Tobacco smoking is the main cause of lung cancer, but it is not the sole causal factor. Significant proportions of workers are smokers and exposed to occupational lung carcinogens. This study aims to systematically review the statistical interaction between occupational lung carcinogens and tobacco smoking, in particular asbestos, crystalline silica and diesel engine exhaust emissions.Articles were identified using Scopus, PubMed, and Web of Science, and were limited to those published in English or French, without limitation of time. The reference list of selected studies was reviewed to identify other relevant papers. One reviewer selected the articles based on the inclusion and exclusion criteria. Two reviewers checked the eligibility of articles to be included in the systematic review. Data were extracted by one reviewer and revised by two other reviewers. Cohorts and case–control studies were analyzed separately. The risk of bias was evaluated for each study based on the outcome. The results of the interaction between the tobacco smoking and each carcinogen was evaluated and reported separately.Fifteen original studies were included for asbestos-smoking interaction, seven for silica-smoking interaction and two for diesel-smoking interaction. The results suggested the absence of multiplicative interaction between the three occupational lung carcinogens and smoking. There is no enough evidence from the literature to conclude for the additive interaction. We believe there is a limited risk of publication bias as several studies reporting negative results were published.There are no multiplicative interactions between tobacco smoking and occupational lung carcinogens, in particular asbestos, crystalline silica and diesel engine exhaust emissions. Even though, specific programs should be developed and promoted to reduce concomitantly the exposure to occupational lung carcinogens and tobacco smoking.The online version of this article (doi:10.1186/s12889-017-4025-1) contains supplementary material, which is available to authorized users. Lung cancer remains the leading cause of cancer deaths among males and females , 2. In 1The rate of smoking is higher among blue-collar workers than white-collar workers . Thus a In fact, the statistical interaction between the occupational exposure to asbestos and tobacco smoking was well studied through systematic reviews and meta-analyses, indicating the presence of a positive additive statistical interaction –15. In tDetermine the nature of the statistical interaction between the occupational exposures and tobacco smoking is of high interest from a public health perspective, in particular to develop prevention programs. Therefore, we conducted a review on the interaction between the three most important occupational lung carcinogens, namely asbestos, crystalline silica and diesel engine exhaust emissions and tobacco smoking to define if the interaction nature is similar irrespective to the lung carcinogen, or if the interaction nature is specific for each carcinogen.The objective of this study is to evaluate the statistical interactions between the occupational exposures and tobacco smoking, with limitation to the three principal lung carcinogens; asbestos, crystalline silica and diesel engine exhaust emissions, through a systematic review including cohort and case–control studies.This systematic review was reported based on the PRISMA checklist (2009) Additional file Articles reviewed in this paper were identified using three bibliographic databases: PubMed, Scopus and Web of Science. The selected studies were limited to those published in English or French, without limitation of time. The most recent research was conducted in June 30, 2016.For asbestos-tobacco, silica-tobacco and diesel-tobacco statistical interactions, all records of the three bibliographic databases were searched using the following key words respectively: ["asbestos" and "lung cancer" and "smoking"], ["silica" and "lung cancer" and "smoking"], and ["diesel" and "lung cancer" and "smoking"].P-value or CI 95%). For studies analyzing the same population, the most recently published article evaluating the statistical interaction that met all of the previous criteria was included.Studies were included in this review if they met the following criteria: human studies, studies published in peer-reviewed journals, cohort or case–control studies, studies evaluating the statistical interaction between tobacco smoking and one of the three studied occupational exposures on lung cancer, studies reporting the occupational exposure assessment, studies reporting the smoking behavior assessment, studies reporting the statistical analysis performed to assess the statistical interaction, and studies reporting the results of the statistical interaction and their statistical significance  selection of articles that studied the association between one of the three occupational exposures and lung cancer, 2) selection of the articles that studied the interaction based on the title or the abstract, and 3) for the remaining articles, the full-text was screened to select studies that evaluated the interaction between one of the three occupational exposures and smoking. The reference list of the selected articles was reviewed to identify other relevant articles. The full-text articles remained was assessed for eligibility to determine the final list of articles included in the qualitative synthesis.Data extraction was performed by one author (MZ), and reviewed by two other authors (FD and AL). The following data were extracted from each study included in the present review: first author, publication year, geographic area, study type , exposure type, industry type, total number of subjects (population and cases/cases and controls), the method to collect the occupational exposure and smoking status details, the definition of occupational exposure, the definition of smoking status, the outcome (lung cancer) classification, the methodology of the statistical interaction evaluation, and the results of the statistical interaction evaluation.. stated that “the concept of interaction is that the effect of an exposure, compared with a reference unexposed group, may depend on the presence of one or more other factors”. In addition, they specified that the statistical interaction is potentially scale-dependent [Rothman et alependent . In epidependent . The metependent .The Newcastle-Ottawa quality assessment scale (NOS) was used to assess the quality of the design and the conduction of the included studies at the outcome level , 21.Using the methodology previously delineated, 2,302 articles were identified for the asbestos-smoking interaction: 1,061 from Scopus, 628 from PubMed, and 613 from Web of Science. In addition, two articles were added from the reference list of the selected articles. 1,028 articles were duplicated and excluded. From the remaining 1,276 articles, 1,250 papers were irrelevant; studies not meeting the inclusion criteria, or meeting the exclusion criteria. After screening phase, 26 full-text articles were assessed for eligibility; 11 articles were excluded because of duplicates population and 15 articles were retained including 6 cohorts, 1 case-cohort study, and 8 case–control studies  and RAE, showing the absence of additive and multiplicative interactions [S. The value of S was not significantly greater than one indicating the absence of additive interaction [The characteristics and the results of the six cohort studies and the case-cohort study evaluating asbestos-smoking statistical interaction are presented in Tables ractions . The casractions . The adderaction .Table 1DThe characteristics and the results of the eight case–control studies evaluating asbestos-smoking statistical interaction are presented in Tables The characteristics and the results of the studies evaluating silica-smoking statistical interaction are presented in Tables Five case–control studies were reviewed in this study to assess the silica-smoking statistical interaction. Two studies, one conducted in several centers in Europe and the other in Italy, showed that there is no multiplicative interaction , 38. A sOnly two articles assessed the diesel-smoking statistical interaction were included in our review Table . These tOverall, this review suggests the absence of a multiplicative statistical interaction between the three most frequent occupational lung carcinogens, asbestos, crystalline silica and diesel engine exhaust emissions and tobacco smoking. On the other side, there is no enough evidence from the literature to conclude on the additive statistical interaction.p-value,. However, conclusions from our study are based on a systematic review of the literature and we did not perform a meta-analysis since it was not the primary aim of this study to focus exclusively on the asbestos-smoking statistical interaction. Instead, the present study aimed at assessing the statistical interactions between the most frequent occupational lung carcinogen and tobacco-smoking. Despite the recent publication of a meta-analysis assessing the asbestos-smoking statistical interaction, performing a new one using more stringent inclusion criteria for studies should be considered.Four meta-analyses were conducted to evaluate the asbestos-smoking statistical interaction; one demonstrated a negative multiplicative interaction , and thrSimilarly to asbestos-smoking statistical interaction, for both silica-smoking as well as diesel-smoking statistical interaction, the absence of a multiplicative statistical interaction seems to be consensual. Regarding additive interaction, for both silica-smoking and diesel-smoking statistical interaction, it is impossible to conclude on the presence of a statistical interaction on the additive scale. Indeed, for silica-smoking interactions, it is impossible to conclude due to discrepancies between original studies whereas for diesel-smoking interaction, no studies included in the present systematic review have addressed this issue.The inconsistency of the statistical interaction results between original studies may come from methodological differences in each study. Every study has limitations that could be the source of opposite results on the interaction evaluation. In the studies that were included, occupational histories and smoking details were collected using employment records or questionnaires. The reliability of the data may have been affected by the quality of the documentation in the records and by the recall bias from the questionnaires used to collect retrospective data. Although the data collection could be complete and accurate, the methods used to identify and assess occupational exposures may also have been a source of bias. For example; the utilization of a job-exposure matrix (JEM) could introduce non-differential misclassifications leading to a large number of false-positives and false-negatives. In consequence, there is a risk of underestimated risks that could affect the evaluation of the interaction , 45.al. and Kalilani et al. suggested to use simultaneously three measures of interaction to evaluate the additive interaction: the attributable proportion due to interaction (AP), the relative excess risk due to interaction (RERI), and the Rothman’s synergy index (S) [S) [m) have been proposed to assess the asbestos-smoking multiplicative interaction in studies with low asbestos exposure level [When evaluating interactions, the method and the scale used to examine the interaction should be reported to avoid confusion and ambiguity and facilitate the comparison between studies . In factndex (S) , 54. Alt (S) [S)  was used (S) [S) . Howeverre level .In many of the reviewed articles, the conclusion regarding the statistical interaction was not always consistent with the results of our evaluation; authors suggested the presence of a positive interaction without evaluating the statistically significance of the measure, or conclude on both scales although the interaction was evaluated on one scale only. The same findings was discussed by Liddell (2001); authors continue to suggest the presence of a positive multiplicative asbestos-smoking interaction without enough or strong evidence from their results or from the literature .In the current review, our conclusions are based on strong evidence, as the majority of the reviewed studies conclude the absence of the multiplicative interaction. In addition, all precautions were taken to avoid missing papers; three different bibliographic databases were used and each reference list of all included studies was reviewed. Finally, we believe that the publication bias is limited as several papers with negative results were published.Statistical interaction  between two risk factors increases cancer risk compared to risk related to each factors acting independently.Two main impacts can be considered from a public health point of view. First, regarding primary prevention, reducing exposure to those two risk factors will induce a greater benefice (number of avoided incident cases) if there is a significant interaction between those two factors. Secondly, regarding targeted screening program (screening proposed to a selected population according to a specific risk threshold), the existence of an interaction will decrease the level of exposure of those two factors corresponding to the defined risk threshold. The same argument could be applied to individual imputability used in compensation system. Therefore, the knowledge of a statistical interaction between two risk factors is crucial and the knowledge of the interaction scale (i.e. multiplicative or additive) is important to conduct risk assessment and risk management.Besides, in the light of the current knowledge, the statistical interaction between two factors do not allow to infer strong hypothesis about biological mechanismsTo our knowledge, this is the first systematic review conducted to evaluate the statistical interactions between occupational exposures to crystalline silica and diesel engine exhaust emissions and tobacco smoking. In general, there is no multiplicative interaction between the three most frequent occupational lung carcinogens and the tobacco smoking. Evidence found in the literature cannot be considered sufficient to conclude on the additive scale. To minimize the risk of lung cancer among workers, specific programs should be developed and promoted to reduce concomitantly the exposure to occupational lung carcinogens and tobacco smoking.


Exosomes are small membranous entities of endocytic origin. Their production by a wide variety of cells in eukaryotes implicates their roles in the execution of essential processes, especially cellular communication. Exosomes are secreted under both physiological and pathophysiological conditions, and their actions on neighboring and distant cells lead to the modulations of cellular behaviors. They also assist in the delivery of disease causing entities, such as prions, α-syn, and tau, and thus, facilitate spread to non-effected regions and accelerate the progressions of neurodegenerative diseases. The characterization of exosomes, provides information on aberrant processes, and thus, exosome analysis has many clinical applications. Because they are associated with the transport of different cellular entities across the blood-brain barrier (BBB), exosomes might be useful for delivering drugs and other therapeutic molecules to brain. Herein, we review roles played by exosomes in different neurodegenerative diseases, and the possibilities of using them as diagnostic biomarkers of disease progression, drug delivery vehicles and in gene therapy. Exosomes were first considered to be vesicles produced by mature blood reticulocytes and secreted into extracellular milieu with topically expressed transferrin receptors , chromatography, density gradient centrifugation and ultracentrifugation are the methods more commonly used  in the CSF of sheep  fibrils and of abnormally phosphorylated tau protein (encoded by MAPT) in neurons  protein, which exists as an equilibrium between monomeric and oligomeric states, is a major component of Lewy bodies in PD , and is another entity involved in ALS. Its pathogenic mechanisms include cytoplasmic mis-localization, misfolding followed by aggregation, and inclusion formation  and pass through interstitial fluid into CSF has highlighted their use as drug delivery vehicles targeting the CNS. Systemic administration of exosomes with an siRNA cargo was utilized for drug delivery to the brains of mice  under physiological and pathological condition have increased interest in exploiting them as drug delivery vehicles and for genetic therapy. This ability is adopted to alter the expressions of genes via the bindings of siRNA or miRNA to complementary mRNA sequences thereby controlling gene expression at the post transcriptional level Bartel, . FurtherIn addition to the delivery of RNA, exosome-based therapeutic protein delivery has also been shown to be beneficial in PD. Characterized by diminished SOD1 and catalase levels . A good example for this phenomena is provided by rabies viral glycoprotein (RVG) and iRGD peptides, which when engineered to exosomes of immature dendritic cells aided targeting of brain and tumor tissues (Alvarez-Erviti et al., Exosomes are nano-vesicles produced by diverse cell types and perform a multitude of functions in different cellular backgrounds. Although they have been mainly studied in the context of cell-to-cell communication, the surface localizations of specific proteins on exosomes and their disease specific molecular signatures makes them strong candidates for disease diagnosis. Furthermore, their abilities to transport proteins and nucleic acids goes well for their potential exploitation as drugs delivery agents. Because of the range of prospective application offered by exosomes, future work in this area seems necessary; to formulate robust and reproducible extraction protocols, to provide clearer understanding of the pathways involved in the biogenesis of exosomes and the loading of targeted therapeutic moieties, and to identify strategies for engineering exosomes that are capable target-specific drug delivery.IC, TSA and ATJ conceived the idea. ATJ and MAM contributed to writing of the manuscript. ATJ, SR, HRY and EJL proofread the contents for upgradation and prepared the figures.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.


The secondary metabolites produced by fungi known as mycotoxins, are capable of causing mycotoxicosis (diseases and death) in human and animals. Contamination of feedstuffs as well as food commodities by fungi occurs frequently in a natural manner and is accompanied by the presence of mycotoxins. The occurrence of mycotoxins' contamination is further stimulated by the on-going global warming as reflected in some findings. This review comprehensively discussed the role of mycotoxins  toward gut health and gut microbiota. Certainly, mycotoxins cause perturbation in the gut, particularly in the intestinal epithelial. Recent insights have generated an entirely new perspective where there is a bi-directional relationship exists between mycotoxins and gut microbiota, thus suggesting that our gut microbiota might be involved in the development of mycotoxicosis. The bacteria–xenobiotic interplay for the host is highlighted in this review article. It is now well established that a healthy gut microbiota is largely responsible for the overall health of the host. Findings revealed that the gut microbiota is capable of eliminating mycotoxin from the host naturally, provided that the host is healthy with a balance gut microbiota. Moreover, mycotoxins have been demonstrated for modulation of gut microbiota composition, and such alteration in gut microbiota can be observed up to species level in some of the studies. Most, if not all, of the reported effects of mycotoxins, are negative in terms of intestinal health, where beneficial bacteria are eliminated accompanied by an increase of the gut pathogen. The interactions between gut microbiota and mycotoxins have a significant role in the development of mycotoxicosis, particularly hepatocellular carcinoma. Such knowledge potentially drives the development of novel and innovative strategies for the prevention and therapy of mycotoxin contamination and mycotoxicosis. The momentum of scientific paper publication toward mycotoxin is an increasing trend where 16,821 papers were recorded in Scopus since the first mycotoxin, aflatoxin (AF) was identified in the year 1965. Data clearly showed the significance of mycotoxin research which will be further discussed later in this review paper. Nevertheless, the global health issue arose from mycotoxin is still frequently ignored in many low-income countries, where mycotoxins affect staple foods  secondary metabolites mainly produced by Speight, . The strSpeight, . Fungal Speight, . BesidesSpeight, . Due to Speight, .in vivo   include decreased plasma glucose, reduced blood cell and leukocyte count, weight loss, alimentary toxic aleukia, as well as pathological changes in the liver and stomach  mRNA expression. Apart from the glucose absorption, SGLT1 also responsible for water reabsorption, thus reduction of SGLT1 transporter induces diarrhea as well  in all brain regions  decreased in the number of goblet cells that secrete mucin in trichothecenes-treated animals. Mucin is primarily involved in the gut barrier function  is a mycotoxin that primarily produced by It is well recognized that ZEA is a non-steroidal estrogenic mycotoxin that is implicated in the reproductive disorders of farm animals  and hyperoestrogenic syndromes in humans  decreased the cell integrity. The study showed that ZEA and its metabolites acted differently in the gut  is the most abundant in nature , Minervini et al.  found FBBesides, high levels of FB1 also induced an overgrowth in intestinal goblet cell of broiler and swine  is the most prevalent and relevant fungal toxin of this group . BEN is a chronic tubulointerstitial disease which slowly progressed into terminal renal failure. Indeed, a 15 years study confirmed that BEN is correlated with upper urothelial tract cancer  in chicks and turkey compared to control. The results showed that animals fed with OTA had higher lesion and oocyst indexes in the intestine and more damage at mucosa  suppressed by OTA  decreased in the intestine of the piglets exposed to the toxin  inhibited cell growth, increased lactate dehydrogenase activity and caused genetic damage. It is found that the mechanism of AFB1 cytotoxicity are associated with reactive oxygen species (ROS) generation, which leads to the damage of cell membrane and DNA  was used in in vivo study where AFB1 affects intestinal barrier function in broiler model as indicated by an increased ratio of lactulose to rhamnose ratio in the plasma  assist in the fermentation of complex polysaccharides that escaped proximal digestion  decrease the population of Bacteriodetes spp. and members of Enterobacteriaceae while promoting the growth of beneficial butyrate-producing microorganisms  in LCT are directly correlated with lactose intolerance and the abundance of lactose-metabolizing bacteria, specifically Bifidobacterium , food allergies, cardiovascular disease, obesity, diabetes, eczema and hepatic encephalopathy, mental disorders , Crohn's disease (CD), ulcerative colitis (UC), obesity and gut inflammation  bacteriophages. Pathogenicity of gut viruses includes gastroenteritis, pneumonitis, and diarrhea  using an in vitro screening and microbial analyses in other recent reviews  had been employed to isolate DON-transforming bacteria and the isolates obtained belong to four different bacterial groups; Anaerofilum, Bacillus Clostridiales, and Collinsella  increased by DON exposure . In human, the shift in the proportion of Bacteroides is highly associated with diseases as individuals with Crohn's disease or celiac diseases often exhibit a higher abundance of Bacteroides than healthy individuals .An Using capillary electrophoresis single-stranded conformation polymorphism (CE-SSCP), it is shown that fumonisins decreased the fecal microbiota SSCP-profiles similarity of the fumonisins-treated swines, compared to the untreated control group. The results indicated that there is an increase in the diversity of microbiota. The balance of the digestive microbiota was transiently but markedly affected after 63 days of chronic exposure to fumonisin, which consists of a mixture of FB1 and FB2 . The reduction of beneficial microbes, lactobacillus and bifidobacteria indicated that the OTA shifted the microbiota balance and possibly led to impaired immunity.A study investigating the effect of OTA on gut microbiota using bioreactors has been carried out by Ouethrani et al. , in whicIn vivo study in rat demonstrated that OTA treatment decreased the diversity of the gut microbiota  reduced in the presence of AFB1  reduced total LAB in the broiler. In contrast, the total number of Gram-negative bacteria and LAB were significantly (P < 0.05) increased in the group of broiler fed with 1.5 and 2 ppm of AFB1 . Nevertheless, the biodiversity of microorganisms in the gut was increased. Apart from that, an increase in the metabolism of amino acid by the gut microbiota was also observed. It was suggested that the increased metabolism of amino acid may be detrimental due to the formation of biogenic amines and procarcinogenic compounds  level in fecal  reduction in the percentages of beneficial microbes such as Lactobacillus group, Bifidobacterium group, and Enterococcus group ] successfully relieved the microbial imbalance and hepatic inflammation, which further decreased liver tumor growth  of urinary AFB-N7-guanine level in the probiotic (L. rhamnosus LC705 and Propionibacterium freudenreichii subsp. shermanii) mixture group compared to the placebo group. Similar finding was found by Mohd Redzwan et al. (P < 0·05) in the Lactobacillus casei Shirota supplemented individuals. Besides, hepatic transcriptome in AFB1-induced HCC was positively altered by probiotics  bioavailability of these fungal compounds. The gut microbiota can vary within the same species, thus different reactions toward mycotoxin can be observed as discussed in this review article. In addition, mycotoxins disrupt the gut microbiota balance, and thereby dysregulate intestinal functions and impair local immune response, which may eventually result in systemic toxicity that leads to chronic mycotoxicosis, HCC. The severity of HCC condition can be positively governed by restoration of gut microbiota balance and gut health via probiotics administration. Probiotic which generally helps restore the natural harmony of gut microbiota coupled with its mycotoxins reducing ability could increase its health-promoting value. Regardless, more studies are needed to elucidate the interaction between the gut microbiota and mycotoxin and the implication of such interaction for mycotoxicosis prevention/treatment.SM-R and W-P-PL provided the conception and the structure of the article. W-P-PL wrote the draft. SM-R and W-P-PL revised the article and approved the final version to be published.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 review article, we describe recent advances in the understanding of the resolution phase of inflammation and highlight therapeutic strategies that might be useful in preventing inflammation-induced cochlear damage. In particular, we emphasize beneficial approaches that have been tested in pre-clinical models of inflammatory responses induced by recognized ototoxic drugs such as cisplatin and aminoglycoside antibiotics. Since these studies suggest that improving the resolution process could be useful for the prevention of inflammation-associated diseases in humans, we discuss the potential application of similar strategies to prevent or mitigate DRHL, NRHL and ARHL.A significant number of studies support the idea that inflammatory responses are intimately associated with drug-, noise- and age-related hearing loss . Consequently, several clinical strategies aimed at reducing auditory dysfunction by preventing inflammation are currently under intense scrutiny. Inflammation, however, is a normal adaptive response aimed at restoring tissue functionality and homeostasis after infection, tissue injury and even stress under sterile conditions, and suppressing it could have unintended negative consequences. Therefore, an appropriate approach to prevent or ameliorate DRHL, NRHL and ARHL should involve improving the resolution of the inflammatory process in the cochlea rather than inhibiting this phenomenon. The resolution of inflammation is not a passive response but rather an active, highly controlled and coordinated process. Inflammation by itself produces specialized pro-resolving mediators with critical functions, including essential fatty acid derivatives , proteins and peptides such as annexin A1 and galectins, purines (adenosine), gaseous mediators (NO, H The most important paradigm recognized and highlighted in this article is that inflammation in any tissue, organ and system, behaves as a beneficial host reaction aimed at protecting individuals from infections and tissue injury. Moreover, inflammation can help to establish an immunological memory that the organism can use later to generate a better response to a particular infectious agent , eicosanoids generated in vivo from arachidonic acid  are ω-3 essential fatty acids derivatives with powerful multilevel anti-inflammatory and pro-resolving properties  bind the ALX/FRP2 receptor, just like LX  are anti-inflammatory and pro-resolving lipid mediators generated by macrophages from DHA  is a powerful anti-inflammatory and pro-resolving protein. ANXA1 synthesis and release is regulated by glucocorticoids  on the plasma membrane of inflammatory and immune cells , which is a sensor of cellular stress, and it has been shown that the CO it generates may limit tissue injury  and lipoxygenases (LOX), interfering with the synthesis of pro-inflammatory mediators  and the ST. The nature of the immune cells infiltrating the cochlea has been discussed in a recent review . On the other hand, cisplatin is able to induce endoplasmic reticulum stress in association with the unfolded-protein response  remains associated with oxidative stress  is the most common form of hearing loss in adults, their cellular and molecular mechanisms are still poorly understood , an agonist of the purinergic adenosine receptor A1AR, increased the activity of antioxidant enzymes and reduced lipid peroxidation (Ford et al., RPIA protects cochlear explants from damage induced by cisplatin and noise (Hu et al., A role for adenosine in auditory function was suggested by experiments in frogs several decades ago (Bryant et al., Thus, drugs that increase the concentration of endogenous adenosine or directly activate adenosine receptors could play a pivotal role in the protection of the organ of Corti against cisplatin cytotoxicity. Once more, mediators of inflammatory resolution could serve as ideal targets for otoprotective therapies.Decades of intensive research have not delivered successful clinical strategies for preventing or ameliorating DRHL, NRHL or ARHL. Currently there is not a single specific, FDA-approved otoprotective agent. In addition, the most common therapeutic approaches, glucocorticoid and antioxidants, produce inconsistent results. Thus, we feel that an alternative research paradigm is absolutely needed to break the stalemate.The typical research approach has been, and still is, to look for prevention of cell damage induced by the toxic agents under investigation. Although this approach is reasonable and absolutely valid, we want to propose an alternative way: enhance the physiological mechanisms designed for our organism for dealing with toxic agents, looking for an accelerated and improved cell and tissue protection, healing and repair. Specifically, we propose to select the pro-resolution pathways associated with the successful termination of inflammatory responses as a new target for research aimed at preventing or ameliorating DRHL, NRHL and ARHL. We strongly believe that improving the resolution of cochlear inflammatory responses is one way, although most likely not the only one, to overcome the current impasse in this important area of hearing research.Inflammation is a beneficial host reaction aimed at protecting individuals from infections and tissue injury. Uncontrolled inflammation, however, is now widely recognized as a common factor in many diseases and organ dysfunctions, including DRHL, NRHL and ARHL. Since inflammatory responses are aimed to eliminate invading organisms and repair injured tissues, they are naturally self-limited. Resolution, as the last step in any inflammatory response, is exquisitely regulated, and it is completed only after any potential for continuous tissue damage has been conquered. Thus, improving the resolution phase of inflammatory responses in the inner ear may naturally result in cell protection, tissue healing and repair, therefore contributing to the prevention or amelioration of auditory dysfunctions.The success of the proposed approach is heavily dependent on the full understanding of resolution biology and the expression and function of pro-resolution mediators and receptors in the mammalian cochlea. Unfortunately, the current number of studies on this topic in the inner ear is clearly insufficient. Therefore, we consider imperative to accelerate the identification of all pro-resolution pathways at work in the cochlea. Next, their specific functions should be explored to understand how to enhance, safely and rapidly, the resolution of inflammatory responses in the inner ear. Of course, we are not proposing to eliminate any of the current research strategies, since it is unlikely that any single approach will be the magic bullet for all non-resolving, chronic inflammatory and autoimmune diseases. Most likely combinatorial pro-resolving therapies also including, perhaps, dietary w-3 and w-6 essential fatty acids and inhibitors of specific pro-inflammatory agents and their receptors, would be necessary to obtain significant effects. Regardless, we are convinced that the elucidation of the mechanisms of pharmacological modulation of the resolution process would be crucial to finding the most effective therapeutic agents for preventing or ameliorating DRHL, NRHL and ARHL.FK saw the need of a review on this topic. GMK and GL reviewed the literature and organized the information. RAU and FK wrote 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. The reviewer MJ and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.


Today, a host of veterans who were exposed to mustard gas suffer from substantially poor quality of life (QoL). However, factors that influence these patients’ QoL have not been yet scrutinized. QoL is deemed as a crucial construct that demands careful attention during evaluation as well as intervention. The present study aimed to delve into the physical, mental, and social factors that affect the QoL of mustard gas victims.All the physical, mental, and social parameters that influence the QoL of mustard gas victims were scrutinized through a systematic review. We searched for Persian and English scientific databases, i.e., PubMed, Scopus, and Google Scholar, and national databanks, namely SID, IranMedex, and Magiran to identify studies related to chemical victims conducted up to the end of 2015. Next, the quality of 21 articles and studies were assessed using the checklist of the National Institute of Health (NIH), and subsequently, 13 articles were selected for the stages of data extraction and analysis.Findings revealed that, among the physical factors, coexistence of several medical conditions caused by chemical injury and the severity of the chemical injury had the greatest impact on the QoL of chemically injured veterans. Besides, suffering from psychological and neurological disorders, along with educational level and employment status, were the most influential psychosocial parameters that influenced veterans’ QoL.The review conducted herein identified the physical and psychosocial factors affecting the QoL of mustard gas victims. In fact, it is the first to present a large collection of descriptive information on QoL contributors in a systematic and orderly fashion. Exposure to different hazardous chemical agents, specifically gases, may result in various adverse acute and chronic medical consequences . Such agIranian researchers have found numerous late complications among victims of chemical attacks, including a wide range of respiratory, ocular, dermal, psychological, hematological, immunological, gastrointestinal and endocrine problems, all of which can influence the QoL of the exposed victims . PhysicaAccording to different studies, chemical victims’ QoL scores were lower as compared to those of normal civilians . ResearcThis study tries to combine all available data on the different aspects of the QoL of chemically injured veterans in order to facilitate further detailed and targeted studies on similar cases. Native articles have been frequently referenced in this study because, as previously mentioned, Iran is still the main victim of vast utilization of chemical agents, and nearly all acute-chronic studies have been established and initiated by Iranian scientists. The purpose of this study was to determine the diverse aspects of the physical and psychosocial factors affecting the QoL of victims exposed to mustard gas. Thus, the present explored to what extent the QoL of chemical victims is influenced by physical and psychosocial factors.This systematic review was conducted according to the guidelines of the Center for Reviews and Dissemination, York University . All stuTo identify other systematic reviews with objectives similar to those of the current study, the Cochrane Database of Systematic Reviews was searched for full-texts of new systematic reviews, and no similar systemic reviews were identified . Next, rAs mentioned above, Iran has sustained the most extensive damage caused by chemical attacks since WWII . TherefoEligible studies comprised all articles which revolved around the assessment of QoL of chemical victims who met the inclusion criteria of the current systematic review. The review team narrowed the search area down to quantitative studies which covered human issues and dealt with problems of the mustard gas victims themselves . Additionally, only original articles were considered for inclusion. Therefore, other sources of information, such as books, review articles, journals, and reports that did not fulfill the inclusion criteria like conciseness and capability to undergo quality assessment were excluded from the assessment. Next, the titles and abstracts of the retrieved articles were separately assessed by two referees (MS & MG). Here, studies that did not clearly satisfy the inclusion criteria were excluded from the systematic review. On completion of this preliminary assessment, the full text of the remaining articles was retrieved so that the referees would perform eligibility assessment once more. Those articles that were subjects of controversy between the referees were referred to a senior scholar (AE) to judge their eligibility.In this study, the studies that could answer the present research question were examined. These articles underwent a critical assessment via a checklist provided by the National Institute of Health (NIH). The checklist comprises 14 items for the quality assessment of articles , which wIn this step, the required data on the dimensions of QoL and its influential factors among mustard gas victims were extracted. The data included demographic characteristics, chemical injury-related characteristics, instruments, educational level, and physical as well as psychosocial dimensions affecting the QoL of mustard gas victims.The current systematic review constituted the four main stages of identification, screening, quality assessment, and analysis . In the In the third stage, full-text versions of the remaining articles were retrieved to assess their eligibility. Thus, 56 articles that did not meet the necessary requirements were excluded from the systematic review. Accordingly, 21 eligible studies that conformed to the present research question and met the inclusion criteria were subjected to through quality assessment using the checklist developed by NIH. The quality assessment revealed that 4 articles did not have the essential data related to the current research question or did not employ the cross-sectional design. Four other articles failed to achieve the minimum required score on the checklist. Therefore, only 13 articles were used for the subsequent stages of data extraction and analysis. Besides, to gather additional facts and details needed for the current study, the review team communicated with the corresponding authors of two articles.Data regarding demographic and chemical injury-related characteristics , and phyMoreover, the following instruments were used for the assessment of QoL among the included studies: the Short Form Health Survey (SF-36) in 4 articles –22, the All included articles reported low QoL scores for the mustard gas victims, and several subjects exhibited an extremely poor level of QoL –22, 25. Among physical factors influencing the QoL of mustard gas victims, concurrent existence of pulmonary, ocular, dermal, and psychiatric complications had the most damaging impact on the QoL of these patients , 26, 29.The results of the current systematic review indicated that mental complications were some of the topmost factors decreasing the QoL of mustard gas victims –27, 29. Several chemically injured veterans suffer from a poor level of QoL though it has been 30 years since the first exposure to mustard gas . TherefoThus far, there have been several attempts to gather comprehensive information on the life experiences of exposed veterans, but such studies have failed to develop a decisive and well-rounded protocol for planning clinical care and psychological services for chemically injured veterans. The current systematic aimed to lay foundations for research and psychosocial intervention to improve the QoL of exposed veterans.Given that mustard gas victims experience particularly distinct aspects of life and they have to deal special problems, it is important to consider diagnoses and care plans fitting their condition .Mustard gas victims sustain several medical conditions  in addition to psychiatric distress. Therefore, their QoL can be assessed from different aspects. Such a multi-dimensional nature also entails using specific instruments that are only designed for mustard gas victims. Considering these factors, major improvements in the QoL of exposed veterans can be achieved by taking small steps to change their lifestyle .The results of the current systematic review also indicated that despite the availability of literature on chemically injured veterans, some details and facts are missing in over half of the studies. Such details and facts mostly related to important parameters such as duration of suffering from chemical injury, intensity of chemical injury, time of mustard gas exposure, and underlying disorders and comorbidities. In fact, several studies assessing the QoL of mustard gas victims reported that these parameters play a significant role . Such daThe current systematic review indicated that, among the physical factors affecting the QoL of mustard gas victims, the most frequently identified influence was the co-existence of several diseases such as pulmonary, dermal, ocular, and psychiatric complications , 26, 29.Among the psychosocial parameters affecting the QoL of mustard gas victims, the following influencing factors were identified: psychological problems –27, 29, It is probable that the sample group suffered from impaired QoL due to physical and mental disorders , 36, 44,In most studies, a high level of education was reported to have a positive influence on the QoL of injured veterans. This may be explained by the fact that the increase in knowledge about methods of symptoms control, together with rise in social interactions, may help improve QoL , 21, 29.One of the constraints that the current review encountered was that though the studies scrutinized herein contained a huge mass of data on veterans’ QoL, some pieces of information, such as mean time since last exposure, frequency of exposure, and severity of chemical injury were neglected. Hence, this study recommends that prospective studies should make use of specific instruments to evaluate the QoL of mustard gas victims and should address the above-mentioned variables.The analysis conducted within this review backs up the theories on the impact of physical and psychosocial factors on the QoL of exposed veterans. The findings suggest that the coexistence of several medical conditions caused by the chemical injury, severity of chemical injury, psychological and neurological complications, educational level, and employment status and job-appropriateness had the greatest impact on the QoL of mustard gas victims. Nevertheless, long-term studies are required to determine the correlation between veterans’ QoL and these physical and psychosocial parameters. In future, research should focus on improving the QoL of these patients by assembling a multi-disciplinary medical team.


Laboratory networks provide accurate and timely laboratory confirmation of infections, an essential component of disease surveillance. The World Health Organization coordinates global laboratory surveillance for many vaccine-preventable diseases. This report describes these laboratory networks and the challenges in sustaining and expanding global laboratory surveillance capacity. Laboratory networks were established to provide accurate and timely laboratory confirmation of infections, an essential component of disease surveillance systems. The World Health Organization (WHO) coordinates global laboratory surveillance of vaccine-preventable diseases (VPDs), including polio, measles and rubella, yellow fever, Japanese encephalitis, rotavirus, and invasive bacterial diseases. In addition to providing high-quality laboratory surveillance data to help guide disease control, elimination, and eradication programs, these global networks provide capacity-building and an infrastructure for public health laboratories. There are major challenges with sustaining and expanding the global laboratory surveillance capacity: limited resources and the need for expansion to meet programmatic goals. Here, we describe the WHO-coordinated laboratory networks supporting VPD surveillance and present a plan for the further development of these networks. Laboratory-supported surveillance is a critical component for strategies to control, eliminate, and eradicate infectious diseases, including vaccine-preventable diseases (VPDs). Surveillance is based on principles of rapid case detection, reporting, and epidemiologic and laboratory investigation. In settings with established regional goals for disease elimination or eradication, high-quality, case-based surveillance (including laboratory confirmation) is required to guide program activities toward achieving milestones, and to verify disease elimination or eradication.The World Health Organization (WHO) and Member States coordinate global laboratory networks to support surveillance for selected VPDs, including polio, measles, rubella, yellow fever (YF), Japanese encephalitis (JE), rotavirus, influenza, tuberculosis, and invasive bacterial disease (IBD) . Here, wFollowing the adoption of a global goal to eradicate polio by the World Health Assembly (WHA) in 1988, the WHO developed a global network of laboratories to ensure high-quality laboratory diagnosis of suspect cases of poliomyelitis . The GloIn 2012, the WHA endorsed the Global Vaccine Action Plan and its objective to eliminate measles and rubella in 5 of the 6 WHO regions by 2020. As of September 2013, countries in all 6 WHO regions had adopted measles elimination goals, and in 3 regions, additional goals for the elimination of rubella and congenital rubella syndrome (CRS) had been adopted . Case-baThe capacity of the GMRLN continues to provide laboratory support to all countries with detection of measles- or rubella-specific immunoglobulin type M (IgM) by enzyme immune assay as the most widely used method for case confirmation . In 2015To support virologic surveillance, the WHO established standard protocols for monitoring global genotype distribution and tracking transmission of measles and rubella viruses . GenotypFollowing the experience of the GPLN, an annual accreditation and proficiency testing program for the GMRLN ensures high-quality laboratory testing . Since 2In 2013, the Strategic Advisory Group of Experts (SAGE) on Immunization recommended a framework for verifying the elimination of measles and rubella that included 3 criteria for the verification of measles or rubella elimination . Two of Surveillance data are used to help monitor rubella virus transmission and to prevent CRS. An approach to verifying the elimination of CRS in the AMR was published in 2011 . In the Yellow fever virus is an arthropod-borne virus with both human and nonhuman primate transmission cycles, which causes sporadic outbreaks in Africa and the Americas. The recognition of YF cases in the early stages of an outbreak is difficult because the differential diagnosis considers several diseases, including malaria, viral hepatitis, dengue, leptospirosis, or other hemorrhagic fevers. However, 1 laboratory-confirmed YF case may initiate an outbreak investigation, necessitating a response, which may include mass vaccination campaigns. A definitive diagnosis of YF infection cannot be made based solely on clinical impressions, and laboratory confirmation is necessary for final case classification , 19. TheA similar approach has been taken to establish and coordinate the laboratory network for Japanese encephalitis (JELN), which is a major cause of childhood mortality and morbidity in countries of South-East Asia Region (SEAR) and Western Pacific Region (WPR). It is the most important cause of arboviral encephalitis globally. JE is a zoonotic disease, transmitted between mosquito vectors and nonhuman vertebrate hosts (primarily birds and pigs). Vaccination is the only effective protection for humans living in areas where the JE virus is circulating. Approximately 3 billion people live in JE-endemic regions, and JE causes at least 50000 acute encephalitis syndrome (AES) cases with an estimated 10000 deaths annually . The JE Introduction of the JE vaccine will reduce the number of JE cases, but it will also increase the need for enhanced surveillance to determine the disease burden and trends, substantiate the need for vaccination, monitor the impact of vaccination programs, and detect outbreaks . LaboratRotavirus is the most common cause of severe diarrhea among children under 5 years of age , 24. In Genotype surveillance is important to monitor possible shifts in rotavirus genotypes . In 2008The GRLN has adopted approaches similar to those of the GPLN and GMRLN to confirm and improve the accuracy of collected data. The GRLN monitors the laboratory performance through site visits, data review and analysis, external quality control program for confirmatory testing, and annual external quality assurance (EQA) using proficiency test panels. In 2015, 113 (97%) of 116 laboratories that participated in EQA passed the EIA testing, and 49 (91%) of 54 labs that had genotyping capacities passed the molecular quality control. Since 2013, the GRLN has been used as a platform for surveillance for other diarrheal pathogens (including the use of molecular diagnostic technologies) for the simultaneous detection of more than 20 enteric pathogens, including bacteria, viruses, and protozoa.Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. These data are used by policy-makers to inform evidence-based decisions on vaccine introduction and to assess the effectiveness of vaccine introduction by monitoring disease trends and serotype/serogroup distribution before and after vaccine introduction [The WHO and partners coordinate a global sentinel surveillance network in selected hospitals for vaccine-preventable IBD that was brought together from preexisting regional IBD networks in 2008. In 2015, the global IBD laboratory network included 117 sentinel hospitals, 20 NLs, 9 RRLs, and the CDC Global Reference Laboratory. The objectives of this network are to gather standardized data on children under 5 years of age suspected to have contracted invasive, severe infection caused by oduction . The IBDoduction .Cerebrospinal fluid specimens are collected from suspected meningitis cases and tested in a laboratory . Culture is performed on clinical specimens collected from suspected pneumonia and sepsis cases. A system of specimen referral between the sentinel hospital laboratories and the NL or RRL has been established to identify the pathogens from clinical samples. The IBD network has established quality-assurance and quality-control systems for laboratory testing. In 2015, 90 of the 98 IBD network laboratories that participated in the EQA program passed.A continuing and significant challenge to all of the WHO-coordinated laboratory networks is the long-standing shortage of human and financial resources. Global donors, as well as national governments, often earmark funds for interventions such as vaccines or injection devices, but fail to recognize the critical role of surveillance to detect diseases and monitor vaccine impacts. Surveillance laboratory networks require sustained investments to support operations that are often in resource-limited and in logistically challenging settings. To some extent, integration of efforts across laboratory networks is possible; therefore, resources that support one network may also have a beneficial effect on other networks. For example, the GMRLN was largely built on  the existing GPLN, and, in turn, the YF and JE surveillance networks were built onto the GMRLN. Of serious concern and a major risk to global VPD surveillance is the imminent diminishing of resources currently supporting polio eradication. There is an urgent need to communicate to donors the important role that disease surveillance plays, and to mitigate the threat of resources flatlining or decreasing, particularly once polio eradication is achieved.Another significant challenge is the needed expansion of the networks to meet increasing programmatic demands for high-quality surveillance data. Within the GMRLN network (particularly in SEAR), there is an immediate challenge to expand as new laboratories are designated in India, Thailand, Myanmar, Nepal, and Indonesia. Accommodating this expansion will require additional resources.Maintaining a well-trained laboratory workforce is often challenging because of staff turnover, changing programmatic demands, and the introduction of new or modified methods. All of the laboratory networks have ongoing training activities through onsite training, intercountry workshops and meetings, laboratory visits and, more recently, electronic media (such as videos and webinars). The GPLN has developed a training program (including standard laboratory practices and procedures and biosafety videos) that is being used by all the laboratory networks. Training needs contribute significantly to the workload and resource requirements of the RRLs, GSLs, and Regional Laboratory Coordinators, and this workload is likely to increase as networks expand.A major logistic challenge is maintaining an uninterrupted availability of supplies and reagents needed to perform the transportation and testing of specimens. As laboratory networks expand, the number of specimens collected and shipped, laboratory tests performed, and associated logistic issues increase. Local specimen transport requires maintenance of a reliable infrastructure for the reverse cold chain. International shipment of reagents, supplies, and clinical samples is becoming more expensive and time consuming because of more stringent regulations. Logistical issues are especially challenging during outbreaks (where there is a need for surge capacity for laboratory staff and supplies and reagents), and close coordination is required to avoid shortages and to ensure that data are collected to guide outbreak-response activities in a timely manner.Responding to the differing programmatic requirements of case-based, syndromic, and sentinel surveillance will be a new challenge as network laboratories move toward more integrated disease surveillance. The various specimen types have different reverse cold chain requirements, and the testing will require a wide range of techniques. Integrated testing for viral and bacterial pathogens may require a substantial amount of additional resources and training . FinallyThe laboratory networks could not function properly without coordination at the global, regional, and national levels of participating laboratories. Coordination is essential and allows for the maintenance of standard performance indicators, quality assurance and accreditation programs, standardized testing methods and data collection, and effective interfacing with the epidemiological units of national programs. Close collaboration to strengthen the networks creates esprit de corps for building long-lasting partnerships to achieve public health goals. However, maintaining the financial support for global and regional coordination is an ongoing challenge.The development of the GPLN demonstrated the great value of having globally coordinated laboratory surveillance, and provided infrastructure for public health laboratories that facilitated the development of the GMRLN and other disease surveillance laboratory networks. Laboratories in the GMRLN have benefited by the infrastructure provided by the GPLN, including the establishment of dedicated cell culture and polymerase chain reaction (PCR) facilities, including the availability of key equipment such as thermocyclers and automated sequencers, which are readily available for other disease surveillance activities. Because IgM detection is still the method of choice for the confirmation of measles and rubella cases, the GMRLN has helped to establish serologic testing for other viral diseases in many laboratories. This capacity for serologic testing is now being used by laboratories in the AMR, AFR, SEAR, and WPR to offer serologic testing for YF and JE. Also, many GMRLN laboratories have established molecular testing, including genotyping—techniques that will prove useful for detection of other pathogens.The GPLN laboratories developed a work culture that valued timely and accurate testing with a strong foundation of capacity-building, quality control, data management, and biosafety and biosecurity, and this culture is shared by the other WHO-coordinated laboratory networks. The laboratory accreditation program initiated by the GPLN was adapted for use by the GMRLN and provides a basis for other assessment programs. In addition, these networks have built capacity though continuous training efforts. The GPLN and GMRLN networks have developed strong programs for referral of samples for confirmation, and both have developed external quality assurance programs through mandatory proficiency panels to assess the performance of serologic and molecular testing.To enhance laboratory-based surveillance, the global laboratory networks are exploring new technologies to replace virus isolation for the identification of pathogens and serologic methods (such as the detection of pathogen-specific IgM) for case confirmation. These technologies are often based on common platforms such as real-time reverse transcriptase–PCR, next-generation sequencing, and high-throughput serologic testing. For example, there is an increasing use of PCR for laboratory confirmation. The network laboratories can take advantage of these common platforms and develop assays that are amenable to supporting surveillance for many viral and bacterial diseases.To secure the investments made by the GPLN, we now have the opportunity to transition the resources targeted for the GPLN to further expand the laboratory networks and to develop an integrated approach that can support global surveillance for VPDs, including polio. The key objective of the transition is to maintain laboratory support for high-quality, case-based, and syndromic surveillance systems that meet performance indicators and can provide high-quality surveillance data needed to verify disease control and progress toward elimination. Efforts are underway to develop next-generation information systems to optimize the use of data for immunization program monitoring and VPD surveillance. Utilization of GPLN assets and experience to help achieve existing goals for other programs is a cost-effective way to transition the Global Polio Eradication Initiative, while developing integrated VPD surveillance to maintain needed polio surveillance capacity.


Postpartum bilateral femoral neck fracture (BFNF) is a rare condition. We here report a case of BFNF due to excessive corticosteroid consumption, twin pregnancy, immobility, and vitamin D deficiency.This is a report of a 32-yr-old woman with bilateral femoral insufficiency fracture five days after emergency cesarean section due to preterm labor, twin pregnancy, and the history of a previous cesarean section at 33 wk. Antenatal repeated courses of betamethasone injections for fetal lung maturity, daily oral use of prednisolone for the history of miscarriage, immobilization, and vitamin D deficiency were the important contributing factors in her past medical history and lab investigations. The bone mineral density examination showed low bone density for the expected age.Clinicians, who deal with pregnant women, should consider the diagnosis of bilateral femoral insufficiency fracture in any pregnant women with pelvic pain. Awareness of risk factors of BFNF might help to reduce the rate of this complication. Simultaneous bilateral femoral neck fracture (BFNF) is an uncommon condition which has been reported to be caused by generalized epilepsy, osteomalacia, hypovitaminosis D, and chronic renal failure. According to the earlier reports, the majority of BFNF cases in postpartum period were the consequence of transient osteoporosis of pregnancy , 2. During the third trimester of pregnancy and lactation period, the considerable fetal consumption of calcium and vitamin D will be met mostly through re-absorption from the maternal skeleton. In this condition, the drastic loss of bone mass suddenly presents, which can lead to the osteoporotic fractures during pregnancy or thereafter . We report a case of bilateral femoral neck insufficiency fracture in a 32-yr-old woman following a cesarean section. To our knowledge, there was no reported case of BFNF associated with pregnancy in Iranian pregnant women.2. Physical examination showed the severe limitation of motion in the right hip and moderately painful left hip. Right femoral neck fracture was clearly identified in the X-rays. In pelvic magnetic resonance imaging, fracture lines at both femoral necks along with peripheral bone edema were visualized, confirming the presence of a simultaneous fracture in the left femoral neck of the patient too. The fracture of the right femoral neck was managed by close reduction and internal fixation (CRIF) along with dynamic hip screw, while CRIF and screw were used for the fixation of left femoral neck fracture . The woman was advised to discontinue breastfeeding, while her medical treatment was initiated with a daily subcutaneous injection of teriparatide (CinnoPar® 20 µg per day) along with calcium and vitamin D supplementation.In the short-term follow-up, no complication was observed. Five weeks later, signs of the union were observed in the follow-up radiographs and the patient was finally able to bear weight for short periods of time on a daily bases. The patient allowed us to report her case and informed consent has been obtained in this regard.Pregnancy-associated osteoporosis is a rarely observed skeletal pathology, which might lead to the fractures of femur before and after delivery . FemoralIn this case report, we have described the diagnosis of postpartum atraumatic BFNF, in the context of excessive consumption of corticosteroid during pregnancy and subsequent osteoporosis. In addition to repeated courses of betamethasone injections, twin pregnancy, immobility and vitamin D deficiency could have contributed to the reduction of bone density in our patient. Besides orthopedic treatment, administration of teriparatide was effective in treating the patient. Bisphosphonates were used for treating transient osteoporosis of pregnancy in few case reports , but the safety of bisphosphonates in premenopausal women with childbearing potential is unclear . So, we Taking into account the diagnosis of BFNF from other differentials of pelvic girdle pain in pregnant women is crucial, to prevent its complications. Furthermore, since hip fracture is reported during the labor of affected patients, cesarean section is preferred, provided the diagnosis is made before delivery . The incMoreover, the decision for the administration of antenatal corticosteroids should be made carefully according to valid and current guidelines. As it might affect the quality of bone and could be considered as a possible cause of BFNF in our patient. Treating women with a history of a single miscarriage with oral prednisolone has not been shown to improve birth outcomes in literature. Moreover, the current guidelines recommend only single courses of steroid injections for fetal lung maturity in women at risk of preterm delivery .In conclusion, we suggest clinicians consider the pregnancy-associated osteoporosis and femoral neck fracture in the differential diagnosis of the painful hip during or after pregnancy, especially in twin pregnancies, in order to prevent further serious complications. Awareness of risk factors and avoiding the use of excessive and unnecessary corticosteroid might help to reduce the rate of BFNF.


A fault diagnosis approach based on multi-sensor data fusion is a promising tool to deal with complicated damage detection problems of mechanical systems. Nevertheless, this approach suffers from two challenges, which are (1) the feature extraction from various types of sensory data and (2) the selection of a suitable fusion level. It is usually difficult to choose an optimal feature or fusion level for a specific fault diagnosis task, and extensive domain expertise and human labor are also highly required during these selections. To address these two challenges, we propose an adaptive multi-sensor data fusion method based on deep convolutional neural networks (DCNN) for fault diagnosis. The proposed method can learn features from raw data and optimize a combination of different fusion levels adaptively to satisfy the requirements of any fault diagnosis task. The proposed method is tested through a planetary gearbox test rig. Handcraft features, manual-selected fusion levels, single sensory data, and two traditional intelligent models, back-propagation neural networks (BPNN) and a support vector machine (SVM), are used as comparisons in the experiment. The results demonstrate that the proposed method is able to detect the conditions of the planetary gearbox effectively with the best diagnosis accuracy among all comparative methods in the experiment. The planetary gearbox is a key component in mechanical transmission systems and has been widely used in wind turbines, helicopters and other heavy machineries . The widHealth conditions of planetary gearboxes can be reflected by various kinds of measurements, including vibration signal, acoustic signal, driven motor current, shaft speed, oil debris, etc. Different measurements have different drawbacks and are sensitive to different types of damage modes or operation conditions. Thus, combining and analyzing these measurements together should be an appropriate approach to detect various types of faults of complex systems. This approach, named multi-sensor data fusion, can achieve more accurate and reliable result than approaches with a single sensor ,6,7.Nevertheless, multi-sensor data fusion for fault diagnosis suffers from two challenging problems . (1) OneDeep neural networks (DNN), also known as deep learning, have been attracting increasing attention from researchers from various fields in recent years ,11,12. TDeep convolutional neural networks (DCNNs), as one of the main types of DNN models, have been successfully used in mechanical fault diagnosis with automatic feature learning from single sensory data ,14,19,20Aiming to address the two problems of multi-sensor data fusion mentioned above, this paper proposes an adaptive data fusion method based on DCNN and applies it to detect the health conditions of a planetary gearbox. Different from conventional methods, the proposed method is able to (1) extract features from raw data automatically and (2) optimize a combination of different fusion levels adaptively for any specific fault diagnosis task with less dependence on expert knowledge or human labor.The rest of the paper is organized as follows. In DCNN is a type of DNN model inspired by visual system structure ,21, and A and B are the dimensions of the input data. Then the output of the convolutional layer can be calculated as follows [cn-th output of the convolutional layer, and the output number is CN, which is also equal to the filter number; cc-th channel of previous layer CC; cn-th filter of the current layer l; the width and height of the filter are CW and CH, respectively; the cn-th bias is denoted with The convolutional layer is composed of a number of two-dimensional (2D) filters with weighted parameters. These filters convolute with input data and obtain an output, named as feature maps. Each filter shares the same weighted parameters for all the patches of the input data to reduce the training time and complication of the model, which is different from a traditional neural network with different weighted parameters for different patches of the input data. Suppose the input of the convolutional layer is  follows :(1)Ccn=cn-th output of the pooling layer, and the output number is CN; S is the pooling block size. This function will sum over each distinct S pooling block in the input data so that the output will become S times smaller along both spatial dimensions.The pooling layer is a sub-sampling layer, which reduces the revolution of the input data and improves the robustness of learned features. A pooling layer generally follows a convolutional layer with a max pooling method and it outputs only the maximum of each sub-sampling patch of the feature maps to subsample the feature maps from the previous convolutional layer. The output can be described as follows :(2)Pcn=K-label problem, the output of the softmax regression can be calculated as follows:The fully-connected layer is the last layer of the DCNN model. It follows several combinations of the convolutional layers and the pooling layers, and classifies the higher-level information from the previous layers. A fully-connected layer is similar to a traditional multilayer neural network with a hidden layer and a classification layer, typically using a softmax regression. Assuming that the task is a It can be seen from the previous description that gradient  based onAn adaptive multi-sensor data fusion method based on DCNN is presented to learn features from raw data automatically and combine fusion levels adaptively to detect faults of a planetary gearbox. Through its deep-layered structure, DCNN can fuse input data and extract basic features in the lower layers, fuse basic features into high level features and decisions in the middle layers, and further fuse these features and decisions in the higher layers to obtain the final diagnosis result.The model of DCNN is adjusted to satisfy the characteristics of mechanical fault diagnosis. Although most applications of DCNN in image recognition chose a 2D convolutional structure ,22,36, aIn spite of the many benefits of the deep-layered structure of DCNN, a “deep” structure also means complicated hyper-parameters as well as various choices of architectures, which increases the difficulty to build an appropriate and efficient model. Although there are several researches ,40 aboutSeveral comparative methods are employed to further test and confirm the performance of the proposed method. The flowcharts of comparative methods are shown in To evaluate the ability of learning features from the raw data of the proposed method, manual feature extraction is used as a replacement and comparison of the feature learning in each comparative method. Eight time-domain features and several frequency-domain features are extracted. Root mean square (RMS), kurtosis, crest factor, skewness, mean, minimum, maximum, and variance are chosen as the handcraft features in the time domain ,37,42. TAs a comparison of the DCNN model of the proposed method, two intelligent models, back-propagation neural networks (BPNN) and support vector machine (SVM), are introduced as replacements of DCNN in each comparative method. BPNN is built into a three-layer model with sigmoid activation functions. SVM uses Gaussian radial basis function (RBF) as the kernel function and the grid search method to optimize the parameters of the kernel. The three comparative models, DCNN, BPNN, and SVM, are marked in green in For testing the performance of the different fusion levels, manual-selected feature-level fusion and decision-level fusion are explored and compared with the data-level fusion of the proposed method. For feature-level fusion with feature learning from raw data, only DCNN and BPNN are applied to learn features from the raw data of each sensor, respectively. The outputs of the second-last layers of DCNN are extracted as the learned features of each sensory data. Then, all the learned features from the four types of sensors are combined together as the feature-level fused features and used as the input of another DCNN for classification. In the same way, the outputs of the second-last layers of BPNN are extracted and fused. Then, the fused features are used as the input of both BPNN and SVM for classification. The comparison of different fusion levels is marked in red in As a comparison of the multi-sensory input data of the proposed method, fault diagnosis with single sensory data is also applied to evaluate the effectiveness of the proposed method, which is marked in purple and shown in An experimental system of a planetary gearbox test rig is established to evaluate the effectiveness of the proposed method. As shown in Seven health conditions of the planetary gearbox are tested, including normal, pitting tooth, chaffing tooth, chipped tooth, root crack tooth, slight worn tooth, and worn tooth. As shown in The acquired vibration signal, acoustic signal, current signal, and IAS signal are preprocessed following the steps in The model of the DCNN is developed using the principles described in Following the flowchart shown in Following the flowcharts shown in Finally, the average testing accuracies of all the comparative methods in the experiment are shown together in PCA is employed to analyze and visualize the learned features of the proposed method. As shown in The experimental results show that the proposed method is able to diagnose the faults of the planetary gearbox test rig effectively, yielding the best testing accuracy in the experiment. It can be seen from The ability of automatic feature learning of the DCNN model with multi-sensory data is proven through the experiment. It can obviously be seen from However, the method with automatic feature learning of DCNN from the raw signal of a single sensor cannot achieve a better result than methods with handcraft features. The effectiveness of the automatic feature learning and adaptive fusion-level selection of the proposed method is further confirmed through PCA. As can be seen from While DCNN has a much better feature learning ability than BPNN, the three comparative models, DCNN, BPNN and SVM, obtain similar results with handcraft features. Methods with multi-sensory data provide better results than those with single sensory data. It can be seen from This paper presents an adaptive data fusion method based on DCNN to detect the health conditions of planetary gearboxes. The processes of data-level fusion, feature-level fusion, decision-level fusion, feature learning, and fault diagnosis are all fused into one DCNN model adaptively. The proposed method can learn features from raw data, and fuse data, features, and decisions adaptively through the deep-layered structure of DCNN with fewer requirements of expert knowledge or human labor for feature extraction and fusion-level selection. The performance of the proposed method is evaluated through the experiment of the planetary gearbox fault test rig. As comparisons, feature-level fusion, decision-level fusion, handcraft features, single sensory data, and two traditional intelligent models, BPNN and SVM, are also tested in the experiment. The comparative results of the experiment verify the effectiveness of the proposed method, which achieves the best testing accuracy among all the comparative methods in the experiment.Our future work will focus on testing the DCNN model-based feature learning and data fusion approaches on more mechanical objects, fault modes, operation conditions, and sensor types, which can further confirm the effectiveness of approaches and help us to find out other useful application guidance. Moreover, due to the large number of parameters of deep learning models, manual parameter optimization often takes many trials-and-errors to find the best one, and conventional automatic searching methods are usually very time-consuming and easily converge into a local optimum. It is meaningful to investigate more effective and faster approaches to optimize the parameters automatically. Finally, combinations of different deep learning architectures should improve the effect of fault diagnosis. Adding recurrent architecture may make the model suitable to predict future fault conditions, and combining with auto-encoder architecture may improve the feature learning ability to capture more complex features.


A 72-year-old male with history of psychiatric disorders was referred to our emergency department in a state of cardiac arrest after a suicide attempt. The patient had attempted suicide by a knife of 30 cm in length. He reported a deep wound to the left side of the neck, together with superficial abdominal wounds. During transportation to the hospital, the patient was orally intubated and cardio-pulmonary resuscitation and fluids were administered with restoration of hemodynamic profile. After arrival, he was stabilized by fluid treatment and blood transfusions.Once stabilized and while ventilated, decision was taken to perform thoracic-abdominal multiphasic contrast-enhanced CT examination to assess further traumatic damages. At the preliminary digital tomogram, a thin, linear area of increased radiolucency that outlines the gastric wall was imaged in the upper left abdominal region Figure , arrow. The most likely explanation of the mucosal trauma was an excess of pressure inside the stomach caused by the attempts of intubation in the ambulance and some air insufflation in the esophageal lumen. The patient was managed conservatively and his condition slowly recovered during the following days.Three conditions of gas collection in the stomach wall have been described: interstitial gastric emphysema, cystic pneumatosis, and emphysematous gastritis .Interstitial gastric emphysema is seen when air from an extrinsic source enters the stomach wall and accumulates in the submucosa, subserosa, or both. The development of intramural air is frequently preceded by gastric distension and vomiting. The main causes include gastric obstruction due to pyloric stenosis, carcinoma of the antrum, gastric volvulus, and partial or complete duodenal obstruction secondary to pancreatic or ampullary carcinoma, duodenal stenosis, gall stones. Other main causes are penetrating gastric ulcers, nasogastric tube placement, endoscopy with air insufflation and rupture of pulmonary bullae or pneumothorax . RadiogrCystic pneumatosis refers to the radiographic observation of multiple 1- to 2-mm gas-filled cysts in the wall of the stomach and the bowel of patients with mild gastrointestinal symptoms.Emphysematous gastritis occurs when there is diffuse infiltration of the stomach wall by pathogenic gas-forming bacteria and it is often associated with parietal thickening and other findings secondary to sepsis .


Non-invasive diagnosis and quantification of liver steatosis is important to overcome limits of liver biopsy, in order to follow up patients during their therapy and to establish a reference standard that can be used in clinical trials and longitudinal studies. Imaging offers several methods in this setting: ultrasound, which is the cheapest technique and easy to perform; magnetic resonance spectroscopy (MRS), which reflects the real content of triglycerides in a specific volume; and proton density fat fraction (PDFF) magnetic resonance, which is a simple method that reflects the distribution of the fat in the whole liver. Other techniques include ultrasound elastography (EUS) and magnetic resonance elastrography (MRE), which can evaluate the progression of non-alcoholic fatty liver disease (NAFLD) into non-alcoholic steato-hepatitis (NASH) and cirrhosis, by quantifying liver fibrosis. Liver biopsy still represents the reference standard for the diagnosis of liver steatosis in adolescents and children, and corresponds to the mainstay in clinical trials in the enrolment of patients and evaluation of their outcomes. It has some limits such as sampling variability, related to the heterogeneity of the distribution of the steatosis; moreover, in the differentiation between simple steatosis and steato-hepatitis (NASH), complications may also occur (bleeding or infection) and it is not appropriate for screening, longitudinal monitoring, or evaluating treatment response, especially in young population ,2. FurthUltrasound is the most common imaging technique used for the evaluation of liver steatosis. Due to its significant advantages, such as being largely available, relatively non-expensive, and easy to use, ultrasound has been adopted as the standard care for the screening of a patient suspected of having NAFLD. Healthy liver parenchyma shows homogeneous echo texture and similar echogenicity compared to the right kidney cortex. However, in hepatic steatosis, the presence of lipid droplets within hepatocytes disturbs the propagation of the sound wave, causing scatter and attenuation. As waves scatter, more echoes return to the ultrasound transducer. This increase in signal from the liver produces a brighter visualization of liver parenchyma, compared to the kidney. Attenuation of the ultrasound waves also causes depth-dependent loss of signal, leading to an obscuration of vessels and bile ducts, and blurring of the diaphragm .normal (liver echogenicity similar to kidney);mild steatosis (diffuse increase in liver echogenicity);moderate severe .Classification of liver steatosis through the use of an ultrasound is based on a 4-grade scale:However, there are two main limits for this technique: an operator and machine dependency and the lack of an objective quantitative analysis ,7,8. MorUltrasound elastography is now being increasingly used in clinical practice, in order to aid the diagnosis and management of diffuse liver disease. The leading role of this technique relies on the differentiation between simple steatosis and non-alcoholic steato-hepatitis, in which liver storage is associated with inflammation and fibrosis. Several ultrasound elastography techniques have been defined, including transient elastography, supersonic shear wave elastography, acoustic radiation force impulse elastography (ARFI), and real-time tissue elastography. Transient elastography is performed with pulse-echo ultrasound, and measures liver stiffness as a function of the extent of liver infiltration. It can detect liver cirrhosis with high accuracy, although the accuracy is decreased at lower fibrosis stages ,10. In aControlled attenuation parameter (CAP) has been proposed as a non-invasive method for the determination and measurement of hepatic steatosis. The mechanism of CAP is the reduction in amplitude of ultrasound that can be estimated as it is amplified through the liver tissue. This procedure uses the same radio-frequency data used for estimation of liver stiffness with Fibroscan , an ultrasound-based vibration-controlled transient elastography device , compariIn contrast, ARFI is used to examine the elasticity of a certain anatomical area during real-time B-mode imaging, with the help of a region-of-interest cursor. ARFI also performs similarly to CAP, but instead measures shearing velocity and compares it to the normal velocity of the liver (1 m/s), as this velocity is reduced when there is fatty infiltration .Different methods can be performed for the evaluation of liver steatosis by magnetic resonance imaging (MRI), but the most widely preferred method is based on chemical shift imaging ,15. ThisProton density fat fraction (PDFF) measurement by MRI appears to be the most objective test for the quantification of liver steatosis, and has been recently adopted as a standard reference in clinical trials ,18. ThisAbove all, it is very easy and practical for fat fraction measurement. In pediatric patients, comparison of biopsy and PDFF has shown promising results . PDFF isMRS is considered the non-invasive reference standard in the assessment of liver steatosis, because it is able to measure the real concentration of triglyceride within the hepatocytes in a specific volume, by analyzing protons of water and acyl-groups of the triglyceride differences in a specific resonance frequency domain ,27,28,29However, MRS has some drawbacks, including that as a liver biopsy, it reflects only the lipid concentration in a small volume, so it does not depict the fat distribution along the liver parenchyma. Additionally, it requires a substantial amount of post-processing expertise, along with the fact that it is not routinely available on all scanners, so it may be impractical in some clinical settings.In the evaluation of patients with NAFLD, it is also important to establish the disease progression into non-alcoholic steato-hepatitis (NASH) and liver cirrhosis. Since NAFLD has the potential to progress into hepatic fibrosis, early diagnosis of fibrosis is important because, if treated, the degree of fibrosis can be minimized or reversed. Magnetic resonance elastography (MRE) can be used to quantify liver fibrosis, as this technique is based on the evaluation of the stiffness of liver parenchyma, and is a non-invasive technique . It alloThe MRE pulse sequences developed for adults have been modified for pediatric patients. This has been done by adopting the absorption rate and field of view for pediatric age groups, along with the power of the driver, which must be decreased by about 20% for patients between five and 18 years of age and by 40–50% for patients younger than two years, compared with the settings used in adult patients . This poImportantly, the success rate and accuracy of MRE has been found to be higher than ultrasound-based transient elastography . FurtherWhile ultrasound elastography is vital for its ability to clearly discriminate simple steatosis from NASH in the evaluation of the progression of NAFLD, among multiple imaging modalities, PDFF magnetic resonance accurately estimates fat storage within the liver parenchyma, is easy to use, and offers an overview of fat distribution within the organ. Therefore, this technique should be considered as the non-invasive reference standard for the diagnosis of liver steatosis. Further research studies should be focused on the non-invasive differentiation between simple steatosis and NASH considering serum-markers, imaging modalities and their association.


A 79-year-old woman was admitted to our emergency department with complaints of fainting and loss of consciousness three times during the past month. She was diagnosed with epilepsy and started to be treated with antiepileptic drug. Physical examination showed, in the left eye, chemosis, limited eye movements in all directions, and minimal exophthalmos as unexisting symptoms on admission developed on the sixth day. Orbital magnetic resonance imaging (MRI) and digital subtraction angiography (DSA) imaging revealed a carotid cavernous fistula (CCF). Epileptic attacks and ophthalmic findings previously present but diagnosed during our examinations were determined to ameliorate completely after performing the coil embolization. Based on literature, we present the first case with nontraumatic CCF manifesting with epileptic seizures and intermittent eye symptoms in the present report. Carotid cavernous fistulas (CCFs) develop as a shunt between the cavernous sinus and carotid arterial system . These fSpontaneous CCFs may also be related to arteriosclerotic changes of the arterial wall, fibromuscular dysplasia, or Ehler-Danlos syndrome . The cliAdmitted to the emergency department after the three episodes of fainting and loss of consciousness for one month, our case was a 79-year-old woman maintaining a sedentary life style and living with her family members. The attacks with sudden-onset started with the following signs, blank stares, lip licking, mouth slurping, and tugging clothes, and then continued with convulsions in arms and legs and fainting. The episodes of unconsciousness and fainting lasted for about five to ten minutes. Her history revealed no specific conditions to affect her fainting, such as tiredness, effects led by external factors, fasting, or fainting at a certain moment of the day and neither an additional medical problem nor history in the family for the falling. Neurological and systemic examinations were within normal limits. All laboratory tests and cranial magnetic resonance imaging (MRI) were normal; however, on electroencephalography (EEG) performed while she was awake, slow waves were observed at delta frequency in the left temporoparietal region. The patient was diagnosed with complex partial epilepsy and started to be treated with carbamazepine. Neurological examination showed chemosis, limited eye movements in all directions, and minimal exophthalmos in the left eye on the sixth day, as nonexisting symptoms on admission .On the eye examination performed by an ophthalmologist on the 6th day, along with exophthalmos, increased intraocular pressure  was detected. Interestingly, on the eye examination performed on the 7th day, the left eye was detected to be completely within normal limits, and all abovementioned symptoms such as chemosis, limited eye movements in all directions, and minimal exophthalmos were seen to disappear. An orbital MRI performed later demonstrated the presence of a dilated left superior ophthalmic vein  and suggAll of the symptoms and signs resolved after performing the transvenous coil embolization , and antIn cavernous fistulas, blood passes from the high-pressure arterial system to the low-pressure venous drainage system. This reversal directs a high amount of blood flow to the ophthalmic vein and rarely leads to the cortical venous reflux and the congestion of cortical blood vessels . The ven