radiation and long-term sequelae like fibrosis and nerve palsy is imperative. The additional screening for negative psychological effects of the disease and its treatment is also very important as psychological challenges are often underestimated. Up to 80% of all HNC patients reported social disruption and about 70% depressive symptoms in a study published in 2012 . The monHealth promotion should be a further aim of good aftercare. The clinician should inform patients about support groups to reveal resources and counsel them to avoid tobacco and alcohol. Additionally, the clinician should explain the patients the positive effects of nutrition, activity, and healthy behavior , 2.In conclusion, the head and neck surgeon is the coordinator of the oncological aftercare, who has to manage the communication to other health providers, include other stakeholders and professions and monitors the patient in a global way. A relevant problem is the lack of evident data in aftercare research.Patients with HNC suffer from severe and often visible functional impairment due to the tumor itself and its therapy. As explained, these impairments include physical and psychological issues. In contrast to other tumor entities, HNC impairs all basic functions of daily life, especially in advanced tumor stages. Swallowing, eating, smelling, voice, speech, and breathing can be directly affected by the tumor and its therapy. Unique to HNC, the effects of treatment may be highly visible, altering appearance, and the confidence to return to social activities .The effects of therapy of HNC on swallowing and nutrition are well-described in literature –16. All Loss of voice and changed speech are severe problems in many patients who underwent therapy for laryngeal cancer. Superior objective voice outcomes have been reported for patients undergoing a partial laryngectomy when compared to total laryngectomy . ConversBreathing is another important aspect in HNC follow-up. Tracheostomy tubes require routine changing which may be performed by the patient or nurse with special training. Our own experiences show, that patients often have problems with closed tracheal cannula, dyspnea, and tracheal infections and the hospitalization rate due to breathing problems is high. Tracheitis and withdrawal from social activities like communal meal are commonly reported . FrequenSpinal accessory nerve injury is a common complication of neck dissection and leads to reduced shoulder mobility and pain . Other nPatients who underwent therapy of HNC are highly affected by psychological co-morbidity . The feaHNC patients suffer from unmet needs and a high rate of under-reported symptoms , 41. In - Benefits for patient to physician communication (more holistic patient and physician communication)- Identification of unreported side-effects and functional impairments- Positive value on shared decision-making process- Better quality of life scores compared to the routine care group- Higher satisfaction with tumor aftercare and follow-up examinationBenefits of PROM:- The questions are irrelevant for the patient- Interpretability of scores measured- Need of time and cost factorsBarriers of PROM implementation Include:To reduce the barriers and reach a higher acceptance in stakeholders of the health system electronical Patient Reported Outcome Measurements were developed. A trial comparing paper completion to an electronic version of the EORTC QLQ- H&N35 did not find a difference regarding response or interpretation of the items . In the In 2006 “OncoQuest” was implemented in clinical routine setting in Amsterdam. This system monitors health-related quality of life using the EORTC QLQ-C30 and QLQ-HN35 questionnaires and the Hospital Anxiety and Depression Scale (HADS) . In sum,The ePRO Measurement instrument “OncoFunction” is also an “in clinic system.” It is based on the International classification of Function (ICF) of the World Health Organization (WHO). The final questionnaire was published in 2017 and is recommended by the German Cancer Society . The sys“OncoKompas” is an eHealth Application specifically designed for use in the clinic . It is aThese three examples show a excerpt of developed PRO measurement systems in the past years. Other publications describe programs such as Kaiku® using an ePROM in HNC patients , 51. MosThe screening and monitoring of late functional outcome have become more and more relevant in recent years. The increasing number of trials which declare the functional outcome after therapy as primary endpoint shows the importance of this field. Due to the fact that more and more younger patients are suffering from HNC, there is a need of individual aftercare especially in long-term follow-up.In 2017, Basch et al. showed a higher survival rate in cancer patients using a web-based PRO instrument between their regular visits . This stBeside the patient-related aspects, administrative aspects will be relevant in the future. Most of the PRO instruments (not only in HNC) are separate stand-alone systems. The development of such systems is easier, and the implementation in a single institution can easily be realized. To bring these systems into comprehensive daily clinical use, links to the local electronic health record is needed . The devHNC patients have special needs (mostly not comparable to other entities) and the problem of “negative selection” exists. Patients who cannot or are not be willing to answer PRO questionnaires will need tailored aftercare concepts.So far, the monitoring of late functional outcome in the clinical routine setting for HNC patients is not comparable between clinics and there is no gold standard. It could be anticipated that in future an increasing number of departments treating HNC patients will integrate PRO assessments in the clinical aftercare and routine practice. The described development of web applications seems to be the next step in monitoring patients also in homecare. The benefit of individual aftercare which is not strictly orientated on time schedules is obvious. The need for intervention maybe detected earlier and the barrier to engage a medical health professional could be lowered. For this purpose, more research in the field of head and neck cancer aftercare is needed and more information about the optimal kind of PRO instruments and the required data must be collected.Patients who underwent therapy of HNC often suffer from highly visible and significant functional impairment. Patient Reported Outcome instruments can lead to better aftercare results and higher patient satisfaction. Beside all positive aspects and advantages, there are many barriers existing in implementing such systems. Nevertheless, PRO instruments will be implemented in an increasing number of oncological departments to collect complete and comparable data. In the future, applications will increasingly be available for homecare use.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In this study, a time-dependent corrosion depth estimation method using atmospheric corrosion monitor (ACM) sensor data to evaluate time-dependent corrosion behaviors is proposed. For the time-dependent corrosion depth estimation of uncoated carbon steel and weathering steel, acceleration corrosion tests were conducted in salt-spray corrosion environments and evaluated with a corrosion damage estimation method using ACM sensing data and corrosion loss data of the tested steel specimens. To estimate the time-dependent corrosion depth using corrosion current by an ACM sensor, the relationship between the mean corrosion depth calculated from the weight loss method and the corrosion current was evaluated. The mean corrosion depth was estimated by calculating the corrosion current and evaluating the relationship between the mean corrosion depth and corrosion current during the expected period. From the test and estimation results, the corrosion current demonstrated a good linear correlation with the mean corrosion depth of carbon steel and weathering. The calculated mean corrosion depth is nearly the same as that of the tested specimen, which can be well used to estimate corrosion rate for the uncoated carbon steel and weathering steel. Steel structures that function as structural members of infrastructure or social structures are generally exposed to corrosive atmospheric environments, including humidity, temperature, airborne salt from the sea, and chemical components in certain areas. These atmospheric corrosive environments result in corrosion problems in steel structures owing to the oxidation characteristics of structural steel materials. Corrosion damage on the surface of steel structures can produce severe structural problems, such as the collapse of plate girder bridges, truncation of truss bridge members, or fatigue cracking of orthotropic bridge decks which have all been reported to degrade structural performance or cause failure ,2. ThereIn this study, a time-dependent corrosion depth estimation method for carbon steel and weathering steel is proposed using the corrosion current obtained from an ACM sensor affected by the corrosion environment based on comparing the time-dependent corrosion depths. Accelerated corrosion tests for carbon steel and weathering steel were conducted in low salt-spray corrosive environments and the corrosion currents were measured using an ACM sensor during the test periods. From the measured corrosion currents and acceleration corrosion tests, the corrosion current was calculated from the ACM sensor and compared with the mean corrosion depth of the tested specimen. The corrosion current demonstrated a good linear correlation with the mean corrosion depth of carbon steel and weathering steel. The real mean corrosion depths of the specimen were compared to the calculated mean corrosion depths.The method of predicting the corrosion rate consists of an electrochemical method and a weight loss method. An electrochemical measurement made by an ACM sensor relates the galvanic current to the corrosion rate. ACM sensors have been applied to monitor corrosion in industrial plants and infrastructures. A linear relationship between the atmospheric corrosion rate and sensor galvanic current output has been suggested for severe marine and rural environments . HoweverAn ACM sensor is composed of two different metal electrodes that are initially insulated from each other, as shown in To evaluate the anticorrosion performance of steel, the most reasonable method is to study the deterioration rate of steel in an atmospheric corrosive environment depending on the exposure period. However, the anticorrosion performance of an actual steel structure is limited by the irregularity of the corrosion rate and deterioration pattern in the installed environment and conditions. The prediction of corrosion rate using corrosion current tends to overestimate the corrosion depth of the corrosion damage. The corrosion currents increase linearly with increasing test time and the corrosion damage decreases with increasing test time in a constant corrosion environment. Therefore, in the method of predicting the mean corrosion depth using an ACM sensor, the mean corrosion depth was calculated using the relationships of corrosion depth and corrosion current under the same corrosion environment.The prediction method was processed from the first to the fourth step, as shown in To review and compare the proposed corrosion damage prediction method, as shown in The test method was combined in the Phase-A cycle with salt spray and the Phase-B cycle without salt spray according to the specification . The salIn general, the mean corrosion depth was calculated based on weight loss, and the evaluation of the relationship between the mean corrosion depth and exposure period was used in a power function, as in Equation (1) :(1)Y=A·XThe mean corrosion depth after 10, 30, 50, and 100 days using the weight loss method is shown in When a thin water film forms on a steel surface, the ACM sensor interprets it as rainfall or dew, and a galvanic current passes between the substrate (Fe) and conductive paste (Ag). It has been reported that this galvanic current demonstrates a good correlation with the corrosion rate of metals, such as steel and zinc. Thus, by measuring the ACM sensor output, the corrosion environments can be evaluated quantitatively. The ACM sensor output for rainfall was greater than 10 μA , and that for dew was greater than 0.1 μA (dew threshold) . The corFor a quantitative analysis, the corrosion current was calculated from the ACM sensor outputs and compared with the corrosion damage of the tested specimens. To examine the prediction method for the mean corrosion depth of uncoated carbon steel and weathering steel, the real and calculated mean corrosion depths of the 100-day specimen were compared. In addition, the long-term corrosion depths were calculated under the measured corrosion current electricity in the accelerated corrosion tests. In this study, to suggest an estimation method for the time-dependent corrosion depth of carbon steel and weathering steel, accelerated corrosion tests and measurements of corrosion current using an ACM sensor were conducted. The measured ACM sensor data were evaluated for examining the time-dependent corrosion depth of carbon steel and weathering steel exposed to salt-spray corrosive environments. The corrosion current was evaluated from the ACM sensor and compared with the corrosion damage of the tested specimens. The corrosion rate tended to decrease as the corrosion current increased. The corrosion current demonstrated a good linear correlation with the mean corrosion depth of carbon steel and weathering steel. To examine the prediction method for the mean corrosion depth of uncoated carbon steel and weathering steel, the tested and predicted mean corrosion depths were compared. The calculated mean corrosion depth was nearly the same as that of the tested specimen. In addition, their long-term corrosion depths were calculated for the measured corrosion current in the accelerated corrosion test. In this study, the long-term corrosion depth of steel was estimated from limited test results and conditions. However, this method can provide a reference to maintain steel structures effectively against corrosion damage generated from the atmospheric corrosion environment in an uncertain steel corrosion problem. The research methods discussed in this paper proves that the mean corrosion depths can be forecasted through ACM sensors.