Penile augmentation using injection of a foreign body into penile skin was mainly performed by non-medical personnel. Majority of these patients end up with complication of an abnormal mass formation known as penile paraffinoma.We described three different surgical techniques for correction of penile paraffinoma based on our single-centre experience. Informed consents were obtained from patients whose photographs were taken during the operation step.In general, three patients had simple excision biopsy with primary suturing, four patients underwent single stage excision of circumferential granuloma with bilateral scrotal skin flap reconstruction and one patient experienced dual stage procedure. Three of them were injected with paraffin, one with silicone and the remaining four were unable to identify the substance used. All patients successfully underwent the surgical procedure and four of them had minor post-operative surgical site infection and wound gapping.All patients recovered well and the mean International Index of Erectile Function (IIEF-5) score obtained was 24.25. In our experience, excision biopsy was adequate for focal mass and reconstructive surgery using bilateral scrotal flap was suitable for circumferential mass. The term paraffinoma was introduced by Newcomer and Grahamin in 1971 to describe abnormal histopathologic findings after the injection of a foreign material , followed by Chinese (two patients) and Indian (one patient). All patients had their injection a few years before seeking treatment. The mean age of patients was 35.5 years. Four of the patients did not recognise the substance used in the injections; however, three informed the use of paraffin and one of silicone. They presented with complications from the first to eighth year after injection and the most common symptom was pain, either to themselves or to the partner during sexual intercourse. On examination, three patients presented a focal mass formation at the ventral aspect of the penis, whereas five exhibited a circumferential hard mass around the penile shaft extending to the base of the scrotum and suprapubic region .There were three types of surgical techniques:Simple excision biopsy and primary suturingSingle-stage excision of circumferential granuloma with bilateral scrotal skin flap reconstructionDual-stage excision of circumferential granuloma and bilateral scrotal skin flap reconstructionThree patients were treated using this procedure. All of them presented granuloma formation at the ventral side of the penile shaft. The mass was excised along with the overlying skin, and the lateral edges were sutured together. Interrupted absorbable sutures were used to approximate both edges. Eventually, they had a linear longitudinal scar that did not cause any shortening of the penis. The mean duration of surgery was 125 min (100 min–140 min). None of these patients manifested any complications post-operatively. Erection performance was considered satisfactory compared to that before surgery and the mean score was 24 according to the International Index of Erectile Function (IIEF-5).The majority of patients underwent this approach (four patients). All patients presented circumferential penile shaft mass extended until the base of the scrotum and suprapubic region, with one of them also presenting a complication of chronic ulcer over the mass. The steps of surgery were initiated with meticulous excision of the circumferential granuloma on the penile shaft, leaving the superficial fascia covering corpus cavernosum and corpus spongiosum . Tissue Only one patient within this period of observation underwent a dual-stage procedure. The procedure was similar to single-stage excision of circumferential granuloma with bilateral scrotal skin flap reconstruction but was performed on two separate occasions. This patient requested that the procedure be divided into two occasions because he refused general anaesthesia. Therefore, both procedures were performed under combined spinal-epidural anaesthesia. At the first-stage, the granuloma was completely excised followed by burying the penile shaft underneath scrotum skin. A 3-month duration was given for proper healing . The secThe first person documented to inject a foreign substance into the human body was Robert Gersuny, an Austrian surgeon in 1899. He injected mineral oil (Vaseline) to substitute an absent testis  and the Penile paraffinoma was a common complication after the injection of these materials under the penile skin. In our series, the mean age of patients at the time of injection was 35.5 years, which was similar to that of 32 years found in a study with one of the largest series of patients . This coUpon presentation, three of our patients who were injected only at the ventral side developed a focal mass formation on the penile shaft. These types of patients required a simple surgical procedure of excision of the mass and primary suturing of both lateral edges. Intra-operatively, the paraffinoma mass could be easily differentiated from the normal tissue and was completely excised with a sharp margin. Inadequate excision may result in re-growth of the mass. Surgical operation time was the shortest compared to the other techniques and achieved satisfactory outcomes.Predominantly, patients had circumferential mass surrounding the penile shaft and extending to the suprapubic region. Meticulous en-bloc excision of the mass was performed, taking care not to breach the superficial fascia covering the corpus spongiosum and corpus cavernosum, which is the main reason for the longer duration of this technique. The next step was the reconstruction of the new penile skin. In our series, all patients underwent bilateral scrotal flap covering, a technique first described by Jeong et al.  in 1996.None of our patients experienced erectile dysfunction post-operatively and could usually perform sexual intercourse 6 weeks–8 weeks after the procedure. According to Pungrasmi et al. (Complications from penile augmentation using foreign body injection performed by non-medical personnel were common. In our experience, excision biopsy was adequate for focal mass and reconstructive surgery using bilateral scrotal flap was the best option for circumferential mass. Larger series and longer follow up are needed to determine the best surgical technique in treating this disease.


This is a high volume referral center for cerebrovascular diseases in southern Iran.Although cerebral venous sinus thrombosis (CVST) is less common than arterial stroke, it affects younger patients.3 and 2012-2016.4 We compared the demographic characteristics, risk factors and the outcome at the time of discharge between these two time periods. We applied Stata software  for statistical analysis. Two retrospective studies were conducted on adult patients with definite diagnosis of CVST in two periods of time, 2000-2008Morbidity and mortality of CVST in our region have diminished dramatically. This is most probably because of the advances in imaging techniques, which lead to more accurate and rapid diagnosis of CVST. Admission of patients with CVST in stroke units may also contribute to the decreased morbidity and mortality. Furthermore, better education of patients who are in risk of thrombosis about the possibility of developing CVST and its alarming symptoms in the recent years, has resulted in earlier admission of patients.5,6 Although not significant, OCP use has declined among our patients with CVST. The increasing frequency of thrombophilia can be attributed to more complete diagnostic work-ups in the recent years. The decrease in frequency of inflammatory diseases cannot be explained.Female gender-related causes are still the most frequent risk factors. It is common that Iranian women misuse oral contraceptive pills (OCP) in order to delay their menstruation during religious ceremonies such as Haj and fasting month of Ramadan.


Postpartum haemorrhage (PPH) is the leading cause of maternal mortality in low-income countries and is a significant contributor to severe maternal morbidity and long-term disability. Carbetocin may be an underused uterotonic for prevention of PPH. A number of studies are being conducted that may challenge the place of oxytocin as the first choice of uterotonics for prevention of PPH. This paper describes the current research into carbetocin and ranking of effectiveness of uterotonics that may provide important new information to assist healthcare decision makers to ensure that women receive an effective uterotonic for prevention of PPH.We searched the WHO International Clinical Trials Registry Platform for current studies on effectiveness of carbetocin for prevention of PPH following vaginal delivery with sample sizes large enough to provide quality evidence to support potential changes to international guidelines. We also searched the Cochrane Library for current systematic reviews including carbetocin used in prevention of PPH.Susceptibility to degradation from exposure to heat is one of the key causes of reduced effectiveness of oxytocin in preventing PPH from uterine atony. Although heat stable and effective in preventing PPH, misoprostol is also subject to degradation due to exposure to moisture and produces some side-effects. Other uterotonics  are also available and used with varying safety and effectiveness profiles and quality issues. Efforts to reduce maternal mortality from PPH include research studies seeking to identify safe, stable, effective uterotonics. Heat stable carbetocin is the subject of two major clinical studies into its effectiveness in preventing PPH following vaginal deliveries, information that could expand its application for prevention of PPH.Heat stable carbetocin is being investigated as a potential alternative to oxytocin. This paper describes two current clinical trials on carbetocin and a network meta-analysis ranking of all uterotonic agents, including carbetocin, which combined may provide evidence supporting expansion of the use of the heat stable formulation of carbetocin in PPH prevention. Postpartum haemorrhage (PPH) is the leading cause of maternal mortality in low-income countries  and is aCurrently, the World Health Organization (WHO)  recommenThe effectiveness of uterotonics in generating the uterine contractions necessary to prevent haemorrhage can be impaired through exposure to conditions that cause the uterotonic to degrade. In many low- and middle-income countries where access to sustained cold-chain is unavailable, the efficacy of oxytocin cannot be assured because it is susceptible to heat degradation , 4. OtheCarbetocin has been widely used for prevention of PPH since 1997 . InnovatThe global health community has long sought an effective uterotonic for prevention of PPH that withstands degradation. The objective of this research paper is to highlight studies into heat stable carbetocin, a molecule which may be sufficiently clinically effective and structurally stable to be included in the list of recommended uterotonics for prevention of PPH.We searched the WHO International Clinical Trials Registry Platform for current studies on effectiveness of carbetocin for prevention of PPH following vaginal delivery with sample sizes large enough to provide quality evidence to support potential changes to international guidelines. We also searched the Cochrane Library for current systematic reviews including carbetocin used in prevention of PPH.Heat stable carbetocin (formerly carbetocin RTS) for preventing postpartum haemorrhage: a randomized non-inferiority, controlled trial – the World Health Organization (CTRI/2016/05/006969 - Protocol). Sample size 30,000 women [00 women Intramuscular Oxytocics: A Comparison Study of Intramuscular Carbetocin, Syntocinon and Syntometrine for the Third Stage of Labour Following Vaginal Birth (IMox) – North Bristol NHS Trust (NCT02216383 - Protocol). Sample size 6285 women [In 2018, results of two major clinical trials on the effectiveness of carbetocin in prevention of PPH following vaginal deliveries will be published:Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis – Cochrane Review [e Review We also identified a systematic review ranking all uterotonics on the basis of effectiveness and side-effects:These three studies will provide the evidence needed to include (heat stable) carbetocin in global recommendations and respond to the need for additional options for the prevention of PPH.Quality of oxytocin available in low- and middle-income countries: a systematic review of the literature, published in BJOG found that across the literature reviewed, on average 45.6% of oxytocin samples failed quality tests mostly due to insufficient amounts of active pharmacological ingredient [Globally, access to effective uterotonics remains a key barrier to reducing maternal mortality. In 2012, the UN Commission on Life Saving Medicines  reportedgredient .Quality medicines in maternal health: results of oxytocin, misoprostol, magnesium sulfate and calcium gluconate quality audits, the researchers found that 74.2% of oxytocin injection samples and 33.7% of misoprostol samples failed the assay test [A further study adding to the evidence on poor quality of uterotonics in low- and middle-income countries was published by the United States Pharmacopoeia (USP) Promoting the Quality of Medicines Program in BMC Pregnancy and Birth in January 2018 . In thissay test .A Current Review of Evidence will be available online in March 2018 and will be followed by an in-depth review of the evidence on oxytocin quality. An outcome of the technical consultation was the release of an advocacy messaging framework aimed at improving the quality of oxytocin at the point of use called “Buy Quality Oxytocin, Keep it Cold” [Additional activities focussed on highlighting the need for action on improving the quality and effectiveness of uterotonics for prevention of postpartum haemorrhage include the October 2017 Technical Consultation on Messaging for Management of Oxytocin organised by the USAID Global Health Supply Chain Program in collaboration with the Reproductive Health Supplies Coalition. The consultation involved technical experts from the WHO, UNFPA and a number of other organizations. The meeting report, it Cold” .While effort is going into improving the quality of oxytocin including advocacy, manufacturing quality improvements, regulatory strengthening and supply chain and storage improvements, research is being conducted into whether (heat stable) carbetocin is an underutilized option for prevention of PPH.Following are summaries of the current major research activities on effectiveness of carbetocin for prevention of PPH and how they could influence guidelines and practices.The research objective of this trial is to evaluate if heat stable carbetocin (formerly carbetocin RTS) 100 μg intramuscular (IM) is non-inferior to oxytocin 10 IU IM, in preventing PPH in women delivering vaginally. Uterine atony is the principle cause of PPH. Administration of an effective uterotonic after delivery of the baby has been demonstrated to reduce PPH caused by uterine atony. The majority of deaths due to PPH could be avoided through the use of prophylactic uterotonics during the third stage of labour .Oxytocin  is recommended as the uterotonic drug of choice. The WHO and other organizations recommend that oxytocin should be stored between 2-8C° to prevent degradation and loss of effectiveness . CarbetoTwenty-three centres from 10 countries  participated in the trial. A total of 29,658 participants were enrolled globally. The blinding of the trial required that both products were refrigerated, although the heat stable carbetocin compound was used.This trial was conducted by the WHO, who completed enrolment at the end of January 2018 and who are currently analysing data and preparing the results. Should this trial demonstrate that heat stable carbetocin is non-inferior to oxytocin in preventing PPH, the WHO will have evidence to support including heat stable carbetocin in its Recommendations for the Prevention and Treatment of PPH and in the WHO Model List of Essential Medicines.The trial is part of a broader collaboration involving regulatory, advocacy and manufacturing activities between Merck for Mothers (MSD for Mothers outside the USA and Canada), Ferring Pharmaceuticals and the World Health Organization (WHO) to make heat stable carbetocin accessible, pending trial results, in the public sector of low and lower-middle income countries at an affordable and sustainable price.The Intramuscular Oxytocics trial aims to compare the effectiveness, side-effects and cost of three uterotonics – carbetocin, oxytocin (Syntocinon) and the fixed dose combination of oxytocin/ergometrine (Syntometrine). All products were refrigerated for this trial to preserve blinding. The trial is important because of the additional comparison with the oxytocin/ergometrine combination, widely used because of its effectiveness in preventing PPH, but which is associated with a number of side-effects.Studies in the use of carbetocin following caesarean section have demonstrated effectiveness in prevention of PPH and a safety and side-effects profile similar to oxytocin . No studThe study’s primary outcome is the proportion of patients requiring additional uterotonic drugs after administration of study drug. Investigators will perform an analysis of cost effectiveness once all results are available. The results of this trial will provide additional support for any changes to international guidelines.Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis is to assess the clinical effectiveness and side-effect profile of uterotonic drugs to prevent PPH and to generate a clinically useful ranking of available uterotonics according to their effectiveness and side-effects [The objective of the -effects . A scienAll uterotonic drugs used for prevention of PPH have been compared with each other including oxytocin, misoprostol, ergometrine, carbetocin, oxytocin plus misoprostol, oxytocin plus ergometrine and placebo or no-treatment.The study included all randomised controlled individual or cluster trials evaluating effectiveness or side-effects of uterotonic drugs for preventing PPH identified from the Cochrane’s Pregnancy and Childbirth Group (PCG) trials register. The interventions considered were uterotonics administered by healthcare providers during the third stage of labour for preventing PPH compared with a control uterotonic or with placebo or no treatment. The targeted population was women having a vaginal birth or a caesarean section in hospitals or community settings.The study found that, based on published studies, ergometrine plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination were most effective in preventing PPH ≥ 500 mL. Ergometrine plus oxytocin combination was most effective in preventing PPH ≥ 1000 mL. Carbetocin had the most favourable side-effect profile amongst the top three options. The carbetocin evidence came from small studies. The authors plan to update the study when the two major carbetocin study results are published. The network meta-analysis (and the forthcoming update) are of particular value in providing information on the relative effectiveness and side-effects of uterotonics whether they have been directly compared in a clinical trial or not, and will therefore assist decision makers and clinicians in determining the best option for particular patient populations.Heat Stable Carbetocin is being investigated as a potential alternative to oxytocin and is the subject of two large clinical trials for use in prevention of PPH in vaginal deliveries. In this discussion, we provided an overview of the two clinical trials on (heat stable) carbetocin and the meta-analysis ranking of all uterotonic agents, including carbetocin.The WHO trial (Heat stable carbetocin for prevention of PPH) is the largest trial ever conducted on uterotonics for prevention of PPH and is clearly designed to support guideline changes. The IMox trial , though smaller is still one of the larger clinical trials in this field and the results will be important.The outcomes of these three pieces of research are likely to result in a change in the WHO Recommendations for the Prevention and Treatment of PPH to include carbetocin as an option for prevention of PPH. The drug may also be included in the WHO Model List of Essential Medicines. Governments and clinicians may have an option to assist in the prevention of maternal mortality resulting from preventable PPH that is heat stable and therefore more effective at the time of use in setting where cold chain is not reliable.


This study aimed to evaluate the contributions of the lateral (fibular) collateral ligament (LCL), popliteofibular ligament (PFL), and popliteus tendon (PT) to cruciate ligament forces under simulated dynamic loading conditions by using selective individual resection. We combined medical imaging and motion capture of healthy subjects  to develop subject-specific knee models that simulated the 12 degrees of freedom of tibiofemoral and patellofemoral joint behaviors. These computational models were validated by comparing electromyographic (EMG) data with muscle activation data and were based on previous experimental studies. A rigid multi-body dynamics simulation using a lower extremity musculoskeletal model was performed to incorporate intact and selective resection of ligaments, based on a novel force-dependent kinematics method, during gait  and squatting. Deficiency of the PLC structures resulted in increased loading on the posterior cruciate ligament and anterior cruciate ligament. Among PLC structures, the PT is the most influential on cruciate ligament forces under dynamic loading conditions.Posterolateral corner (PLC) structures of the knee joint comprise complex anatomical soft tissues that support static and dynamic functional movements of the knee. Most previous studies analyzed posterolateral stability  Isolated injuries of the posterolateral corner (PLC) structures of the knee are generally uncommon and can be easily overlooked in knee joint inspections, especially when there are concomitant with anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) tears –4. The PIn the past decade, the complexity of the PLC structures in the knee joint has been revealed, biomechanically and clinically , 9. The s under dynamic conditions ..39].The most important finding of this study was that the deficiency of PLC structures significantly affected not only the PCL but also the ACL, which was more frequently shown under gait cycle conditions. In addition, the ACL force was more influenced than the PCL force by the deficiency of PLC structures during the loading conditions of the gait cycle. The PT was the most influential PLC structure to provide significant effect on dynamic loading conditions. We also found that there was a remarkable increase in cruciate ligament force when the PLC structures such as LCL, PFL, and PT, were sectioned compared to the condition with PLC structures being intact.Therefore, the first hypothesis was supported and the second hypothesis was rejected. Background knowledge about the importance of the individual anatomy of the posterolateral region of the knee joint for static stability was derived from sequential resections of these structures during static testing , 11, 13.A computational knee joint model allowed the exclusion of the disadvantages of an in vitro study, such as the inefficiency of cadaveric specimens during resection and repair, and limitations in static loading conditions. We introduced and validated and MSK knee model with 12-DOF  to simulate force-dependent kinematics during gait and squatting. The knee joint model was subjected to a series of rigorous validation steps, and the results showed good agreement with the results of an external rotation test and a previous experimental study . There wNo study has investigated the deficiency of PLC structures for both cruciate ligament forces under dynamic loading conditions. This is the first study that has evaluated both cruciate ligament forces following PLC resection under dynamic loading conditions. We also corrected popliteus muscle model to obtain a more faithful representation of its anatomy than the existing one. We found that the PLC structures, including the LCL, PFL, and PT, had a significant impact in the ACL and the PCL forces under dynamic conditions. Most previous studies have focused on the solely PLC and PCL , 43–45; Bonanzinga et al. found that anterior-posterior (AP) laxity combined with a complete lesion of the PLC structure at 30° of knee flexion could be controlled in isolation, but not in hyperflexion of the knee joint . At 90° In this study, the PFL did not significantly affect the increased force exerted on the cruciate ligaments under gait-loading conditions. In previous studies, the PFL, rather than the popliteus muscle-tendon unit, was found to have a major role in external rotation stability , 51. HowThe importance of PT deficiency in the PLC structure was also suggested by a previous cadaveric study . HoweverAn important finding was that deficiency of the entire PLC structure caused greater PCL forces at high flexion angles, but greater ACL forces at low flexion angles, under squat loading conditions. The LCL significantly influenced the cruciate ligament forces at low knee flexion angles under gait loading conditions. PFL deficiency influenced only the pPCL bundle force under gait loading conditions, and the aPCL and pPCL bundle forces under squat loading conditions, but the results were not significant. The PT was the dynamic stabilizer and influenced the ACL and PCL forces under gait and squat loading conditions.It is important to highlight several strengths of the present study. First, using one well-validated computational model is a proven method of evaluation of orthopedic biomechanics –29, 35. Nevertheless, several limitations of the present study should also be noted. First, we could not implement the deficiency of the PT alone because the PFL is connected to the PT in the model. Second, the ligaments were represented by only two or three bundles. Third, it is unclear how the force on the ligament, which was the outcome of interest of this study, could affect actual clinical outcomes. More research is needed to determine clinically meaningful detrimental force changes. Nevertheless, ligament forces are key factors that should be investigated to determine their roles the evaluation of biomechanical effects on computational biomechanics , 55, 56.In terms of clinical relevance, posterolateral insufficiency of the knee affects significantly ACL and PCL forces in daily dynamic activity. Therefore PLC injuries associated with cruciate ligament injuries must be restored as well. In particular, surgical restoration or rehabilitation of the PT, which is the most crucial dynamic stabilizer, could be highlighted.The effect of the deficiency of each of the PLC structures on ACL and PCL forces was evaluated under dynamic loading conditions in this study. The deficiency of the entire PLC structures resulted in increased loadings on both PCL and ACL forces. The present results showed that PT is the most influential structure for the cruciate ligaments forces under dynamic loading conditions.S1 Fig(DOCX)Click here for additional data file.S1 Data(XLSX)Click here for additional data file.


The analysis of mutation induction in human families exposed to mutagens provides the only source of reliable estimates of factors contributing to the genetic risk of human exposure to mutagens. In this paper, I briefly summarize the results of recent studies on the pattern of mutation induction in the human and mouse germline. The results of recent studies on the genome-wide effects of exposure to mutagens on mutation induction in the mammalian germline are presented and discussed. Lastly, this review also addresses the issue of transgenerational effects of parental exposure to mutagens on mutation rates in their non-exposed offspring, which are known as transgenerational instability. The possible contribution of transgenerational instability to the genetic risk of human exposure to mutagens is discussed. Given that mutations induced in the germline can persist for a number of generations following parental exposure to mutagens, they may substantially contribute to the burden of inherited diseases and thus represent one of the key risk factors of human exposure to mutagens ,2,3. It Traditionally, the effects of exposure to ionizing radiation and mutagenic anticancer drugs was studied by analyzing the frequency of malformations and incidence of infant mortality among the children of exposed parents ,2,3. ForThe sensitivity of any approach for monitoring mutation induction depends on the rate of spontaneous mutation. If the number of de novo spontaneous mutations per offspring is high, then the effects of exposure to mutagens can be robustly established within a broad range of doses. In this respect, tandem repeat human mini satellite loci represent an attractive biomarker of exposure to mutagens as the spontaneous mutation rate at these loci by several orders of magnitude exceeds those for protein-coding genes ,7. In ouAnother group of highly unstable tandem repeat DNA loci  was found in the mouse genome . The ratESTR mutation induction was also analyzed in the germline of male mice exposed to a variety of mutagens, including tobacco smoke  and partIn summary, the results of our studies have shown that tandem repeat DNA loci provide a useful and convenient tool for monitoring radiation-induced mutations in humans. It should, however, be stressed that since the germline mutation at human mini satellites is almost exclusively attributed to complex meiotic gene-conversion-like events , the mecRecent advances in whole-genome sequencing provided new tools for the analysis of germline mutation. In our recent study, we used comparative genome hybridization and whole-genome sequencing to establish the genome-wide pattern of mutation induction in the germline of male mice exposed to 3 Gy of acute X-rays . The resIn summary, the results of genome-wide analysis of mutation induction in the mouse germline highlight the key advantages of this technique. First, since the total number of de novo mutations detected by the genome-wide analysis is quite high , nexAs already mentioned, mutation induction in the parental germline is regarded as the main component of the genetic risk of human exposure to mutagens, including ionizing radiation . However2) offspring of irradiated male mice [1) of male mice exposed to the alpha-particle emitter plutonium-239. According to the results of this study, the F1 rate of dominant lethal mutations was highly significantly elevated. In 2000, the issue of transgenerational instability was revisited [1 genomes. These results were later confirmed by analyzing ESTR mutation rates in the germline of non-exposed F1 and F2 offspring of irradiated male mice from three different inbred strains [One of the first experimental results for transgenerational effects was obtained by Luning and co-workers by analyzing the incidence of dominant mutations among the second-generation  and somatic tissues of Fale mice ,51. Figuale mice . This po1 offspring of irradiated female mice mated with non-exposed males [1 genome stability. These results remain unexplained and future work should address the mechanisms underlying the differential transgenerational responses following paternal and maternal irradiation.We have also analyzed the transgenerational effects of maternal irradiation among the Fed males ,25. In s1 offspring of male mice exposed to the previously mentioned anticancer drugs was close to that in the offspring of irradiated males  or three commonly-used anticancer drugs—cyclophosphamide, mitomycin C, and procarbazine ,54. The ed males a.1 offspring of irradiated males, it cannot, therefore, be explained by Mendelian segregation of de novo mutations induced in the germline of exposed parents [1 genome stability. In our study, the amount of endogenous DNA damage (single-stranded and double-stranded DNA breaks) was measured in the F1 offspring of control and irradiated male mice [1 offspring of irradiated males significantly exceeded that in controls. The intriguing observation for this study is that the efficiency of DNA repair in the offspring of irradiated males is not compromised. Considering these data, it would appear that destabilization of the F1 genome may somehow be related to deregulated DNA replication or a compromised apoptosis/cell cycle arrest. A detailed analysis of the expression profiles in F1 tissues should elucidate the still unknown mechanisms underlying the phenomenon of radiation-induced genomic instability.Judging from the results obtained by analyzing the offspring of exposed parents, the phenomenon of transgenerational instability is attributed to the yet unknown epigenetic mechanisms. Given that an equally elevated ESTR mutation rate was detected in practically all F parents . Despiteale mice . Accordi1 genomes is a genome-wide phenomenon, a related question is whether it can affect a number of health-related traits in the offspring. The results of some publications suggest that it may be the case. As already mentioned, the data obtained by Luning and co-authors show that paternal irradiation can substantially increase the rate of dominant lethal mutations in the germline of non-exposed F1 offspring [Given that transgenerational destabilization of Fffspring . Increasffspring ,56, whic1 and, possibly, F2 genomes may be regarded as an additional component of the genetic risk of human exposure to mutagens. However, the manifestation of transgenerational effects among the children of irradiated parents has been analyzed only in a handful of studies [1 genomes. It would also appear that high-dose parental exposure to some anticancer drugs could result in transgenerational effects among their children.The results of previously mentioned animal studies may imply that transgenerational destabilization of F studies ,58. Thei studies  or a bas studies . AccordiAs already mentioned, recent advances in molecular genetics have provided highly sensitive tools for the genome-wide analysis of genetic variation. The whole-genome sequencing will provide fundamental quantitative information on the genetic effects of exposure to mutagens in humans and will, therefore, be important in improving the accuracy of the estimates of genetic risks of exposure to ionizing radiation and other mutagens in humans. It should be stressed that this technique will quantify the effects of parental exposure to mutagens and characterize the spectra of induced mutations found in the offspring of control and exposed parents. Considering the result of animal studies on transgenerational instability, further work aimed at establishing the mechanisms underlying this epigenetic phenomenon as well as its manifestation in humans are clearly warranted.


The earliest stages of development are critically sensitive to environmental insults. An unfortunately timed stress on the developing brain can have dramatic consequences for the neurodevelopment and future mental health of the individual. In particular, infection of the mother during pregnancy has been correlated with increased risk of psychiatric and neurodevelopmental disorders. Evidence suggests that maternal immune activation, independently from the infection itself, can be responsible for the outcome in the offspring. This recognition has resulted in expanding study designs from epidemiologic correlations to the search for a causal relationship between activation of the maternal immune system and cognitive consequences for the offspring. However, this causality analysis remained limited in humans until recent work that longitudinally linked specific markers of maternal inflammation during pregnancy with alterations of the newborn brain and cognitive development of toddlers. This focused narrative review compares and discusses the results of these recent studies and places them into the broader landscape of maternal immune activation literature. New data point, in particular, to the association between the levels of interleukin 6 (IL-6) and modifications of the offspring’s salience network and subsequent cognitive impairments. This article further emphasizes the need to carefully control for potential confounders in studying the effects of maternal immune activation on the neonatal brain as well as the under-investigated consequences of intra-partum fever on offspring neurodevelopment. Nevertheless, the IL-6 levels were still correlated with modifications of the neonate brain in the UCI studies. More specifically, the average level of maternal IL-6 during pregnancy was associated with modifications of the: (1) volume of the right amygdala, and of the connectivity between bilateral amygdala and regions involved in sensory processing and integration, salience detection, and learning and memory, as measured using whole-brain analysis (Graham et al., A broader context for the results of Spann et al.  is estabThe studies further investigated how levels of inflammatory markers and brain alterations were associated with the subsequent behavioral development of the offspring Figure . At 24-mIn the four studies reviewed here, it is worthwhile noting that the reported IL-6 levels were not outside of the normal limits. Nonetheless, IL-6 levels were correlated to the offspring outcome, suggesting that even modest and subthreshold variations in maternal IL-6 are associated with altered neonatal functional connectivity and later cognitive function in humans. It therefore seems reasonable to hypothesize that even subtle changes in the intra-uterine milieu during critical time windows affect the offspring. For example, mild changes within physiologic levels in maternal hormone levels can modify gene expression profiles in the offspring (Miranda and Sousa, It is also important to note that Spann et al.  found a The articles briefly reviewed here (Graham et al., JB-B wrote the first draft of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Opportunistic infections are on the rise because of an increasing number of patients with immunosuppression and their prolonged survival 2. AlthouA 67-year-old woman was admitted for retro-orbital and periorbital pain, increasing over 1 week and accompanied by progressive exophthalmia and palpebral ptosis on the left side. She was being treated for lung cancer metastasized to the liver and cerebellum. Physical examination revealed a complete ptosis of the left eyelid and complete absence of extraocular movements of the left eye, referable to the third, fourth and sixth cranial nerve. Head computed tomography (CT) showed mucous thickening of the left sphenoid and maxillary sinuses. Brain MRI revealed an expansive lesion involving the left cavernous sinus Figure ,b, whereThe saccular (pseudo-)aneurysm described in this report did not appear to have any MRI or MRA features suggesting its mycotic origin, at least based on the configuration of the aneurysm itself. However, particular imaging features of the parent artery and surrounding structures in close vicinity to the aneurysm provided important clues toward its mycotic origin. First, the circumferential wall thickening restricted to the perianeurysmal parts of the carotid artery, not present earlier in time and in the absence of atherosclerosis elsewhere, could have suggested the presence of arteritis. Aspergillus arteritis may manifest with vessel wall thickening and stenosis or dilatation of the arterial lumen and with formation of pseudo-aneurysms in case of vessel perforation 5. In addThe current case indicates how the mycotic origin of intracavernous carotid aneurysms may be deduced from perianeurysmal inflammatory changes rather than from the configuration of the aneurysm itself. In the studied case, circumferential vessel wall thickening of the carotid artery near the aneurysm, as well as its continuity with T2-hypointense inflammatory changes in the sphenoid sinus, was supportive of its mycotic origin. Further reports with detailed documentation of MR features are required to see if the latter is an invariable finding in additional cases.The authors declare that they have no competing interests.


Escherichia coli either exponentially growing under varied conditions or in response to environmental disturbance were analyzed. A total of 168 microarray data sets representing 56 transcriptome variations, were categorized by genome size (full length or reduced) and cellular state (steady or unsteady). At the genome-wide level, the power-law distribution of gene expression was found to be significantly disturbed by the genome size but not the cellular state. At the regulatory network level, more networks with improved coordination of growth rates were observed in genome reduction than at the steady state. At the single-gene level, both genome reduction and steady state increased the correlation of gene expression to growth rate, but the enriched gene categories with improved correlations were different. These findings not only illustrate the order of gene expression attributed to genome reduction and steady cellular state but also indicate that the accessory sequences acquired during genome evolution largely participated in the coordination of transcriptomes to growth fitness.Transcriptomes not only reflect the growth status but also link to the genome in bacteria. To investigate if and how genome or cellular state changes contribute to the gene expression order, the growth profile-associated transcriptomes of an assortment of genetically differentiated  Escherichia coli (Bacillus subtilis (E. coli) would provide novel insights compared to the studies either focusing on specific genes horizontally transferred or comparing genomes of different species.Genome reduction performed in bacterial cells is a practical approach not only to study the essential gene set of a living cell but also to estimate the potential contribution of redundant genomic sequences. An assortment of reduced genomes has been constructed in hia coli  and Bacisubtilis . In addisubtilis  are perfsubtilis . In partsubtilis , indicatsubtilis . Althougsubtilis , a direcE. coli of both the wild type genomes (full length)   and the  length) . These sE. coli strains, and we investigated the common properties of the gene expression order at genome-wide, regulatory network and single-gene levels. The power-law distribution of gene expression and the growth rate-correlated expression of both single genes and transcriptional networks were examined. The multilevel analyses were performed in a comparative manner, i.e., genome size (full length or reduced) vs. cellular state (steady or unsteady).It remains unclear if and how genome reduction and cellular state interrupt the order of global gene expression. To address this question, we analyzed 168 growth profile-associated microarray data sets of an assortment of E. coli microarray data sets that varied in strains, culture conditions, and growth status were collected from previously published studies . These transcriptomes were manually categorized based on the genome size and the cellular state. That is, the full length  and reduced (12 variations) genomes, and the steady (34 variations) and unsteady (22 variations) cellular states . The details of the data sets, experimental conditions, and the analytical results were summarized in Supplementary Table S1.The  studies , 2016. TFigure 1B) independent of the analytical methods . It demonstrated that the manual categorization of the transcriptomes based on genome size and cellular states was reasonable. In addition, the transcriptomes of the steady cellular states showed high similarity regardless of genome size . It indicated that the genome reduction did not alter the regulatory mechanisms of gene expression that determined cellular states.Common clustering analysis showed that all 56 transcriptomes were roughly in the order of the differentiation in cellular states and genome size (Zipf’s law (K of low P(K) as previously reported . A distribution of r, varied from 2.2 to 2.8, was acquired from the total 56 transcriptomes . Intriguingly, differentiation in the mean r of the power-law distributions in gene expression was detected in the reduced genomes (p < 0.05) even though the mean values of the both steady and unsteady cellular states remained equivalent . Although gene expression dynamics follow the power law commonly from E. coli to Homo sapiens . These data indicated that the power-law distribution was independent of growth rate, which was consistent with the similar slopes found for both steady and unsteady cellular states . Because no significant fitness-coordinated changes were detected at the genome-wide level, the growth rate-correlated expression at the individual gene and transcriptional network levels were subsequently investigated. Note that the changes in the slope r of reduced genomes remained significant , even the analysis was performed without the 16 transcriptomes of zero-growth rate .In addition, the correlation of the power-law distribution to the growth rate was evaluated because transcriptome reorganization is linked to growth fitness in E. coli . HoweverSupplementary Table S1) were calculated, and the changes in correlation coefficients caused by genome reduction and cellular state were further evaluated. The correlations of mrdB (JW0629) in full length genomes between expression levels and growth rates were shown as an example . The correlation coefficients between the gene expression levels and the corresponding growth rates in all  was varied from that in only 23 steady states . All 3213 and 2415 genes in full length and reduced genomes were evaluated, and the distributions of their correlation coefficients were formed . The full length genomes of all 44 transcriptomes formed a single peak distribution . It indicated that the order of growth rate-correlated expression showed higher correlation but with fewer genes. In addition, the distribution of correlation coefficients remained as a single peak but became broader when the unsteady cellular states were excluded . That is, the correlation between gene expression and growth rate was more significant in the steady cellular state, i.e., the exponential growth phase. The broad distribution formed by the steady cellular states suggested an increased number of genes with better correlations between expression and growth rate as well as a decreased number of genes with poor correlations. In addition, the analysis was also conducted toward the data sets without the unsteady states of zero growth. The results showed that the distributions of correlation coefficients of the steady states turned similar to that of the full length, although the correlations of individual genes altered . It implied that the differentiated distribution  was largely caused by those of zero growth.Changes in growth rate-correlated expression triggered by either genome reduction or steady state at the single gene level were evaluated. Correlations between the expression levels of individual genes and the corresponding growth rates  compared to the full length genomes that showed single peak distributions. Removal of the disappearing genes in the reduced genomes from the analysis did not alter the shape of the distribution as a single peak . The change of the distribution from monomodal to bimodal demonstrated that the number of the growth rate-coordinated genes was increased due to genome reduction. The result indicated that the deletion of redundant sequences improved the order of gene expression in a fitness-coordinated manner. The directional change of the distribution from narrow to broad was commonly observed in the reduced genomes and steady cellular states.Interestingly, the reduced genomes showed a bimodal distribution . The genes that exhibited highly significant improved correlations between expression level and growth rate were first identified. A total of 146 genes of which expression levels had no correlation to growth in the full length (FL) genomes (p > 0.01) but presented high correlations to growth in the reduced genomes (p < 0.001) were determined . In addition, 130 genes of which expression levels had no correlation to growth in all conditions (p > 0.01) but presented high correlations to growth in steady cellular states (p < 0.001) were determined . Subsequently, these genes were divided into 20 gene categories (p < 0.01), respectively . Such differentiation in gene function enrichment indicated that the genome reduction and the steady cellular state re-ordered the expression of the genes responsible for the enzymatic reactions and the molecular interactions, respectively.Differentiation in gene categories of improved correlations to growth triggered by genome reduction and steady cellular state was observed . Only 22 and 25 out of a total of 146 and 130 genes showing reverse directional changes in correlations were determined in the genome reduction and steady state, respectively. Such directional tendency remained even those transcriptomes of zero growth were removed from the analysis . The reduced genome remained more on the same direction in growth correlation because fewer genes in the genome reduction showed reverse directional changes in correlation compared to those in the steady state. Enrichment analysis also showed that the gene categories of improved correlations had the same directional changes . Taken together, genome reduction and steady cellular state favored the same directional change in gene expression, but the changes varied in gene functions. Thus, the genome reduction was linked to metabolic changes, whereas the cellular state was linked to the factors.The improvement of the correlations favored the same direction, that is, either an increase in positive correlation or a decrease in negative correlation (rpoS’s regulation in the full length (FL) genomes showed no correlation to the growth rates . However, these regulatees presented a better but statistically insignificant correlation to the growth rates in steady cellular states . A total of 44 and 42 TFs  that comprised more than 15 regulatees in the full length and reduced genomes, respectively, were subjected to the correlation analysis. The histograms of these 44 and 42 correlation coefficients showed there were more regulatory networks in the reduced genomes (rd) than in the full length genomes that presented better correlation of network expression to growth . However, the increase in the number of the regulatory networks of improved correlations to growth rate was not detected in the steady (st) cellular state . Note that the results from the data sets excluding the zero growth remained the same .In addition to the growth-correlated expression of individual genes, the growth-correlated expression of regulatory networks was further analyzed. The expression levels of the genes regulated by the assigned regulator  were averaged and defined as the mean expression of this transcriptional network. For example, the mean expression levels of 227 downstream genes (regulatees) under Figure 5C) according to the statistical significance of the correlation coefficients of all regulatory networks . The transcriptional network regulated by argR presented increased correlation coefficients between the growth rate and the mean expression of the regulatees . It was the only regulatory network significantly influenced by genome reduction and steady state. Additionally, more transcriptional networks were solely influenced by genome reduction  than that by steady state . These results indicated that the priority of re-ordering gene expression at network levels was varied in genome reduction and steady state.The regulatory networks showing the improved correlations to growth rates due to either genome reduction (rd) or steady states (st) were identified  have been initially reported in the present study. These results strongly suggested that the deleted genomic sequences, which might be acquired by HGT during genome evolution  revealed that the deletion of the redundant and/or accessary sequences improved the growth-coordinated changes in gene expression. Such improved order of gene expression agreed with the previous finding demonstrating that the chromosomal periodicity is fixed in the reduced genome but flexible in the wild type genome . The genes of significant changes in correlations were enriched in the categories of Factor and Enzyme . For instance, the genes of rseA and yefM, which were enriched in Factor (f), encoded an anti-sigma factor and an antitoxin, respectively. It suggested that the genes play an essential role in growth changes were attributed to the minor regulatory mechanisms. This finding is valuable for understanding the gene expression order for genome evolution and fitness increase. Future studies to clarify the reason why the correlation coefficients were improved in reverse direction  are important to understand the genome evolution and growth fitness of the cells. Moreover, the regulatory networks showed that the improved correlations in expression specifically attributed to genome reduction or steady state reflected the varied mechanisms of gene expression re-ordering. The only transcriptional network that was specifically influenced by steady state was rpoN, a sigma factor (σ54) participating in global transcriptional regulation  presented similar regulatory functions  at single gene levels in steady cellular states. Besides, it shaped more by the expression of downstream regulatees  at network levels in genome reduction  were calculated; and those of the early responsive states, such as, 5–30 min after heat shock or amino acid depletion, were defined as zero, because the cells paused to grow. All this information  was carefully re-confirmed and categorized according to two standards, namely genome size (full length or reduced) and cellular state (steady or unsteady), as summarized in Supplementary Table S1. The growth rates (h-1) were cited or calculated according to previously published reports  of the gene had a significant p-value (p < 0.05), then the gene remained in the data sets. Thus, relatively reliable values among the 168 data sets were used. A total of 3123 genes in the full length genomes of MG1655 and DH1 derivatives (128 data sets) as well as 2415 genes in the MDS42 reduced genome and its derivative (40 data sets) were subjected to global normalization, resulting in a common mean value (logarithmic) in all data sets. The normalized 168 data sets comprising the biological replicates (N = 2 to 7) were subsequently averaged, which resulted in 56 variations, including 44 of full length and 12 of reduced genomes. These 56 data sets were used for the following computational analyses.A total of 168 microarray data sets , which were all based on the platform of EcFS, were obtained from published studies. These microarray data sets were all associated with growth information, such as growth rates, as previously summarized. Microarray raw data sets assigned with the GEO access numbers of GSE33212, GSE49296, GSE55719, GSE52770, and GSE61749 were first cut with a statistic threshold according to the Figure 1 and Supplementary Figure S1. The power-law analysis used all 3123 and 2415 genes in the full length and reduced genomes, respectively. The cumulative probability of the gene expression level    was calcal study  as previal study . Gene castudy (1 . Only trKY and B-WY performed the analyses. B-WY conceived the research and wrote the paper. All authors read and approved the final 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.


Mosquito-borne viruses are the cause of some of the greatest burdens to human health worldwide, particularly in tropical regions where both human populations and mosquito numbers are abundant. Due to a combination of anthropogenic change, including the effects on global climate and wildlife migration there is strong evidence that temperate regions are undergoing repeated introduction of mosquito-borne viruses and the re-emergence of viruses that previously were not detected by surveillance. In Europe, the repeated introductions of West Nile and Usutu viruses have been associated with bird migration from Africa, whereas the autochthonous transmission of chikungunya and dengue viruses has been driven by a combination of invasive mosquitoes and rapid transcontinental travel by infected humans. In addition to an increasing number of humans at risk, livestock and wildlife, are also at risk of infection and disease. This in turn can affect international trade and species diversity, respectively. Addressing these challenges requires a range of responses both at national and international level. Increasing the understanding of mosquito-borne transmission of viruses and the development of rapid detection methods and appropriate therapeutics  all form part of this response. The aim of this review is to consider the range of mosquito-borne viruses that threaten public health in Europe and the eastern Mediterranean, and the national response of a number of countries facing different levels of threat. Europe is dominated by a temperate climate although there is great variation affected by proximity to seas and elevation. Simplistically these range from a Mediterranean climate (warm and dry) in the south, to oceanic in the west , continental (cold winters and warm summers) to polar in the far north. Despite this variation, mosquitoes are present across the whole continent although the species assemblage and seasonal abundance varies dramatically. A consistent phenomenon is that the summer months in Europe (July to September) support mosquito activity whereas the winter months (December to February) generally lead to a cessation of activity. Ecological studies in southern  and nortAe. albopictus into Spain. The mosquito was first detected in 2004 in the city of Sant Cugat del Vallès in the northeast of the country [Ae. aegypti, a species last reported in Spain in 1939 [Ae. albopictus raises the risk of autochthonous disease transmission within the human population wherever it is found. This problem is affecting an increasing number of countries around Europe.In addition to native mosquitoes, Europe has been colonized by a series of invasive aedine mosquitoes  that hav country . Within  country . This ex in 1939 . In addiCulex [Culex pipiens [Culex modestus [Autochthonous transmission of viruses by mosquitoes in Europe has been dominated by the emergence of a series of exotic viruses. The best example of this has been the repeated introduction of West Nile virus (WNV), transmitted predominantly by mosquito species of the genus Culex . Italy iCulex . A seconCulex . In 2018Culex . Yearly Culex . The obs pipiens  especialmodestus .Ae. albopictus in southern Europe has provided fertile ground for the introduction of Aedes mosquito-transmitted viruses by viraemic humans travelling from endemic regions. Examples of this include outbreaks of fever caused by dengue virus (DENV) in southern France [Turdus merula). Arguably this is a significant threat to avian biodiversity in many regions of Europe [The presence of n France  and chikn France , and hasn France , leadingf Europe .The variety of mosquito-borne viral threats , their sCulex modestus, has been detected in areas adjoining the Thames Estuary in southeast England [The UK is free of pathogenic mosquito-borne viruses and the only recorded arthropod-borne virus is louping ill virus, a pathogen in sheep and grouse transmitted by ticks . Despite England  and its  England . DespiteAe. albopictus eggs in the south of England [Surveillance for arthropod-borne disease is based on detection of human cases by Public Health England (PHE). However, these infections result from travel to disease-endemic areas, particularly ZIKV following its introduction into South America , rather  England , althoug England .Two mosquito-borne viruses have been detected in Sweden . The cliFrance faces the circulation of two mosquito-borne-flaviviruses with episodic re-emergence of WNV over a long period and the first introduction of USUV in 2015. The first reported WNV outbreak that affected humans and horses took place in the southeast of France in the 1960s, in the Camargue region, an area of natural wetland on the Mediterranean coast between the cities of Montpellier and Marseille. The re-emergence of this virus 40 years later was detected in the same region (2000 and 2004) as well as in two other administrative areas (Departments) bordering the Mediterranean Sea, Var in 2003 and Pyrénées Orientales in 2006  Figure . After nTurdus merula) in Haut-Rhin department, near the French-German border. It was also isolated in Culex pipiens mosquito pools trapped in 2015 in Camargue [The dynamic spread of USUV has been different. This virus was first isolated in 2015 from a resident blackbird  and horses (supervised by the Ministry of Agriculture), which is reinforced in Departments from the Mediterranean area during the vector circulation period between the 1st June until the end of October . Equine Corvus corone), magpies (Pica pica), blackbirds (Turdus merula) and sparrows (Passer domesticus), as well as nocturnal or diurnal raptors. This is coordinated through a network for the epidemiological surveillance of wildlife diseases (SAGIR network) set up by the National Hunting and Wildlife Agency  and the National Federation of Hunters . Finally an entomological surveillance is delivered by the Interdepartmental Alliance for Mosquito Control on the Mediterranean Coast  when the viral circulation is confirmed in an affected area. WNV surveillance, prevention and control activities are described in the national guidelines [In addition, there is monitoring of abnormal mortalities in wild bird, especially priority species such as crows . Nonetheless, compared to the overall picture within the EU, the number of cases observed in Italy in 2018 are higher than those observed in any of the previous years.West Nile virus is considered endemic in Italy with repeated emergence during the summer months. This has been heightened in 2018 with the sudden increase in human cases compared to previous years. The Istituto Zooprofilattico Sperimentale Abruzzo e Molise has, in collaboration with the National Health Institute (ISS), the responsibility for data collection and analysis on West Nile disease (WND) and surveillance activities conducted within Italy. The data observed in Italy concerning the number of human cases of WNF  are not Corvus cornix), and the Eurasian jay (Garrulus glandarius) are targeted, with the objective of sampling at least 100 subjects per province in endemic areas, plus a passive collection of dead wild birds of any other species. The surveillance activities are planned at the national level, and the local veterinary services manage their practical execution. p = 5.6 × 10−11). The monthly numbers of positive mosquito pools were significantly correlated to the monthly numbers of target birds positive to WNF  and the monthly positivity in mosquitos was also correlated to the monthly positivity in wild birds . A conclusion of this analysis suggests that the variations in the incidence of infection in mosquitos led to similar variations in the incidence in both the vertebrate reservoirs of the infection (target birds) and in the accidental hosts .The surveillance performed in Italy for WNV includes the testing of pools of mosquitos collected using a range of traps. Entomological sampling begins in March with the purpose of detecting WNV in areas before transmission to humans occurs (recently reviewed in ). FurthePossible factors responsible for the high incidence of WNF in 2018 include the temperature and rainfall. Comparison of the data on the last month (July 2018), the last season (spring 2018) and the last year (2017) to the entire period on record (years 1800-2018)  suggesteDue to its geographic location and Middle-Eastern climate, Israel has always been endemic for mosquito-borne diseases. Currently, the major mosquito-borne diseases circulating in Israel are WNF and the bovine disease, three-day sickness, or bovine ephemeral fever, caused by the bovine ephemeral fever virus (BEFV) . Other rThe WNV outbreak during 2000 caused significant economic effects to goose farms in Israel, which necessitated the development of an autologous vaccine to combat the infection . Wild biBovine ephemeral fever (BEF) was first described in Israel in 1931 with occasional outbreaks every few years  and is cThe reported study included only 8 farms, each with an average of 250 lactating cows, with approximately 40% morbidity in each herd. Therefore, a gross estimation of the effect of a single outbreak was US$28,000 per herd for lactating cows, excluding non-lactating cows and high milk somatic cell count damage . Bovine Located on a major bird migration route, the geographic location of Israel, combined with a relatively warm climate and the dense human population in the central and northern parts of the country, are all factors that promote the rapid spread of introduced or re-emerging arboviruses. Recent assessment of the possible incursion of exotic arboviruses concluded that the environmental conditions, including the presence of an established vector, could permit potential autochthonous transmission of DENV and CHIKV . HoweverStrix nebulosa) in the Federal States of Saxony-Anhalt and Bavaria, and wild goshawks (Accipiter gentilis) in Saxony-Anhalt. Moreover, two WNV cases were found in dead blackbirds (Turdus merula) in the capital, Berlin, and the State of Mecklenburg-Western Pommerania as well as WNF in horses . One human infection with WNV was eventually reported in a pathologist who developed a febrile illness after dissecting a great grey owl in Poing, near Munich, Bavaria [Surveillance for emerging mosquito-borne disease is based on country-wide collection of mosquito populations  and wild Bavaria . These cA recent study by the European Centre for Disease prevention and Control (ECDC), the transnational body for Europe that monitors and provides advice on human infections, identified vector-borne diseases as one of the eight major infectious threats for the EU, in “competition” for example, with antibiotic resistance in bacteria or with pandemic influenza . This haAe. aegypti and Cx. quinquefasciatus that are found in tropical and sub-tropical regions. The introduction, establishment and spread of invasive Aedine mosquito species, particularly Ae. albopictus has resulted in autochthonous transmission of both DENV and CHIKV in southern Europe. Control efforts are able to suppress local populations but eradication of Ae. albopictus is unlikely and the species is likely to continue to expand into new areas of the continent [All European countries face the introduction of mosquito-borne viruses and malaria from travelers returning from tropical and sub-tropical regions. This trend will continue as the volume of air travel increases and mosquito-borne viruses continue to cause sudden outbreaks throughout Africa, Asia and South America . Until rontinent ,86. In tontinent ,87,88.Surveillance for mosquito-borne viruses has been adopted as the most effective means of predicting the emergence of disease before human populations are affected. By targeting mosquito populations and sentinel species such as wild birds and horses, the aim has been to identify areas where virus circulation is occurring before human infections result. This requires considerable effort to process and test samples, coordination between different organisations dealing with public and veterinary health, and the rapid dissemination of information when virus is detected to prevent mosquito transmission and secure blood supplies. Development of high-throughput testing and multiplex molecular and serological testing has enabled this to be achieved in the timeframes needed to be effective ,90. All Cx. pipiens. Indigenous Cx. pipiens in The Netherlands appear particularly susceptible to infection with USUV and capable of transmission [Most European countries have been affected by USUV although both the British Isles and Scandinavia remain free of the disease. Water bodies such as the English Channel and the Baltic Sea, respectively, may prove to be barriers to transmission if mediated by mosquito populations. However, if bird movement and migration are key players in virus translocation then it is likely that both regions will be visited by this virus. It is possible that cryptic spread has already occurred but USUV has not established in local populations of the main mosquito vector, smission , whereassmission . WhateveThe trends in mosquito-borne virus introduction and spread are likely to continue in future years. The warm summer temperature experienced during 2018 may have been responsible for the earlier emergence of WNV than in previous years , the inc


Dear Editor,In this report, we present two cases within the spectrum of Klippel-Feil syndrome (KFS)accompanied by posterior partial split of the spinal cord. The first case involved awoman who underwent magnetic resonance imaging (MRI) of the cervical and thoracic spineto investigate the presence of hemivertebrae and scoliosis. The images showed fusionfrom C2 to C5, together with posterior spinal cord cerebrospinal fluid cleft . The sec. Theclassic clinical triad, as described by Maurice Klippel and André Feil, consistsof shortening of the neck, low posterior hairline, and limited range of motion of theneck, being present in only 50% of cases. A wide range of brain and spinal cord malformations have beenreported in patients with KFS. Diastematomyelia, one of the most widely reportedmalformations accompanying KFS, is characterized by complete division of the neural tubeand the formation of two hemicords separated by osseocartilaginous septum, typically inthe lower thoracic and lumbar regions(3). Among the few reported cases of KFS, spinal cord alterationsoccur in up to 50%, and posterior spinal cord cleft  is one such alteration(-6).KFS is characterized by congenital fusion of two or more vertebral bodies, of unknowncause. Etiological hypotheses include injury occurring at 3-8 weeks of gestation and anassociation with the genes that control the process of embryonic somiteformation. Thecla of cases. A wide lteration-6..One of the proposed mechanisms of vertebral fusion is extension of the cartilageformation process to the intervertebral disc material after completion of the primarysegmentation (given that there is no change in the number of nerve roots), culminatingin the union of the vertebrae. Spinal cord cleft has an even more obscure origin, and it hasbeen suggested that it is due to focal injury with a superficial tissue repair process,although without repopulation with somite cells.The relationship between vertebral fusion (KFS) and posterior partial spinal cord cleftis poorly documented and does not have a plausible origin like the defects involving theduplication of the notochord, which would explain in a more appropriate way theformation of diastematomyelia and the production of hemivertebrae or the so-called"butterfly" vertebrae.One of vertebrae. Spinal ite cells.(-6). Because ofthe small number of cases reported, we raise the question about the actual prevalence ofthis combination and reiterate the need for active case finding, given that isolated KFSseems to be much more common in clinical practice than is the combination of KFS andspinal cord malformation, especially now that MRI has become much more accessible.In patients with KFS, spinal cord changes are considered to be one of the most importantfactors in the neurological deterioration process, second only to nerve involvementcaused by degenerative spondylosis-6. Becau


EQUitable Impact Sensitive Tool (EQUIST) to enable global health community address the issue of equity in maternal, newborn and child health (MNCH) and minimize health disparities between the most marginalized population and the better-off. The purpose of this study was to use EQUIST to provide reliable evidence, based on demographic health surveys (DHS) on cost–effectiveness and equitable impact of interventions that can be implemented to improve MNCH outcomes in Benin, Burkina Faso, Ghana, Mali, Nigeria and Senegal.United Nations Children’s Fund (UNICEF) designed Using the latest available DHS data sets, we conducted EQUIST Situation Analysis of maternal and child health outcomes in the six countries by sub-national categorization, wealth and by residence. We then identified the poorest population class within each country with the highest maternal and child mortality and performed EQUIST Scenario Analysis of this population to identify intervention package, bottlenecks and strategies to address them, cost of the intervention and strategies as well as the number of deaths avertible.Under-five mortality was highest in Atlantique (Benin), Sahel (Burkina Faso), Northern (Ghana), Sikasso , North-West (Nigeria), and Diourbel . The number of under-five deaths was considerably higher among the poorest and rural population. Neonatal causes, malaria, pneumonia and diarrhoea were responsible for most of the under-five deaths. Ante-partum, intra-partum, and post-partum haemorrhages, and hypertensive disorder, were responsible for highest maternal deaths. The national average for improved water source was highest in Ghana (82%). Insecticide treated nets ownership percentage national average was highest in Benin (73%). Delivery by skilled professional is capable of averting the highest number of under-five and maternal deaths in the six countries. Redeployment/relocation of existing staff was the strategy with highest costs in Burkina Faso, Nigeria and Senegal. Ghana recorded the least cost per capita ($0.39) while the highest cost per capita was recorded in Benin ($4.0).EQUIST highlights the most vulnerable and deprived children and women needing urgent health interventions as a matter of priority. It will continue to serve as a tool for maximizing the number of lives saved; decreasing health disparities and improving overall cost effectiveness.The online version of this article (10.1186/s12992-018-0422-1) contains supplementary material, which is available to authorized users. As the United Nations (UN) Millennium Development Goals (MDGs) initiative of 2000 rounded off in 2015, available reports indicated that most countries made various levels of progress towards achieving the MDGs 4 and 5  . Despite. The MMR of some of the West African countries are among the highest in the world such as Sierra Leone , Nigeria , Liberia  and The Gambia  [Of all the sub-regions of Africa, the West-Africa with a population of more than 357million (about 1/3 of entire African population) , 5, is aRecent studies sponsored by the West African Health Organization (WAHO) report that contextual barriers such as road conditions, culture, knowledge of risks and the status of women, and health systems barriers including geographic distance of health centres, services delivery organisation, the availability and ability of health services, and the quality of care, all act together to increase maternal and child mortality in the sub-region , 7. It hEvidence abound which showed that decrease in maternal and child mortality in low and middle-income countries (LMICs) including the African region has been accompanied by increased inequity in health outcomes between the poor and those better off –13. ConsEQUitable Impact Sensitive Tool (EQUIST) to enable the global health community improve equity in MNCH and reduce health disparities between the most marginalized mothers and young children and the better-off [http://equist.info/en/pages/home), which has been described as a medium-term strategic planning, modelling and monitoring platform that serves to improve child and maternal health as well as nutrition equity in LMICs [To this end, a number of tools have been developed to assess the relationship between cost–effectiveness and equitable impact in maternal and child mortality reduction . Some oftter-off , 19. EQUin LMICs –22.The purpose of this study was to use EQUIST to provide reliable evidence, based on globally available demographic health surveys (DHS) on cost–effectiveness and equitable impact that will facilitate the implementation of interventions that will improve MNCH outcomes in West Africa with a focus on six West African countries . The goal was to provide decision makers and global health community with scientific information that will enable them think about issues of equity in MNCH in a more systematic and evidence-informed way, in order to design health intervention strategies that will lead to stronger, more resilient health systems in West Africa. In this study, we used EQUIST to: (i). create an accurate picture of the health status of the most deprived children and women in Benin, Burkina Faso, Ghana, Mali, Nigeria and Senegal; (ii). identify which populations are at greatest risk, why they are at risk, and how many lives can be saved with appropriate action; (iii). identify the highest impact, most cost-effective strategies to level disparities; and (iv). measure the potential effects in terms of lives saved and costs.Geographically, the West African sub-region is bounded by the Atlantic Ocean in the west and by the Gulf of Guinea in the south and is characterised by a very rich ethnic and social diversity. Most of the countries of West Africa are classified as poor and their economies are not very well developed or diversified with the Human Development Index (HDI) rank among the poorest in the world . The 201An explanation of the main concepts, assumptions and default data sources used in EQUIST are presented in the EQUIST technical note , while tProfile analysisEQUIST is pre-loaded with DHS data sets and we used the latest available DHS data sets of the six West African countries we considered in this study. The DHS are country-wide household survey that are nationally-representative and which provide a wide range of systematic information on health indicators and health services. We used the 2011 DHS data set of Benin, 2010 of Burkina-Faso, 2014 of Ghana, 2013 of Mali, 2013 of Nigeria and 2014 of Senegal to perform both profile and frontier situational analysis . We condUsing the EQUIST Profile analysis, we assessed the general extent, nature and implications of inequities as they affect MNCH in the six countries. Under the Demographic Parameters of the Sector Category, we examined under-five mortality and neonatal mortality with reference to the key drivers of inequity, the underlying factors that explain inequities  and analysed the scale of inequity . Under the Epidemiological Parameters of the Sector Category, we performed EQUIST Profile analysis to determine the key epidemiological causes and the specific number of under-five, neonatal and maternal mortality each of them causes.(b) Frontier analysisUnder the Theme Category, we also performed EQUIST Profile analysis of the percentage of Effective Coverage of maternal and child health interventions including: (i). Family care practices ; (ii). Preventive services (immunization plus); (iii). Curative services . We related these interventions and effective coverage to the six countries by wealth (poorest and richest) and by residence .Using the EQUIST Frontier analysis, we identified the factors most likely to drive inequity, and compared the number of Under-five and maternal deaths that could be averted in the poorest wealth quintile in the six West African countries. Under the Frontier, we performed two analyses.First, we performed the Equity Frontier analysis to identify how many under-five and maternal lives that could have been saved if the six countries equalize coverage values for the least disadvantaged within the most disadvantaged population (poorest quintile). This was to enable us know the number of deaths that will be averted if the coverage gaps for the most disadvantaged population was equivalent to that of the richest in each of the countries’ context.Second, we performed the Operational Frontier analysis to determine the number of under-five and maternal deaths that could be averted if effective coverage of evidence based high impact interventions are implemented and if their bottlenecks are reduced with the same proportion as observed in the most disadvantaged quintiles in best- performing countries.Analysis of epidemiological prioritiesWe conducted EQUIST scenario analysis for the six selected West African countries by wealth focusing on the poorest quintile.(b) Analysis of interventionsUsing the EQUIST epidemiological priorities we identified three categories of mortality and their main causes in the poorest quintile as follows: (i). Neonatal mortality ; (ii). Post-neonatal and child mortality ; (iii). Maternal mortality .(c) Analysis of bottlenecks, causes & recommendationsWe identified the priority interventions with which to address the epidemiological issues we selected. The interventions are grouped in nine “packages” further grouped into three service delivery modes: family care practices, preventive services, and curative services.(d) Analysis of enabling environment and strategies to address bottlenecks and their causesWe identified the priority bottlenecks to implementing the interventions we selected. We related the priority bottle necks with the eight EQUIST scenario coverage determinants including: (i) Availability of commodities, (ii) availability of human resources, (iii) geographical accessibility, (iv) financial affordability, (v) sociocultural acceptability, (vi) initial utilization, (vii) adequate coverage, and, (viii) effective coverage. The bottleneck analysis framework in EQUIST assumes that eight conditions (coverage determinants) must be met to provide effective coverage of any health intervention . Using t(e) Analysis of impact and costWe performed the analysis of the enabling environment which is classified into four  and identified the direct causes. We also performed the analysis of the strategies classified into five health systems building blocks  to address the bottlenecks.The EQUIST impact and cost analysis was performed to determine the following: (i). The operational frontier for maternal, under-five and neonatal mortality: that is amenable deaths if the deprived population coverage value was equal to the best performing countries, (ii). The equity frontier for maternal, under-five and neonatal mortality: that is amenable deaths if the deprived population coverage value was equal to the non-deprived population coverage value; (iii). Amenable under-five and maternal deaths among the poorest by intervention package in the six West African countries; (iv). The cost of strategies to avert both maternal and under-five mortality; (v). The cost per capita averting the number of deaths.The EQUIST profile analysis of under-five mortality by sub-national regions under the demographic parameters of the sector category in the six West African countries showed the regions recorded the highest mortality Atlantique (Benin), Sahel (Burkina Faso), Northern (Ghana), Sikasso , North West (Nigeria), and Diourbel . The number of deaths/1000 live births in these regions were more than twice the number recorded in the regions with the lowest number of deaths/1000 live births and the values were considerably higher than the national average in the six countries  was higher in Ghana (82%), Mali (73%), and Senegal (81%), compared to the remaining three countries. ITN ownership percentage national average was highest in Benin (73%) and Mali 61%) but lowest in Nigeria (13%). The percentage of the ITN ownership was lower among the poorest compared to the national average in Benin (73% vs. 68%), Burkina-Faso (47% vs. 42%), Mali (61% vs. 56%), Nigeria (13% vs. 9%) and Senegal 43% vs. 38%) . the best performing countries  and (ii) the non-deprived population coverage value (equity frontier) are shown in Table Asphyxia is responsible for the highest number of amenable neonatal deaths by operational and equity frontiers in the six countries. Ante-partum haemorrhage, intra-partum haemorrhage, post-partum haemorrhage and hypertensive disorders are the diseases responsible for the highest number of amenable maternal deaths among the poorest quintile in Ghana, Mali and Nigeria Table .Amenable deaths among the poorest by intervention package and equity/operational frontier for under-five and maternal mortality in six West African countries are shown in Table The cost of intervention strategies to avert the mortality as provided by the EQUIST impact and cost analysis are presented in Table The outcome of the EQUIST analysis generally showed that the six West African countries have unacceptably high maternal and child mortality that is perhaps among the worst in the world. Santi and Weigert  noted inAvailable reports from Nigeria support the outcome of the EQUIST situational analysis which indicated the highest maternal and child mortality in the North-West region of the country . The NigSikasso is among the regions with the worst health statistics, having the highest infant mortality rate and under-five mortality rate in the country [In Mali, a recent report confirms that the  country . Accordi country . In Sene country , 32.The EQUIST situational analysis showed that the rural dwellers and poorest quintile population had consistently higher maternal and child mortality in all the six countries. Also, higher number of deaths due to epidemiological causes were recorded among the rural dwellers and poorest quintile population. In an earlier report on maternal mortality and access to obstetric services in West Africa, Ronsmans and co-workers noted that most rural women give birth at home in the absence of skilled care, while urban women tend to give birth in a hospital with a skilled attendant, consequently, maternal mortality is extremely high in rural areas, and substantially lower in urban areas . In addiThe EQUIST situational analysis showed that neonatal causes, malaria, pneumonia, and diarrhoea were the major causes of under-five mortality in all the six countries. Result also showed that sepsis, asphyxia, and prematurity were the leading causes of neonatal mortality in the countries. Both under-five mortality and neonatal mortality were highest among the poorest and the rural dwellers in the six countries. Available evidence from previous studies conducted in Nigeria indicated that these diseases were responsible for the highest under-five and neonatal mortality numbers in various parts of the country especially among the rural and the poorest , 27. A sEQUIST analysis showed that obstetric hemorrhage is the leading cause of maternal mortality in all the six countries. Of the three types of Obstetric haemorrhage, post-partum haemorrhage was responsible for the highest number of maternal mortality. In a previous study on maternal mortality undertaken in northern Nigeria, post-partum haemorrhage was a leading cause of maternal mortality, contributing 75% of the cases . ReportsThe EQUIST situational and scenario equity and operational frontier analysis showed that thousands of under-five and maternal deaths could have been averted if the countries had equalized coverage values for the least disadvantaged within the most disadvantaged population (poorest quintile). According to the UN Chronicle report, universal coverage of scientifically proven cost-effective interventions are capable of reducing child deaths from about 2 million to just 650,000 . AccordiIn terms of the coverage of intervention package to improve maternal and child health outcomes, EQUIST analysis revealed that Ghana, Senegal and Mali had higher national average of 82%, 81% and 73% respectively compared to the remining three countries. A recent report indicated that Ghana achieved its Millennium Development Goal (MDG) water target about a decade before the 2015 deadline . As in GThe EQUIST analysis indicated that the percentage of the ITN ownership, DTP3 immunization and curative services such as essential care and case management of premature babies was lower among the poorest compared to the national average in most of the countries. A recent study on equity trends in ownership of ITNs involving eight West African countries  and 11 other sub-Saharan African countries, showed that richer households were more likely to own ITNs than the poorest households . The relThe EQUIST scenario analysis for mortality by intervention package showed that delivery by skilled professionals has the potential of averting the highest number of under-five and maternal mortality in all the six countries. Findings from a number of previous studies have shown that between 13 and 33% of maternal deaths and up to 25% of newborn deaths could be averted by the availability of skilled attendant at delivery , 49. AccOne of the major strengths of the EQUIST scenario analysis is the estimation of the actual cost of the strategies to avert the mortality. Redeployment/relocation of existing staff and task-shifting/task sharing are the strategies with the highest costs in Burkina Faso, Nigeria and Senegal. According to Santi and Weigert, the health sector is skilled-labour-intensive and in all countries of the West African region, the increase and effective management of health staff is crucial to the improvement of health systems . InsightCarrera and colleagues  have notThe major limitation of this study is that it is entirely based on DHS data. The weakness of information collected in DHS are well-established , 52. OneAlthough EQUIST can be described as a valuable tool which can assist decision makers to engage equity-focused approaches to improving MNCH outcomes, the knowledge and application of the tool is not yet wide-spread in LMICs. This study is the first attempt to demonstrate the usefulness of the EQUIST in the provision of scientific evidence on equity–focused approaches to health interventions to improve MNCH outcomes in West Africa. It has been argued that this type of information is very crucial as it supports an evidence-based prioritization of vulnerable populations and priority interventions, as well as an initial understanding of the broad health system issues that will need to be addressed in order to reduce health disparities in a region like West Africa .Throughout the world and especially in LMICs, policy makers and other key stakeholders in the health sector have come to the realization that resources for scaling up cost–effective MNCH interventions in their populations are scarce. Consequently, they are faced with the complex task of identifying and implementing the most efficient and cost-effective interventions that will results to more deaths averted per fixed investment , 54. AccEQUIST will continue to serve as a tool for maximizing the number of lives saved; decreasing health disparities and improving overall cost effectiveness . The impAdditional file 1:Outcome of EQUSIT Scenario analysis for poorest quintile in Benin. (PDF 345 kb)Additional file 2:Outcome of EQUSIT Scenario analysis for poorest quintile in Burkina Faso. (PDF 345 kb)Additional file 3:Outcome of EQUSIT Scenario analysis for poorest quintile in Ghana. (PDF 345 kb)Additional file 4:Outcome of EQUSIT Scenario analysis for poorest quintile in Mali. (PDF 345 kb)Additional file 5:Outcome of EQUSIT Scenario analysis for poorest quintile in Nigeria. (PDF 345 kb)Additional file 6:Outcome of EQUSIT Scenario analysis for poorest quintile in Senegal. (PDF 345 kb)