In mediation analysis if unmeasured confounding is present, the estimates for the direct and mediated effects may be over or under estimated. Most methods for the sensitivity analysis of unmeasured confounding in mediation have focused on the mediator-outcome relationship.The Umediation R package enables the user to simulate unmeasured confounding of the exposure-mediator, exposure-outcome, and mediator-outcome relationships in order to see how the results of the mediation analysis would change in the presence of unmeasured confounding. We apply the Umediation package to the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) study to examine the role of unmeasured confounding due to population stratification on the effect of a single nucleotide polymorphism (SNP) in the CHRNA5/3/B4 locus on pulmonary function decline as mediated by cigarette smoking.https://github.com/SharonLutz/Umediation A tutorial on how to install and use the Umediation package is available in the Additional file Umediation is a flexible R package that examines the role of unmeasured confounding in mediation analysis allowing for normally distributed or Bernoulli distributed exposures, outcomes, mediators, measured confounders, and unmeasured confounders. Umediation also accommodates multiple measured confounders, multiple unmeasured confounders, and allows for a mediator-exposure interaction on the outcome. Umediation is available as an R package at The online version of this article (doi:10.1186/s12859-017-1749-y) contains supplementary material, which is available to authorized users. CHRNA5/3/B4 locus on chromosome 15q25.1 that is associated with decreased lung function (FEV1)  on FEVts (PCs) . It is pWhile the assumption of no unmeasured confounding is required for mediation analysis, in reality this assumption may often be violated in large population based genetic studies. Thus, it is critical to assess the likely degree of bias introduced by unmeasured confounders within any given study. With the Umediation package, users may examine the hypothetical influence of an unobserved confounding variable on the estimation of direct and mediated effects, in the presence or absence of a statistical interaction between the exposure and mediator variables. Importantly, the package is flexible enough to allow for confounders of the exposure-mediator, mediator-outcome, and exposure-outcome relationships. While the data analysis example focused on population stratification which can confound the SNP-mediator and SNP-outcome associations, the strongest potential for unmeasured confounding is lifestyle and socioeconomic factors of the mediator-outcome association, such as physical activity and education. A strength of the Umediation package is that one can simultaneously account for all of these unmeasured confounders.1) through the mediator cigarettes smoking, the Umediation package is applicable and useful in any scenario where there may be unmeasured confounding of the exposure-mediator-outcome relationship (i.e. the exposure was not completely randomized). For example, Umediation has many practical and clinical uses. A relevant clinical example is the pathway by which maternal preeclampsia contributes to the risk of chronic lung disease in the newborn [While the data analysis example focused on confounding bias due to unobserved population stratification in the decomposition of the total effect of a SNP on lung function  to health outcomes at a later stage of life (such as childhood or adulthood). For example, maternal smoking in pregnancy has been consistently associated with a greater risk of childhood overweight and obesity in the offspring . MaternaUmediation examines the role of unmeasured confounding via simulations studies by running mediation analysis  both witAdditionally, the Umediation package currently assumes no correlation between the measured confounders C and unmeasured confounders U. While this is a reasonable assumption for the data example where the measured and unmeasured confounders are PCs, the investigator needs to determine if this is a reasonable assumption for their particular question of interest. While the Umediation package allows for an exposure-mediator interaction on the outcome of interest, it is important to note that the Umediation package does not allow for interactions of the measured and unmeasured confounders with the exposure or mediator on the outcome of interest. Also, the Umediation package currently only accommodates one mediator of the exposure-outcome relationship.While we have focused on the effect of unmeasured confounding of the exposure-mediator-outcome relationship in mediation analysis, there are methods that allow for unmeasured confounding, such as instrumental variable methods. There have been instrumental variable methods proposed that can be extended to handle mediation analysis for continuous, normally distributed outcomes  and binaUmediation allows investigators to make reasonable quantitative estimates of the magnitude of the effect due to unmeasured confounding of the exposure-mediator, mediator-outcome, or exposure-outcome associations. This R package accommodates multiple unmeasured confounders, which may be either Bernoulli or normally distributed. The utility of Umediation becomes apparent whenever the need arises to examine the impact of unmeasured variables in a mediation analysis: in a post-hoc setting, when data collection and analysis have already been conducted, or in the early stages of study design, when exploring the relative value accrued by collecting data on variables that may be costly or difficult to obtain. By estimating the degree of bias produced at the plausible upper and lower boundaries of the association between each unmeasured confounder and the exposure, mediator, or outcome, investigators will be able to assess whether the mediated or direct effects are likely to be over or under estimated due to unobserved confounders.


Stress fractures are injuries most commonly seen in the lower limbs and are usually caused by repetitive stress. While the distal and middle third of the tibia is the most frequent site for stress fractures , stress fractures of the proximal tibia is relatively rare and could be confused with other types of tibial fractures, thus altering management plans for the clinician. Early diagnosis of stress fractures is also important to avoid complications. Imaging plays an important role in the diagnosis of stress fractures, especially bone scan. Combined with single-photon emission computed tomography/computed tomography (SPECT/CT) it is an important imaging technique for stress fractures in both upper and lower extremities, and is widely preferred over other imaging techniques. In this case, we present the case of a 39-year-old male patient diagnosed with stress fracture of the proximal tibia and demonstrate the contribution of CT scan fused with SPECT imaging in the early diagnosis of stress fracture prior to other imaging modalities.


The purpose of this study was to identify clinician characteristics associated with higher prescription rates of long-acting injectable (LAI) antipsychotics, as well as the sources that influence medical decision-making regarding the treatment of schizophrenia. We surveyed 202 psychiatrists during six regional French conferences . Data on the characteristics of practice, prescription rates of antipsychotic, and information sources about their clinical decisions were collected. Most psychiatrists used second-generation antipsychotics (SGAs), and preferentially an oral formulation, in the treatment of schizophrenia. LAI SGAs were prescribed to 30.4% of schizophrenic patients. The duration and type of practice did not influence the class or formulation of antipsychotics used. The clinicians following the higher percentage of schizophrenic patients were associated with a higher use of LAI antipsychotics and a lower use of oral SGAs. Personal experience, government regulatory approval, and guidelines for the treatment of schizophrenia were the three main contributing factors guiding clinicians’ decision-making regarding the treatment of schizophrenia. The more clinicians follow schizophrenic patients, the more they use LAI antipsychotics. The development of specialized programs with top specialists should lead to better use of LAI antipsychotics in the treatment of schizophrenia. Schizophrenia is a chronic illness with a high risk of relapse that is frequently associated with treatment discontinuation. Ensuring treatment adherence is one of the principal challenges in schizophrenia management. This requires awareness of several risk factors  .The development of long-acting injectable first-generation antipsychotics (LAI FGAs) in the 1960s and, more recently, of long-acting injectable second-generation antipsychotics (LAI SGAs) has been an important step in the management of schizophrenia. These formulations are considered as one of the most efficacious pharmacological interventions available to address adherence problems in patients suffering from schizophrenia ,3. They LAI FGAs and LAI SGAs have been shown to be effective in the long-term treatment of schizophrenia, with the specific impact of reducing the risk of relapse . While tFor a long time, the use of LAI antipsychotics has been reserved for patients with chronic illness and poor adherence. However, recent guidelines for the use and management of LAI antipsychotics in clinical practice evoke the possibility of using this formulation for patients with first-episode or recent-onset schizophrenia ,10,11,12We hypothesize that there are some characteristics in clinicians’ practice that might be associated with different modalities of prescription of LAI antipsychotics. The aim of our study was to identify (i) the characteristics of practice associated with higher LAI antipsychotic prescription rates; and (ii) the sources of information that influence medical decision-making regarding the treatment of schizophrenia.A total of 202 psychiatrists participated in the survey . The meaPersonal experience, government regulatory approval, and guidelines for the treatment of schizophrenia were the three main contributing factors guiding clinicians’ decision-making regarding treatment of schizophrenia . Publishp = 0.029). The use of guidelines for the treatment of schizophrenia was significantly associated with a higher proportion of schizophrenic patients in the follow-up of clinicians (p = 0.049).There were some differences in the factors influencing the clinical decision-making of psychiatrists about treatment according to their practice characteristics . PersonaIn this naturalistic sample of French psychiatrists, practitioners declared that more than 30% of their treated schizophrenic patients received LAI SGAs.-Clinicians treating the highest proportion of schizophrenic patients prescribed significantly more LAI antipsychotics and fewer oral SGAs.-Other clinicians’ practice characteristics were not significantly associated with a differential use of LAI antipsychotics.-Personal experience, government regulatory approval, and guidelines for the treatment of schizophrenia were the main factors guiding clinicians’ decision-making regarding the type and formulation of antipsychotic prescribed.Specifically, our findings showed the following:Career duration appeared to be associated with decision-making regarding treatment based on the personal experience of psychiatrists. Conversely, the proportion of schizophrenic patients seemed to be associated with evidence-based decision-making on the part of clinicians (using guidelines for the treatment of schizophrenia).Psychiatrists reported prescribing SGAs  for most of their schizophrenic patients, as recommended as first-line treatment by international guidelines for the management of schizophrenia . The preThe LAI antipsychotic prescription rate of varies widely in other countries around the world  ,19. The Among the practice characteristics of psychiatrists involved in this study, only the proportion of schizophrenic patients was significantly associated with the prescription of LAI antipsychotics. Clearly, the higher the percentage of schizophrenic patients followed by clinicians, the more LAI antipsychotic formulations were used. Previous studies have shown that clinicians with more experience of LAI antipsychotics provided more information about LAI antipsychotics to their patients and had more favorable attitudes toward LAI antipsychotics than psychiatrists with less experience ,21. TheyThere was no significant correlation between the type of antipsychotic used (class or formulation) and the other characteristics of clinicians . In contrast, a previous German study showed that “older” psychiatrists offered and prescribed significantly more LAI FGAs and fewer LAI SGAs than did their “younger” colleagues . A possiIt is worth mentioning that factors influencing the decision-making about the treatment of schizophrenia were mainly a combination of experience and evidence-based medicine. In comparison with a previous French study, we noted a steep increase in the use of guidelines in clinical practice from 12.5%, in 2007–2008, to 26%, in the present study . One hypThe level of experience in treating schizophrenic patients also appeared to be significantly more correlated with the use of treatment guidelines. Though guidelines have been established to help clinicians choose appropriate care in specific clinical circumstances, most of them have been developed for specific psychiatric disorders . Clearly, general psychiatrists cannot do not have the time necessary to read all of the different guidelines (and their updates) from the different agencies or societies for all the serious mental disorders. Consequently, the fact that more specialized psychiatrists in schizophrenia used guidelines for the treatment of schizophrenia in clinical practice more frequently makes sense.These points highlight the need to develop specific strategies to provide optimal care for patients with schizophrenia. In the United States (Texas), the potential solution was the creation of the A ShoT At Recovery (A-STAR) program. In this organization, the aim of the integrated team is to enhance the use of LAI medication by providing data and education, both to prescribers and to patients . In FranThe main limitation of this study is the cross-sectional design that did not allow analysis of the causal relationships between the type of antipsychotic used and the practice characteristics of clinicians. Another relevant issue is that the participants may not necessarily be representative of all French psychiatrists due to a possible selection bias. Gender distribution of the participating psychiatrists was close to the national values published by the French National Medical Council ; however, our survey involved psychiatrists younger than the national mean age (43 vs. 51 years old) . FinallyWe conducted a cross-sectional survey among psychiatrists during six regional conferences  of the French Society for Biological Psychiatry and Neuropsychopharmacology between December 2014 and April 2015.We identified a randomized sample of 250 participants from the global list of participants (approximately 500). Recruitment of clinicians took place during each conference. All subjects participated with informed, voluntary, and written consent.The procedures followed in the study were approved by an independent national ethics committee (CPP Sud-Est 6) and were conducted in accordance with the revised version of the Helsinki Declaration (1989).A self-administered questionnaire was completed anonymously and returned at the end of conference by each participating psychiatrist.-demographic characteristics and characterization of practice ;-estimation of antipsychotic prescription rates by the psychiatrists ;-sources of information influencing the medical decision-making regarding the treatment of schizophrenia—clinicians had to grade the sources of information proposed  from 1 (first-line source) to 5 (last-line source).The questionnaire comprised three sections:Means and standard deviation were calculated for continuous measures, and categorical data were presented as frequencies. Correlation analyses of the type of antipsychotic used in schizophrenic patients and practice characteristics of clinicians were performed using Spearman correlations. Inter-group comparisons, according to the sources of information influencing decision-making about treatment, were performed using the Wilcoxon–Mann–Whitney test.Statistical analyses were performed using SAS 9.3 software . All statistical tests were two-tailed, and the significance level was set at 5%.Despite recent evidence showing the benefits of the use of LAI antipsychotics early in the course of the management of patients with schizophrenia, the gap in their use in clinical practice has remained wide. Numerous barriers, including the overestimation of patients’ adherence, patient refusal, or perceived coercion, have been identified. However, no effective strategies have reduced these barriers or changed the prescribing behavior of psychiatrists. Our findings highlight the significance of the current development of Expert Centers and other programs specialized in the management of schizophrenic patients and of patients with other serious mental disorders across the globe.


Randomized controlled trials and controlled before-after studies of interventions including technical patient handling equipment were included. The titles and abstracts of 9554 publications and 97 full-texts were screened by two reviewers. The qualitative synthesis included one randomized controlled trial (RCT) and ten controlled before-after studies. A meta-analysis of four studies resulted in a pooled risk ratio for musculoskeletal injury claims (post-intervention) of 0.78 . Overall, the methodological quality of the studies was poor and the results often based on administrative injury claim data, introducing potential selection bias. Interventions with technical patient handling aids appear to prevent musculoskeletal complaints, but the certainty of the evidence according to GRADE approach ranged from low to very low.The physical load ensuing from the repositioning and moving of patients puts health care workers at risk of musculoskeletal complaints. Technical equipment developed to aid with patient handling should reduce physical strain and workload; however, the efficacy of these aids in preventing musculoskeletal disorders and complaints is still unclear. A systematic review of controlled intervention studies was conducted to examine if the risk of musculoskeletal complaints and disorders is reduced by technical patient handling equipment. MEDLINE Numerous studies report a risk of occupational back complaints due to lumbar disc disorders, sprains and strains among health care workers ,7,8,9,10A main reason for health care workers’ risk of musculoskeletal disorders is the manual lifting and transferring of patients, which places stress on the ligaments of the spine, especially the lumbar spine ,13,14. TLumbar disc disorders and complaints result in substantial medical expenses and productivity loss in workers ,25,26,27Freiberg et al.  examinedTechnical patient handling aids, also known as mechanical assistive devices, can reduce the number of manual patient lifts required. The resulting decrease in lifting forces experienced by health care workers during patient handling can help to prevent complaints and disorders due to overloading ,32,33,34The aim of this research was to review the evidence regarding the effect of technical patient handling devices on preventing complaints and disorders, including acute presentations of debilitation and pain , to the lower back, upper back, and the shoulder joints among health care workers. In contrast to small aids , technicA comprehensive search of the medical literature was performed to identify all controlled intervention studies examining whether providing technical patient handling aids to health care workers prevents musculoskeletal complaints and disorders. The review research question and subsequent study inclusion criteria were defined according to the PICO framework  as follo® (via PubMed® and OVID®), EMBASE® (via OVID®), Allied and Complementary Medicine Database (AMED via OVID®), and Cumulative Index of Nursing and Allied Health Literature (CINAHL® via EbscoHost®) were searched up to 16 February 2018 using search strings with keywords corresponding to the research question. The PubMed search strategy is available as an online supplement  and conflicts reconciled by a third reviewer (Alice Freiberg). The full-texts of the studies were also assessed for inclusion independently by two reviewers  and disagreements discussed until resolved.Data extraction was conducted by one reviewer (Wera Berge/Alice Freiberg) and the accuracy and completeness verified by a second reviewer . The methodological quality of RCTs was assessed using the Cochrane risk of bias . In accoStatistical synthesis of the resulting data  was conducted with Review Manager (version 5.3)  when at least two of the studies considered similar outcomes with comparable/combinable effect estimates . FinallyAfter the removal of duplicates, the search for articles resulted in the screening of 9554 titles and abstracts and 97 full-texts. A flowchart depicting the process of literature identification and reasons for the exclusion of full-texts is shown in Originally only studies of technical aids interventions compared to control groups without any technical aids were to be included , this reSix studies examined musculoskeletal injury rates based on administrative claims data without considering the anatomic locations afflicted, making this the most frequent outcome examined ,51,55,57Of the three studies reporting injuries with  externally valid measurements  ,54,57, oTwo studies examined the effect of distributing portable technical lifting equipment to nursing, acute care hospital units, and long-term care (LTC) units on the musculoskeletal injury claim rates using the rates among all workers not provided with technical patient handling equipment over the same time period to control for temporal trends and to estimate what the authors called adjusted rate ratios (RR) ,53. EvanTwo further CBAs examined the effect of multimodal interventions ,48. The The RR estimates for the outcome of acute musculoskeletal events (injury claims) post- vs. pre-intervention reported by four of the studies ,48,50,53Only Lim et al.  examinedPrevalence of back pain or low back pain was examined by five studies ,52,56,57Yassi et al.  examinedDennerlein et al.  assessedSmedley et al.  assessedn = 50; control: n = 54) using a lift counter (LC) log. The total average number of lifts conducted was reduced in the intervention group from 35 to 21 after the introduction of the patient hoists, while the total average number of lifts in the control group remained stable at 24. The 12-month prevalence of back pain could also be significantly reduced in the intervention group from 74 to 64%, while the prevalence in the control group increased slightly from 62 to 66%. The authors acknowledge that the observed pre-intervention differences were probably due to unintended selection, and speculate that the post-intervention reduction in lifts logged were the result of family members assuming some of the required lifting tasks in the absence of the home care nurses with the help from the hoists.The study by Knibbe and Friele  was the Baldasseroni et al.  graduallThe pooled post-intervention prevalence ratios indicated the effectiveness of the intervention but did not reach statistical significance . In addiTwo CBAs examined the pain and injury claims for the cervical spine ,48. BlacOnly Yassi et al.  examinedBlack et al.  found thThe results of the risk of bias assessments with the “Downs and Black” and the Cochrane risk of bias are summarized in an online supplement See the . All of The methodological quality of the studies contributed to the overall assessment of the body of evidence for each of the outcomes. The evidence was examined with the GRADE approach for what were considered to be important outcomes using the GRADEpro software . The selOverall the results of the studies seem to indicate that interventions with technical patient handling aids may help prevent musculoskeletal complaints and disorders in health care workers. However, due to the very low quality of the available evidence, this preventive effect is uncertain. Although Freiberg et al.  found noThe non-randomized studies often reported selecting “at risk” units to receive the intervention, obscuring the results of the assessment. This risk imbalance could have resulted in an overestimation of the effect due to the greater potential impact of the interventions in “at risk” units. However, if the impact of the intervention was not dependent on the pre-existing increased risk, the post-intervention RRs may underestimate the potential effect of the intervention. In other words, the intervention brought the increased pre-intervention back pain prevalence in the intervention groups to levels similar to, yet slightly lower than that of the control group, resulting in a post-intervention RR closer to the null value. Thus the observed effect might have been greater if the groups had been comparable from the start.Two of the studies appeared to have used planned renovations as an opportunity to examine the impact of ceiling lifts on patient handling practices and injury claims ,55. HoweUnfortunately, none of the studies used medical evaluations or physician diagnosed disorders as outcomes. Such information could have provided objective insights regarding the progression of musculoskeletal degeneration following interventions. A number of studies examined self-reported complaints , for the most part with validated and widely used instruments. However, most of the studies evaluated injury claims data as a form of secondary data analysis, since these data were readily available. Although this registry data was less likely to be biased due to the lack of outcome assessor blinding, injury claims may be subject to selection bias. Some workers may choose not to report their injuries, and some claims require a long time to process and might have been overlooked. While musculoskeletal injuries can result from a single traumatic incident, an accumulation of subclinical trauma over many years places workers at risk for acute presentations of incapacitating pain. Longer follow-up times and differentiated examination of injury types could provide more convincing evidence regarding the impact of technical aids on musculoskeletal injuries.Prevalence of back pain was assessed by four studies, with three studies specifically examining low-back pain ,48,56, wp < 0.005) while unchanged in the control group. Yassi et al. [Several papers attempted to assess compliance with the intervention or actual use of the equipment with partially contradictory results. For example, Miller et al.  and Engsi et al.  found thi et al.  outfittei et al.  conducteNo evaluation of publication bias was conducted, because so few studies could be considered in the meta-analyses. Therefore, we cannot rule out that publication bias may exist for studies of technical aid interventions. Unfortunately, it is questionable whether online registries for clinical trials would be used to report planned ergonomic intervention studies.To the best of our knowledge this is the first systematic review to consider evidence regarding the effectiveness of technical patient handling aid intervention studies. This review intended to include and consider all available medical literature meeting the a priori inclusion criteria. Results of studies were summarized with meta-analyses when possible, and the strength of the body of evidence was assessed by considering the risk of bias of the individual studies and by applying the GRADE approach.As a consequence of the very low level of existing evidence, quality research is still needed. However, this evidence may need to come from high quality observational studies, as technical aids are already widely available in workplaces where frequent patient handling is required. It would be impractical, if not unethical, to withhold such equipment from employees in order to conduct controlled experimental studies.Interventions with technical patient handling aids indicate that this equipment may help prevent musculoskeletal complaints and disorders, but the certainty of the evidence according to GRADE ranged from low to very low. However, the wide-spread availability of technical patient handling aids will make future intervention studies problematic.


The purpose of this study was to determine the muscular contributions to the acceleration of the whole body centre of mass (COM) of older compared to younger adults that were able to recover from forward loss of balance with a single step. Forward loss of balance was achieved by releasing participants (14 older adults and 6 younger adults) from a static whole-body forward lean angle of approximately 18 degrees. 10 older adults and 6 younger adults were able to recover with a single step and included in subsequent analysis. A scalable anatomical model consisting of 36 degrees-of-freedom was used to compute kinematics and joint moments from motion capture and force plate data. Forces for 92 muscle actuators were computed using Static Optimisation and Induced Acceleration Analysis was used to compute individual muscle contributions to the three-dimensional acceleration of the whole body COM. There were no significant differences between older and younger adults in step length, step time, 3D COM accelerations or muscle contributions to 3D COM accelerations. The stance and stepping leg Gastrocnemius and Soleus muscles were primarily responsible for the vertical acceleration experienced by the COM. The Gastrocnemius and Soleus from the stance side leg together with bilateral Hamstrings accelerated the COM forwards throughout balance recovery while the Vasti and Soleus of the stepping side leg provided the majority of braking accelerations following foot contact. The Hip Abductor muscles provided the greatest contribution to medial-lateral accelerations of the COM. Deficits in the neuromuscular control of the Gastrocnemius, Soleus, Vasti and Hip Abductors in particular could adversely influence balance recovery and may be important targets in interventions to improve balance recovery performance. Older adults fall more frequently compared to their younger counterparts in part because of a reduced capacity to recover from loss of balance –3. PerhaMost studies of stepping behaviour in older adults to date have focused on recovery from forward loss of balance, perhaps because trips during walking are a common cause of loss of balance in community dwelling older adults , 8. StudDetermining how the motor system contributes to the control of balance recovery performance is difficult because muscle forces cannot be measured directly or easily. Musculoskeletal models provide a framework whereby the role of muscle forces in the production and control of movement can be investigated . In partFourteen community dwelling older adults aged 65 to 80 years  and six younger adults  were recruited from the local community. Individuals previously diagnosed with neurological, metabolic, cardio-pulmonary, musculoskeletal and/or uncorrected visual impairment were excluded. Ethics approval was obtained from the Griffith University Human Research Ethics Committee and all relevant ethics guidelines including provision of written informed consent were followed.The balance recovery protocol was undertaken as reported previously , 9, 27. Ten older adults and all younger adults recovered with a single step while the remaining four older adults required multiple steps to recover. A multiple step strategy was identified using previously defined criteria  as a) a All data analysis were performed using OpenSim (version 3.2)  in conjuModels were evaluated according to the recommendations of Hicks et al.,  to ensurA between group Analysis of Variance was used to determine the effect of age group (young versus old) on step length and duration, trunk, pelvis and hip, knee and ankle joint angles for the stance and stepping limbs at each event , 3D COM accelerations and individual contributions of each muscle to the 3D COM accelerations during balance recovery averaged over the periods defined from cable release to toe-off (CR-TO), toe-off to foot contact (TO-FC) and foot contact to knee joint maximum (FC-KJM). Statistical analysis was performed using the Statistical Package for the Social Sciences  and significance was accepted for p<0.05.There were no significant age-related differences in step length , total step duration (CR-KJM)  or the duration of any phase of the step recovery . Further, no age-related differences in trunk, pelvis or stance or stepping limb joint angles were detected at CR, TO, FC or KJM.There were no significant age-related differences in the 3D accelerations of the COM throughout balance recovery. For both groups, the COM experienced a net vertical acceleration throughout balance recovery, which was highest following FC. From CR to FC the mean horizontal COM accelerations for both groups were directed anteriorly and towards the step leg. Following FC, the anterior-poster COM acceleration was directed posteriorly .There were no significant age-related in the muscle contributions to the 3D accelerations of the COM. The main muscles responsible for accelerating the COM in the sagittal plane throughout balance recovery were the stance and step side Soleus, Gastrocnemius, Hamstrings and Vasti. The contributions of these muscles to the sagittal plane COM accelerations are depicted in This study found no age-related differences in the muscular control of recovery from forward loss of balance with a single step. These findings are consistent with studies that report a similar lack of difference in recovery mechanics between healthy young and healthy older adults , 27. MorThe stance and stepping leg Hamstrings and Gastrocnemius muscles simultaneously accelerated the COM forwards throughout each phase of balance recovery and thereby opposed the braking action of the stepping leg Vasti and Soleus following foot contact. Although the forward-directed COM accelerations generated by the bilateral Hamstrings and Gastrocnemius might be interpreted as counterproductive to balance recovery, they are necessary for controlling the stepping action , and higThe Hip Abductors accelerated the COM in the opposite direction from their anatomical location throughout balance recovery (i.e. the stepping leg Hip Abductors accelerated the COM towards the stance side and vice-versa). Our results are in agreement with those reported for gait  and staiThe vertical COM acceleration exceeded gravitational acceleration during the two periods of double support (i.e. from cable release to toe-off and following foot contact), and was below gravitational acceleration for the majority of the period of single leg stance from toe-off to foot contact. Gastrocnemius muscles of the stance and stepping limbs were primarily responsible for the provision of support of the COM from cable release to toe-off, with lesser contributions from the stance and stepping limb soleus. However following foot contact, the stepping limb Soleus became the dominant contributor to support with some lesser assistance from the Soleus muscle on the non-stepping (stance) leg. These findings are consistent with studies that demonstrate Soleus is the principal muscular source of support in the late stance phase of walking  and stanThe results of this study should be considered with the following limitations in mind. Firstly, muscle force estimates and the accelerations they induce are sensitive to errors in the musculoskeletal geometry of the model. Errors associated with Scaling, IK and RRA were however kept within recommended tolerances  see S1  Figs. SeThis study demonstrated that the muscular control of the whole body centre of mass during single step recovery from forward loss of balance is similar for healthy young and older adults. Complex and sometimes opposing interactions of lower limb muscle forces are were used by young and older adults to control of the COM trajectory. The bilateral Gastrocnemius and Soleus were primarily responsible for providing vertical support, whereas the bilateral Hamstrings and Gastrocnemius accelerated the COM forwards throughout balance recovery and the stepping leg Vasti and Soleus decelerated the COM following foot contact. The stance and stepping leg Hip Abductors exerted opposing actions on the medio-lateral acceleration of the COM throughout the task. Deficits in the neuromuscular control of these key muscles could adversely influence recovery and should therefore be considered in interventions to improve balance recovery performance.S1 Fig(TIFF)Click here for additional data file.S2 Fig(TIFF)Click here for additional data file.


Eye Movement Desensitization and Reprocessing (EMDR) is considered highly efficacious for the treatment of Post-traumatic Stress Disorder and has proved to be a valid treatment approach with a wide range of applications. However, EMDR’s mechanisms of action is not yet fully understood. This is an active area of clinical and neurophysiological research, and several different hypotheses have been proposed. This paper discusses a conjecture which focuses on the similarity between the delta waves recorded by electroencephalography during Slow Wave Sleep (SWS) and those registered upon typical EMDR bilateral stimulation  during recurrent distressing memories of an emotionally traumatic event. SWS appears to have a key role in memory consolidation and in the reorganization of distant functional networks, as well as Eye Movements seem to reduce traumatic episodic memory and favor the reconsolidation of new associated information. The SWS hypothesis may put forward an explanation of how EMDR works, and is discussed also in light of other theories and neurobiological findings. Eye Movement Desensitization and Reprocessing (EMDR) is a well-established psychological treatment for Post-traumatic Stress Disorder (PTSD) . FurtherThe neurobiological correlates of PTSD have been increasingly investigated by neuroimaging studies showing changes in cerebral blood flow , metabolSeveral neuroimaging investigations have demonstrated the effect of EMDR on cortical and sub-cortical regions involved in PTSD, depicting a clear association between disappearance of symptoms and the normalization of brain changes . Whole sA strong demand for the need of knowing how EMDR works has followed and here we shortly describe some of the hypotheses.The original theory of Adaptive Information Processing (AIP) proposed by The orienting and relaxation response (OR) hypothesis offers a theoretical framework which may support the explanation that bilateral stimulation produces relaxation. The OR is a natural attentional reflex that can occur with any novel environmental stimulus increasing readiness to respond to danger , 2004. TThe working memory account postulates that a central executive system is responsible for the integration of information stored in different slave subsystems, i.e., the visuospatial sketchpad processing visual and spatial information , 2013. Tvia lateral cerebellum, facilitating the integration of somatosensory, memory, cognitive, emotional, and synchronized hemispheric functions that are disrupted in PTSD.The thalamic binding model  posits tThese studies assigned an important role to EMs, which seem to be not only the underpinning mechanism of EMDR complementing traumatic memory extinction, but also the factor accounting for a faster response to treatment compared to other psychotherapies .Figure 1).It was recently highlighted  that durDespite these evidence, the role of EMs or, in general, bilateral stimulation in producing the neurobiological effects of EMDR is still unclear.Based on this neurobiological evidence it is tempting to hypothesize a role of rapid eye movement (REM) and slow wave sleep (SWS) in the mechanism of action of EMDR. This follows the REM hypothesis for the mechanism of action of EMDR proposed by Sleep has a bracing function, facilitates emotional processes and it is important for synaptic plasticity, emotional processing and memory formation. Long-lasting sleep disturbances are hallmark symptoms of PTSD that could interfere with a correct memory processing  also cauTo properly introduce our reasoning of a further role of SWS, it is essential to quote concepts and physiological bases well detailed in the works by Memory recordings occurring during the waking state are temporarily stored in short-term memory and transferred to the neocortex during sleep. The combined episodic and emotional memory is replayed in the memory-editing matrix of the hippocampal-amygdalar complex as well as in neocortex during the first stage of SWS. In this process, memory is reinforced and extinguished by potentiation and depotentiation, respectively, of synapses of neurons recruited to form the memory chain. The excitatory glutamatergic pre-synaptic neurons release an amount of glutamate proportional to the strength of the signal. This in turn binds to the transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor (AMPA), mediating the fast-synaptic transmission in central nervous system (CNS) networks, as the memory trace system. The opening of AMPA allows positively charged sodium into the post-synaptic neuron causing its depolarization. Stronger and repeated signals, as occurs during memory formation, cause more AMPA receptors to be transferred onto the surface of the post-synaptic neuron resulting in a larger sodium influx and in the opening of N-Methyl-D-aspartate (NMDA) glutamate receptors. This in turn favors the influx of positively charged calcium further strengthening the signal transmission. Synapses of the memory track are then potentiated, generating new proteins and gene expression resulting in the growth of new dendritic spines and new synaptic connections. The subsequent genetic expression and formation of permanent long-term memory occur mainly during REM sleep. In case of over-potentiation, low-frequency stimulation has a normalizing role depotentiating AMPA receptors, subsequently removed from the post-synaptic membrane, resulting in memory degradation. Following depotentiation, the receptors can no longer open and subsequently a substantial amount of them is removed from the post-synaptic membrane. The over-potentiated synapse is no longer able to convey the strong signals and henceforward is weakened. Potentiation and depotentiation  are carried out on synapses in the hippocampal-amygdalar complex and changes in their balance within the neural mechanisms of memory should be the molecular target for effective therapy.Physiological normal sleep presents cyclic alternated pattern of REM and non-REM (SWS). EEG recordings show synchronous delta wave activity  during SWS, and synchronous theta waves (4–8 Hertz) during REM sleep. SWS provides an optimal milieu for transferring edited memories from the hippocampus to the neocortex, as well as stimulating the integration of these into neocortical neuronal networks.When new information is filtered by the sensorimotor cortex and simultaneously transferred to hippocampal networks, only the strong and repeated signals induce specific replication when the memory is replayed during SWS in the following night(s). During such phase, the cortical networks in which encoding originally took place produce slow oscillations (<1 Hz) that reactivate the hippocampal memory. This memory replay originates an input directed toward the same cortical synapses in synchronicity with high frequency activity originating in the thalamus. The combined action of these two signals, as described above, potentiates the synapses supporting the consolidation of long-term memory. In this phase, it is the combination and the alternation of slow and rapid waves that favors the transfer from hippocampus back to neocortex of the fresh memory encoded during the waking state. During REM sleep, also due to the absence of slow waves, there is a decrease of such activity suggesting a more intense memory consolidation at neocortical level. In this phase, new associations of emotional events mediated by limbic structures take place.To summarize, during wakefulness autobiographical, emotional and potentially traumatic events are conveyed and represented into the sensorimotor cortex. From such perceptual representation system information are transferred to subcortical limbic structures as hippocampus (episodic) and amygdala (associated affect) where an initial formation and potentiation of memory occurs. During SWS global synaptic weakening along with slow consolidation of information take place. Relevant memory circuits are reactivated and long-term potentiation is induced. During REM sleep, a further potentiation of the reactivated connections in neocortical memory network occurs.The recording of the episodic aspect of memory in the hippocampus results in a normal potentiation of hippocampal synapses. Traumatic events may cause over-potentiation of amygdalar synapses and all post-synaptic AMPA binding sites will be occupied by glutamate. In such circumstances, the transfer to neocortex mainly through anterior cingulate cortex cannot occur since memories need the same synchronized signal intensity at emotional and cognitive level for the correct processing. Fragmented non-processed episodic and traumatic memories are trapped in hippocampus or amygdala without the contextual integration needed to encode them in long-term memory in association neocortex and persist sometimes for life.Bilateral stimulation typical of EMDR causes immediate slowing of the depolarization rate of neurons from the dominant waking state frequency of around 7 Hz to about 1.5 Hz , 2012. TIn animals, low-frequency stimulation (5 Hertz) has shown to cause a depotentiation of amygdalar AMPA receptors involved in the retention of traumatic memory  and 900 During EMDR sessions therapists performs bilateral stimulation at about 1–2 cycles/s (1–2 Hz) eliciting slow waves similar to the ones recorded during SWS. This suggests that memories aroused during therapy are continuously reactivated, replayed and encoded into existing memory networks.A memory trace is weakened when held in attention and in such condition it is easily depotentiated. During an EMDR session the focus of the attention is on the fragmented traumatic memory and its synaptic traces in the amygdalar-hippocampal complex. EMDR decreases affective aspects of traumatic memories in the amygdala and leaves intact the associated cognitive aspects in the hippocampus. The affective and cognitive aspects of the memory are then merged in anterior cingulate cortex and sent to higher brain centers, where an encoding process within the association areas provide a clear distinction between the past and the present. The pathological memory trace is no longer confined by its over-potentiation to the limbic memory areas.D in EMDR results from Depotentiation of fear memory synapses  and fast  waves are elicited by the alternation of bilateral stimulation and installation of positive cognition. This would mimic the previously described condition occurring during sleep in which memories are transferred from subcortical structures and encoded into neocortex.If confirmed by future studies, the molecular and neurobiological mechanisms underlying our model could merge the effects explained by the OR theory, by the working memory account and by the hypothesis of In fact, we posit that bilateral stimulation mimics the low-frequency stimulation typical of SWS, inducing a depotentiation of the AMPA receptors of amygdalar synapses, which in turn lead to a weakening of the traumatic memory. This reduction of the over-potentiation of amygdalar synapses makes traumatic memory more accessible, and facilitates the connection between emotional memory and episodic memory, thus promoting a shift of memory to associative and neocortical areas. This is also consonant with the findings of These effects are the same described in clinical setting by the OR and the working memory models.In assonance with OR hypothesis, delta waves elicited by bilateral stimulation facilitate the access to the dysfunctionally stored traumatic memory during wake consciousness. Thanks also to the absence of danger characterized by the therapeutic context, favoring relaxation, the extinction of traumatic memory and its reprocessing by associative and cortical areas could take place. The relaxation associated with the fading of the emotional memory is likely due to the reduction of the over-potentiation of amygdalar synapses occurring in real time during EMDR therapy.Our speculation is also in agreement with the working memory account, since the effects of SWS-like neurophysiological conditions reproduced by EMDR bilateral stimulation, reducing in real time the over-potentiation of the amygdala and the relative hyperarousal, impact during therapy on vividness and on emotionality of traumatic memories, contributing to the sense of distancing from the original event described by patients.Both models are based on the weakening of a memory when recalled and held in attention, but with different underlying explanations. In the working memory account, the imagery deflation effect is explained by the dual tasking  that affect the limited-capacity of the working memory. In our SWS model, memory degradation is determined by the depotentiation of AMPA receptors by EMDR bilateral stimulations miming SWS low-frequency stimulations occurring during sleep.Lastly, our hypothesis follows the footsteps drawn by Hippocampal-amygdala complex memories are transferred to neocortex, replayed, and consolidated into semantic associative memory networks. Information is then integrated to create meaning and learning from the event. The transfer might occur during slow-wave-sleep (1–3 Hz) and definitive memory consolidation during REM sleep (about 4–6 Hz). The traumatic episodic memory is weakened and then removed from hippocampus.In conclusion, this perspective article proposes that bilateral stimulation during EMDR might reproduce the neurophysiological conditions favorable for memory integration in associative neocortex, weakening the perception of the traumatic memory, reducing its vividness and inducing a sense of relaxation and safety.We are not claiming that we have solid evidence for all of the links and interpretations in the train of logic presented here.[…] Our goal is to demonstrate that there is a reasonable explanation of how EMDR works, which is consonant with modern neurobiology and cognitive neuroscience[…].”Quoting Our aim is also to encourage further research in investigating the mechanisms of action of already proven effective psychotherapies such as EMDR, with experimental studies that might combine theoretical assumptions, molecular biology, neurophysiology, neuropsychology, brain imaging and clinical evidences in patients’ cohorts.MP was responsible for the conception of the work, that was integrated and critically revised by SC, BA, and RL-R. All authors have approved the final manuscript.All authors have been invited as speakers in national and international EMDR conferences.


Image distortions can attract attention away from the natural scene saliency  to obtain simulated barrel-lens-aberration distortion, manipulated color contrast, motion-blurred distortion, and distorted contrast/intensity versions (right panels). We then fed these images to the Saliency model  and compared the performance of the visual search on original and distorted images. The model does not need a training phase or parameter setting and generates the simulated saccadic path of human observer instantly. As already noticeable in Figure As a demonstration of the proposed opinion, we simulated an attention-demanding detection task while driving in a purely computational environment. We tested the model of bottom-up visual attention for the effects of distortions on a traffic sign search task, using manipulated static images containing different traffic signs in cluttered scenes. If a stimulus like traffic sign is sufficiently salient, it will pop out of the visual scene. The speed of this saliency-based form of attention is on the order of 25–50 ms per item .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer MZ and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.


Bearing fault diagnosis is imperative for the maintenance, reliability, and durability of rotary machines. It can reduce economical losses by eliminating unexpected downtime in industry due to failure of rotary machines. Though widely investigated in the past couple of decades, continued advancement is still desirable to improve upon existing fault diagnosis techniques. Vibration acceleration signals collected from machine bearings exhibit nonstationary behavior due to variable working conditions and multiple fault severities. In the current work, a two-layered bearing fault diagnosis scheme is proposed for the identification of fault pattern and crack size for a given fault type. A hybrid feature pool is used in combination with sparse stacked autoencoder (SAE)-based deep neural networks (DNNs) to perform effective diagnosis of bearing faults of multiple severities. The hybrid feature pool can extract more discriminating information from the raw vibration signals, to overcome the nonstationary behavior of the signals caused by multiple crack sizes. More discriminating information helps the subsequent classifier to effectively classify data into the respective classes. The results indicate that the proposed scheme provides satisfactory performance in diagnosing bearing defects of multiple severities. Moreover, the results also demonstrate that the proposed model outperforms other state-of-the-art algorithms, i.e., support vector machines (SVMs) and backpropagation neural networks (BPNNs). In the case of rotating machines, bearings are vital and common parts of the machine systems that are used in a variety of industries . BecauseIn recent years, deep learning has made a remarkable impact on pattern recognition, image processing, and natural language processing. Deep learning mimics the learning process of the human brain in artificial networks and has displayed superior ability in capturing useful information from the input data via non-linear transformations. In contrast to conventional machine learning algorithms, deep networks can extract highly representative features via multiple layered architectures, simplifying the learning task. In addition, deep networks keep only the most representative information in each layer and discard the rest, thereby reducing the dimensionality. Hence, due to the simplified learning capability and built-in feature reduction mechanisms, deep networks can be used for fault diagnosis of complex rotary machine bearings.Despite the existence of several state-of-the-art bearing fault diagnosis schemes, there is still room for improvement in machine fault diagnosis; for instance, dealing with the bearing signals that exhibit nonstationary behavior due to variable working conditions and multiple fault severities. Fault pattern identification and crack size identification are two key aspects of bearing fault diagnosis. Fault pattern identification is essential as it can allow the localization of faults on a given component, whereas determining the fault severity is vital because it can highlight the urgency of repairing or replacing a damaged component. A fault diagnosis scheme that can perform both fault pattern identification and fault severity classification can be very challenging; it requires better feature representation and a strong classifier. Existing fault diagnosis schemes are vulnerable to fault misidentification due to the presence of fluctuations and random amplitudes in the vibration signals caused by multiple crack sizes.To solve this issue, we present a two-layered fault diagnosis scheme that uses a set of hybrid features and a sparse stacked autoencoder (SSAE)-based deep neural network (DNN). The fluctuations and random amplitudes caused by multiple crack sizes cannot be overcome by analyzing the signal in just the time or frequency domain. However, a hybrid feature pool that is constructed after analyzing the vibration signal in different domains can provide sufficient information to effectively segregate bearings of different health conditions. Sparse stacked autoencoders (SSAEs) are deep neural networks (DNNs) that can extract intrinsic information from the input hybrid feature pool effectively, due to the highly nonlinear activation function used in the hidden layers. The first layer of the proposed scheme is for fault pattern identification, whereas the second layer identifies the crack size in each fault type.The rest of the paper is organized as follows: The workflow of the proposed scheme is presented in The main idea of the work is to utilize a hybrid feature pool in combination with an SSAE-based DNN to extract high-level representative features, which would enhance the performance of the fault diagnosis model in the presence of multiple crack sizes. The hybrid feature pool provides more discriminating information about the raw vibrational signals and can overcome the nonstationary behavior of the input signal to boost the performance of the subsequent SSAE-based DNN. To create the hybrid feature pool, various feature extraction paradigms, including envelope power spectrum analysis, time domain analysis, and wavelet packet energy features, are used together.RMS), kurtosis value (KV), square root of the magnitude (SRM), peak-to-peak value (PPV), standard deviation (SD), skewness value (SV), margin factor (MF), crest factor (CF), impulse factor (IF), kurtosis factor (KF), and mean value (MV). The given representative features are listed in The representative set of statistical time domain features used in  was adopA typical bearing found in a motor has four components: the outer raceway (OR), inner raceway (IR), cage (C), and the rolling elements (RE). At a constant speed, when a bearing has a defect on any of these components, periodic vibrations are generated. There are four fundamental defect frequencies: the ball spin frequency  . It can The wavelet packet transform (WPT) is a variation of the basic wavelet transform (WT) that decomposes the input signal into h and g are the low-pass and high-pass filters associated with the mother wavelet, respectively. These are predefined scaling factors. In the WPT, the scale parameter (level) is represented by j, and the frequency parameters (nodes) are represented by The WPT coefficients can be formulated asExisting methods based on the WPT for bearing fault diagnosis consider the entropy, standard variation, and energy as input features to the subsequent classifier. Among these, using the wavelet packet energy is an intuitive approach to differentiating the fault types. The WPT nodes contain an abundance of information about the fault types and energy fluctuations in a specific node and can be useful in specifying the fault type.In the current work, signals are decomposed up to ribed in , which rIn the equation above, The maximum value of the vector is selected for each input signal and included in the hybrid feature pool. The extracted wavelet energy features can be seen in A simple autoencoder is basically a variation of an artificial neural network (ANN) with a minimum of three layers that uses an unsupervised learning process. The structure of a basic autoencoder is presented in The first layer of the autoencoder is the input layer, which receives the input data. The intermediate layer tends to extract high-level representative features  from the input data. The latent codes are, in essence, the result of principal component analysis (PCA) of the inputs and reduce the representation of the original data. The dimensionality of the latent codes depends on the number of nodes used in the hidden layer. The last layer decodes the latent codes and tries to reconstruct the original input. In short, an autoencoder performs two key tasks: to encode the input data into latent codes and then reconstruct the data from the latent codes. The resulting latent codes have lower dimensionality than the input data. In this regard, an autoencoder contributes to dimensionality reduction. The encoding The simplest form of an autoencoder has one hidden layer. The encoder stage receives input data fication . The modTo demonstrate the efficacy of the proposed model, seeded fault data provided by Case Western Reserve University was used. As illustrated in Using an electro-discharge machine, faults with diameters of 0.007, 0.014, and 0.021 inches were seeded on the inner raceway (IR), outer raceway (OR), and rolling elements (RE) at the drive end bearings. Variable length vibration acceleration signals were collected via an accelerometer attached to the housing of the drive end bearing at 12 o’clock with a sampling data rate of 12,000 Hz. The motor was subject to four loads ranging from 0 to 3 horsepower (hp), which resulted in four motor speeds, approximately from 1722 to 1797 revolutions per minute (r/min).In this study, the dataset comprises vibration acceleration signals for normal bearings and bearings with three types of faults, i.e., faults on the inner raceway, outer raceway, and rolling element. For each fault condition, the dataset consists of signals recorded for bearings with three levels of fault severities  at four different shaft loads. For normal bearings, there are four signals in the dataset—one for each shaft load. The signals are subjected to a segmentation process using a fixed sized window of 12,000 data points. The segmentation process splits all the fault signals into 10 samples each, but three of the four normal signals yield 20 samples each, while the fourth normal signal yields only 10 samples. The length of each sample for both normal and faulty bearings is 12,000 data points. Thus, the seeded fault dataset used for the experiments contains a total of 610 samples . After segmentation, a hybrid feature vector is constructed for each sample in the dataset. These feature vectors are then divided into training and test sets. The training set contains feature vectors for 310 samples , while the test set consists of feature vectors for 300 samples . The details of the bearing dataset with seeded faults are given in A bearing dataset with seeded faults was provided by Case Western Reserve University  and usedThe SSAE-based DNN, because of its hierarchical structure and by using nonlinear transformation in the hidden layers, could extract discriminating information from the hybrid feature pool, enhancing the overall performance of the proposed model. This observation is validated by The fault pattern recognition layer is followed by the crack size identification layer. The results of the subsequent layer mainly depend on the results of the first layer; if the performance of the first layer is poor, the results of the subsequent layer will also be poor. From the results of the pattern recognition layer, it is evident that the proposed method could classify most of the input instances, which ultimately boosted the performance of the proposed scheme. This observation is validated by the results of the crack size identification layer. To further validate the reliability of the proposed method, a comparison is made with an existing bearing fault diagnosis scheme , in whicIn this paper, a two-layered bearing fault diagnosis scheme was proposed. The first layer is for fault pattern identification in rotary machine bearings, while the subsequent layer is used for crack size identification of a given fault. A hybrid features pool comprising time domain statistical features, envelope power spectrum features, and wavelet energy features is used in combination with sparse stacked autoencoder (SSAE)-based deep neural networks (DNNs) for the diagnosis of different bearing defects with various levels of severity. The hybrid feature pool was formed to overcome the nonstationary and nonlinear behavior of the vibration acceleration signals. A bearing dataset containing four health conditions and three fault severities was used to validate the proposed model. It is observed that the SSAE-based DNN is able to extract effective representative features from the hybrid feature pool, resulting in a superior diagnostic performance of the proposed model for both fault pattern as well as for crack size identification. Moreover, the proposed model was compared with three state-of-the-art fault diagnosis algorithms . The results demonstrated that the proposed scheme is more effective compared with the other methods regardless of the nonlinearity contained in the vibration signals due to multiple fault severities. However, in the case of roller fault identification, the performance of the proposed method slightly deteriorated, which underscores the need for more sophisticated signal processing algorithms as future work that could eventually result in superior diagnostic performance. It can be concluded that the proposed method provides satisfactory bearing fault diagnosis results and can be used for fault diagnosis of bearings containing various fault severities.


With longer life expectancy, dementia based on the age-related Alzheimers’ disease (AD) has turned into one of the most prevalent disorders of older age, representing a serious medical and socio-economic issue. There has been growing interest in early diagnosis of this disease, particularly regarding the initiation of new treatment strategies ahead of the onset of irreversible neuronal damage. It is accepted that the pathologic changes underlying AD appear in the brain years to decades before the symptomatic stages. Consequently, clinical measures of cognitive impairment, as used for definition of dementia, will not allow early diagnosis of AD-pathology in the mild or asymptomatic stages. Thus, a need for complementary sensitive biomarkers is apparent. Brain imaging markers are among the most promising candidates for this diagnostic challenge. Particularly, [18F]FDG PET as a marker of regional neuronal function has been demonstrated to represent a most sensitive and specific method for early identification of AD-pathology and thus for prediction of dementia of the Alzheimer type (DAT), even in the mild and asymptomatic stages. Currently, systematic data of comparable quality are hardly available for any other imaging procedure. The purpose of this article is to describe the typical findings of [18F]FDG PET in different stages of AD and to demonstrate its value for early and reliable diagnosis of Alzheimer's disease, particularly ahead of the stage of dementia of the Alzheimer’s type.


The prefrontal cortex is the superlative structure of brain that needs the longest developmental and maturational duration that highlights the region of attention deficit hyperactivity disorder (ADHD) in neuroimaging studies. Prefrontal cortex functions generate enormously complex and its abundant feedback neurocircuitries with subcortical structures such as striatum and thalamus established through dual neural fibers. These microneurocircuitries are called corticostriatothalamocortical (CSTC) circuits. The CSTC circuits paly an essential role in flexible behaviors. The impaired circuits increase the risk of behavioral and psychological symptoms. ADHD is an especial developmental stage of paediatric disease. It has been reported that the CSTC circuits dysfunctions in ADHD are related to homologous symptoms. This study aimed to review the symptoms of ADHD and discuss the recent advances on the effects of the disease as well as the new progress of treatments with each circuit. Currently, it has been able to establish the corresponding relationship between brain areas and mental symptoms or functional abnormalities and to locate the symptoms in the dimension of the symptoms by neuroimaging techniques. As the most advanced part of brain development, the prefrontal lobe has attracted a large number of related studies including the executive function located in the dorsolateral prefrontal cortex (DLPFC) ; emotionThe prefrontal lobes are not functional separately. They combine with the striatum, thalamus, and cortex structure through the contact fibers to establish the loop structure, playing the overall function. Neurons in the cerebral cortex are connected with many other neurons to form the cortical neural circuits which play the priming effect of brain function. Particularly, the prefrontal cortex has an important impact on mental behavior. This neural network can transform a simple signal into a complex signal, eventually regulating the function and behavior of the brain. The psychiatrist can use a drug or treatment that regulates the function of a neurotransmitter on a particular neural circuit to affect the patient's clinical symptoms, therefore having a better understanding of the pathophysiology of the disease. Meanwhile, accumulating evidence has shown the abnormalities of the corticostriatothalamocortical (CSTC) circuits in ADHD patients –8, whichThe CSTC circuit mediates the transmission of information to “downstream” and leaves the cortex; meanwhile the cortex gets a feedback and determines how to process the information. Neural information is projected from the prefrontal cortex to the striatum and then from the thalamus to the striatum. The thalamus produces local interactions only with specific regions of the cortex. The neural circuits that pass through the striatum can be synapse-linked to the part of the striatum that leaves the striatum to the thalamus, returning to the initial region of prefrontal cortex finally; sometimes, it can return to the original pyramidal cells . The neuWith analysis of the representative nerve circuit in CSTC, we discover that they all initiate and end in cortical pyramidal cells. Since the pyramidal cell is involved in the neural circuitry of the cortical circuit, the neurotransmitters in these pyramidal cells will be affected when receiving some medicines or physical therapies and directly affect the function of these neurons, subsequently providing significant diagnostic and therapeutic effects . TherefoRecently, a total of five circuits in CSTC with vital research value have been summarized . In thisThe DLPFCSTC circuit is involved in regulating sustained attention and problem-solving. It is also known as sustained attention or executive function circuit. Neural impulses in DLPFCSTC circuit originate in the DLPFC and project into the superior caudate nucleus in the striatum, then spread to the thalamus, and finally return to the DLPFC shown in 1H-magnetic resonance spectroscopy (1H-MRS) demonstrates that N-acetylaspartate/creatine (NAA/Cr) value in right DLPFC is positively correlated with learning disabilities of ADHD, while NAA/Cr value in left DLPFC is negatively correlated with the morning behavior. It is indicated that the DLPFC neurometabolities between cerebral hemispheres of ADHD are correlated with different ADHD symptoms and each hemisphere controls its special executive functions [In the study of the circuit, unctions . ADHD paunctions .The VLPFCSTC circuit, also known as emotional circuit, participates in the emotional processing , 19. The1H-MRS confirms the severity of ADHD symptom is negatively correlated with myo-inositol/creatine (ML/Cr) in the right VMPFC and positively correlated with choline/creatine (Cho/Cr) value in the left subcortical striatothalamic area and is negatively correlated with glutamate-glutamine-GABA/creatine (Glx/Cr) value in the left putamen. These results indicate that there is widespread abnormality on the circuit; the significantly decreasing metabolic rate of nerve cells leads to a tendency of serious symptoms [Individuals with congenital malformation in the VLPFC perform the specific ADHD-like symptoms: egocentricity, lack of empathy, lack of respect for authority, impaired moral judgment, poor frustration tolerance, and many apathy symptoms . In the symptoms , 24. Thesymptoms .The ACCSTC circuit, also known as selective attention circuit, is responsible for the emotional regulation and selective attention. The signals of the circuit generate from the ACC and project onto the inferior striatum, then reach the thalamus, and finally return to the ACC shown in Stroop test normally activates the ACC but cannot activate the region in ADHD patients accordingly, and the right ACC thickness is negatively related to the diversity of symptoms . This ciThe MC plays a critical role in regulating motor activity. The MC is classified into primary motor cortex (M1) and secondary motor areas including the premotor cortex (PMC) and supplementary motor area (SMA) . The MCSCommon symptoms of activity in ADHD include fidgeting, leaving one's seat, running/climbing everywhere, and constantly playing without purpose and troublemaking. fMRI has shown that the extent of neural activation in ADHD decreases in the left M1, bilateral PMC, and SMA . FurtherThe OFCSTC circuit, which is called impulsive/compulsive-related circuit, controls impulsive behavior . The nerEither impulsive behavior or impulsive choice is related to the transfer function of dopamine and adrenaline neurotransmitter in the OFC regions which are the therapeutic target of stimulant. Impulsive symptoms of ADHD including hyperlogia, interrupting without thinking, blurting out, and unwilling to wait in sequence are associated with the circuit. Structural covariance network (SCN) reveals that the gray matter volume significantly loses in the right lateral OFC of ADHD . Further1H-MRS treatment for stimulant treated in the DLPFCSTC circuit. In contrast, in treatment-naïve ADHD patients, the lower corpus striatum Glx was significantly associated with more severe symptoms of inattention, and the differences in Glx levels were not due to the use of stimulant medication [Some drugs (methylphenidate and atomoxetine), which aim to increase the dopamine (DA) and noradrenaline (NE) receptor activation levels, have been widely used for ADHD. In the study of PT on the DLPFCSTC and VLPFCSTC circuits, compared with treatment-naïve ADHD, no differences were shown in dication . NIRS indication . Methylpdication , even stdication .1H-MRS showed that the ACC glutamate-glutamine-GABA/myo-inositol (Glx/ML) in ADHD patients who were treated with methylphenidate was significantly lower than that of patients without PT. The central stimulants make ADHD patients able to activate the ACC and thereby interfere with the emotional regulation and selective attention [In the study of medicines for the ACCSTC circuit, ttention .Only few reports have shown that methylphenidate and atomoxetine can activate the SMA , 47, sugStimulant may provoke abuse that impacts on the OFCSTC circuit. Impulsive control is associated with stimulant abuse, thus contributing to ADHD treatment. Atomoxetine directly inhibits NE concentration in the OFCSTC circuit, therefore reducing dopamine function in the same area, and nucleus accumbens has too little NE neuron to increase NE and DA in that region; that is the main reason why atomoxetine differs from methylphenidate for susceptibility of stimulant abuse .It has been reported that NPT can also improve and normalize cortical and subcortical function of ADHD . TranscrIt has not been reported that tDCS is as a therapy in ADHD, but the effect of tDCS has been reported on the other participants. ATDCS in VMPFC and pre-SMA in MC improve participants' inhibitory control and accelerated the stopping efficiency and stopping speed . Also hiTDCS treatment for subcortical structures is limited. Deep brain stimulation (DBS) has been applied for replacing the stereoscopic neurosurgery for the treatment of neural damage. DBS creates high-frequency electrical simulation that is similar to the damage effect of reversible functional nerve block. Clinical effects are obtained by activating nerve axon fibers networks across CSTC circuits; targets could be reachable to the striatum and thalamus . ADHD, O


Over the last two decades, important advances have been made in explaining some pathophysiological aspects of heart failure with preserved ejection fraction (HFpEF) with repercussions for the successful clinical management of the syndrome. Despite these gains, our knowledge for the natural history of clinical progression from the pre-clinical diastolic dysfunction (PDD) until the final clinical stages is significantly limited. The subclinical progression of PDD to the clinical phenotype of HFpEF and the further clinical progression to some more complex clinical models with multi-organ involvement, similar to heart failure with reduced ejection fraction (HFrEF), continue to be poorly understood. Prospective studies are needed to elucidate the natural history of clinical progression in patients with HFpEF and to identify the exact left ventricular remodeling mechanism that underlies this progression. The clinical phenotype of patients with reduced ejection fraction (HFrEF) is extensively studied and understood, but the clinical phenotype and natural history of patients with preserved ejection fraction (HFpEF) remain poorly defined. There is incomplete knowledge and understanding of HFpEF pathophysiology. The relevant clinical trials are suboptimal in their design, and the treatment to a great extent is empiric . The numDuring the last two decades emerged a new nomenclature of the clinical congestive HF syndrome that is based on the ejection fraction. This classification categorizes the patients with HF into those with HFrEF EF < 50%) and those with HFpEF (EF > 50%). In the community, the prevalence of both phenotypes of HF, HFpEF and HFrEF, is equal . HFrEF i0% and thTo a number of clinicians, in view of the fact that the majority of the patients with HFrEF display to some extent diastolic dysfunction, the clinical distinction between the two syndromes is considered unnecessary . AccordiIn exploring the fundamental molecular mechanisms of HFpEF, it is important to define the exact molecular processes responsible for the slowing of myocardial relaxation and for the increase of elastic stiffness in both the myocardium and the arterial wall of the peripheral arteries. In hypertension, the increased left ventricular afterload is a stimulus for ventricular structural remodeling and stiffening. These structural changes are leading to higher systolic left ventricular wall stress and slowing of ventricular relaxation . The norIt is important to differentiate the name ‘diastolic dysfunction’ from the term of ‘diastolic heart failure’ syndrome. The age-dependent diastolic dysfunction does not necessarily indicate people with an increased risk of diastolic HF . The preThe rising levels of biomarkers, brain natriuretic peptide (BNP) and the N-terminal pro-B-type natriuretic peptide (NT-proBNP), reinforce the clinical diagnosis of HFpEF. Their high negative predictive value excludes the diagnosis in some patients with suspected HF . HoweverIn general, very few original papers are addressed to the natural history of PDD and to the clinical progression from PDD to overt symptomatic HF . FurtherSome publications provided useful epidemiological facts to the preclinical prevalence of diastolic dysfunction in the general population ,13. The In OCHFS (Olmsted County Heart Function Study), for a period of four years, changes were recorded in diastolic function in randomly-selected individuals, 45 years or older . The triIn a cohort of PDD subjects, progression to clinical HF according to Framingham criteria was expected to be low with a two-year cumulative probability of 1.9% . MoreoveThe development of left ventricular diastolic dysfunction is linked to left ventricular hypertrophy (LVH). Yet, different studies in animals and humans indicate that the diastolic dysfunction starts before the appearance of LVH. Dupont et al.  demonstrIn a population-based study, 388 patients, mean age 67 ± years, with a prevalence of renal insufficiency (glomerular filtration rate <60 mL/min) of 34% and with a Grade 2–4 diastolic dysfunction in echocardiography, were followed-up over three years . The objDiabetic cardiomyopathy is linked to the presence of myocardial hypertrophy and stiffness that induce diastolic dysfunction. In diabetic patients, poor glycemic control is related to an increased risk of HF, but it remains unclear whether treating hyperglycemia will reduce progression or reverse the presence of HFpEF syndrome . From etRen et al.  evaluateIn the I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction Study) study, the mode of death in patients with HFpEF and the role of irbesartan to alter this possibility were examined . It was The present therapy of HFpEF has not been effective in reducing morbidity and mortality. Angiotensin-converting enzyme inhibitors (ACEI), angiotensin-II receptor antagonists (ARA), diuretics and beta blockers were proven ineffective to decrease the composite product of hospital readmission and death in patients with HFpEF ,26,27,28The HOPE  study revealed that in patients having high cardiovascular risk, particularly patients with borderline hypertension, the risk of developing HF was reduced after therapy with ACEIs . In the A new HFpEF paradigm was presented recently with the emphasis moved from the left ventricular afterload increase to coronary microvascular inflammation. Paulus and Tschope , suggestThe previously-recorded studies were limited in focus and clinical follow-up of patients with PDD and HFpEF. The subclinical progression of the PDD to the clinical entity of HFpEF and the further clinical advance to more complex clinical models of HF, analogous to HFrEF, continue to be poorly understood. Few large animal models that imitate the human HFpEF syndrome are described. Conceicao et al. in a recent article are suggesting that “although most of the heart failure animal models currently available represent heart failure with reduced ejection fraction, several HFpEF animal models have been proposed. However, few of these fulfill all the features present in human disease” . The relHFrEF syndrome has the characteristics of an entity with a progressive clinical deterioration with a relentless course toward end-stage myocardial failure with periods of clinical stabilization and periods of clinical instability . At presThus, in answer to the above questions, the availability of a more suitable model paradigm of clinical HFpEF progression is required. Furthermore, well-designed future longitudinal clinical trials are needed in order to validate specific subgroups of HFpEF phenotypes from the PDD phase up to the terminal stages. This approach will address better the complexity of HFpEF syndrome and will speed the development of novel diagnostic and therapeutic procedures.There is limited information of the natural history and clinical progression of PDD and HFpEF syndromes. The HFpEF syndrome is a term that involves many distinct mechanisms of disease. Thus, diastolic function abnormalities may be driven more by calcium handling in one patient and tissue fibrosis in another and ventricular-aortic coupling in another. This has further complicated our ability to define the natural history and clinical progression of this heart failure syndrome. The insufficient clinical and epidemiological data prohibit the comparison of their natural history with this of HFrEF syndrome. It is also speculated that the HFpEF patients have a different LV remodeling mechanism than that of HFrEF patients. As a consequence of that, they have developed different clinical progression rates. Prospective studies are needed to describe the progressive nature of PDD and HFpEF syndromes. We need to be better at disease phenotyping in HFpEF in order to make progress in this area. LVEF alone will not be adequate.


Glyptostrobus pensilis and compared with those of other Cupressaceae sensu lato and other conifers. Some Cupressaceae apparently possess a proliferation of axillary structures in their cone scales. In our interpretation, in Glyptostrobus each bract of both typical and atypical seed cones bears two descending accessory shoots, interpreted here as seed scales . The primary seed scale is fertile and forms the ovules, the second is sterile and forms characteristic tooth-like structures. The bract and the two axillary seed scales are each supplied with a single distinct vascular bundle that enters the cone axis as a separate strand; this vasculature also characterises the descending accessory short shoots in the vegetative parts of the crown. In wild-type seed cones, the fertile seed scale is reduced to its ovules, and the ovules are always axillary. In contrast, the ovules of some of the teratological seed cones examined were located at the centre of the cone scale. An additional tissue found on the upper surface of the sterile lower seed scale is here interpreted as the axis of the fertile seed scale. Thus, the central position of the ovules can be explained by recaulescent fusion of the upper fertile and lower sterile seed scales. In several teratological cone scales, the ovules were enveloped by an additional sterile tissue that is uniseriate and represents an epidermal outgrowth of the fertile seed scale. Close to the ovules, the epidermis was detached from lower tissue and surrounded the ovule completely, except at the micropyle. These teratological features are potentially significant in understanding seed-cone homologies among extant conifers.Both wild-type and teratological seed cones are described in the monoecious conifer  Current understanding of coniferous seed-cone structure, especially the cone scale, is based partly on comparisons with extinct species known only from fossils and partly on studies of living Pinaceae extended by inference to other coniferous groups . ConiferIn most conifers, this bract/scale complex is so tightly integrated and modified that only one integrated organ is readily discernible, termed the cone scale. Among extant conifers, the two distinct components of the cone scale are visible only in Pinaceae and Sciadopityaceae . A factoTaxodium and Glyptostrobus; their number is not strictly correlated with the number of abaxial teeth and their homologies have been disputed . Glyptostrobus belongs to subfamily Taxodioideae of the conifer family Cupressaceae sensu lato, in which a range of spontaneous mutations have been already demonstrated  K. Koch  is a monoecious tree species in which both seed and pollen cones are produced terminally on short lateral branchlets. A total of two cone types were investigated for this paper: (1) wild-type seed cones at the stage of pollination and at maturity , (2) teratological seed cones showing a range of proliferations . All cones were collected by one of the authors (VD) from trees grown as pot plants. Wild-type seed cones were collected from a tree cultivated in the Botanic Garden of the Ruhr-University, Bochum (Germany). All proliferated seed cones were collected from a tree cultivated in the Botanic Garden of the Eberhard Karls University Tübingen (Germany).The rare deciduous conifer Freshly collected material was photographed, then fixed in FAA  before being stored in 70% ethanol. Cone anatomy was studied from serial sections using the classical paraffin technique and subsequent astra blue/safranin staining . MacrophSeed cones are developed terminally on short lateral shoots and subtended by closely spaced scale-like leaves. At pollination stage, the cone is typically shaped like a spiked ball or mace  with a mMature seed cones are pyriform to obovate in shape . The apeThe teratological seed cones examined here showed two distinctly different types of anomaly: strongly swollen ovuliferous scales , and apiIn the majority, the cone scales had anomalous strongly swollen teeth that formed a large ventral bulge, causing those cone scales to spread apart from the others. As in wild-type cones, the ovules remained in their original position, deeply hidden within the cones and not dislocated by the strongly swollen abaxial tissue of the anomalous teeth. Thus, as in wild-type seed cones, in these cones the ovules are not visible externally .G. pensilis; no transitional leaf types were observed in this region  by an additional envelope consisting of a single layer of non-lignified cells  and 5A, G. pensilis confirm that the ovules are axillary, though they later fuse with the abaxial teeth and the bract. This feature is extremely diverse in Cupressaceae. Ovules are also axillary in the other two genera of the subfamily Taxodioideae (Cryptomeria and Taxodium), but not in the monogeneric subfamilies Athrotaxoideae (Athrotaxis) and Cunninghamioideae (Cunninghamia), in which the ovules develop close to the cone axis on tongue-like structures that can be understood as representing the tips of the ovuliferous scale. Assuming that the bract is a modified leaf that bears the ovuliferous scale in its axil, as widely interpreted, the ovuliferous scale of Athrotaxis and Cunninghamia has shifted from its original axillary position by recaulescence; specifically, by adnation (fusion) of the ovuliferous scale to the subtending bract, resulting in its displacement onto the bract  and Taiwanioideae (Taiwania), differ strongly in this respect from other taxodiaceous Cupressaceae in lacking visible parts of the ovuliferous scale and in ovule insertion close to the cone axis, always in basal regions of the upper surface of the cone scale, but never axillary. Thus, for Sequoioideae and Taiwanioideae, the ovuliferous scale is reduced to its ovules; any further visible parts that could be interpreted as vegetative outgrowths of the ovuliferous scale are invisible (Our observations of wild-type seed cones of he bract . The othnvisible .Glyptostrobus), the teeth start to develop relatively late, significantly after ovule formation, so that they are shorter than the ovules at pollination , where they replace the abscised short shoots , each axillary row of ovules can be understood as an axillary ovuliferous shoot evolutionarily reduced to its ovules. In taxodiaceous Cupressaceae, the presence of descending accessory shoots is strongly supported by the increased number of ovules compared with other conifers. In particular, Sequoioideae show very high ovule number, arranged in one (Metasequoia), two (Sequoia) or three rows (Sequoiadendron) inserted in the axil of the bract , each bract bears two descending accessory seed scales, one fertile and one sterile; the primary ovule-bearing seed scale is reduced to its ovules, while the second lower tooth-bearing seed scale is sterile . Descendt shoots . Althoughe bract . In thesGlyptostrobus seed cones investigated here provides further evidence for the presence of descending accessory shoots. Three distinct vascular bundle strands are present in a typical fertile bract/scale complex  proliferation of axillary structures in their cone scales. The extensive fossil history of cal time . Examinacal time . On the cal time . In Scital bract . However species .G. pensilis seed-cone A show also some similarities with extinct—but well-documented—fossil Voltziales, though with some important distinctions. Within all Voltziales, the ovules were not axillary, but instead were always located on the upper surface of the ovuliferous scale. Seed-scale shapes and number of ovules per scale were diverse within Voltziaceae , a member of the YABBY gene family, are implicated in the evolution of the outer integument  bears atypical shoot-like structures in the axils of basal bracts, interpreted by DEFICIENS AGAMOUS-LIKE (DAL) genes belonging to the AGAMOUS (AG) clade, which includes genes that are active in determination of both floral meristem and organ identity in angiosperms. They found that in the wildtype of P. abies, DAL14 is expressed only in the seed scale at early stages , but it is not expressed in these chimeric organs in the mutant form, indicating that it could function to suppress meristematic activity in a more typical ovuliferous scale in this species. Teratological conifer seed cones in Picea can produce a proliferation of seed scales without each additional scale being subtended by a bract, suggesting that their absence may not be a major impediment to this interpretation.For example, the DAL orthologs compared with Pinaceae seed-cone scales. Our observation of a mutant form of G. pensilis that features a remarkably distinct boundary layer between the ovulate tissue and the ovuliferous scale tissue is highly relevant in the context of understanding the homologies of conifer cones, and opens up the possibility of future gene-expression studies on similar mutants.However, Pinaceae are relatively distantly related to Cupressaceae among extant conifers . Within


Morquio syndrome or MPS IVA is a rare type of lysosomal storage disease associated with highly specific dental abnormalities. We present two siblings with enamel hypoplasia and skeletal abnormalities. A diagnosis of mucopolysaccharidosis type IVA was reached based on the clinical, radiographic, and dental findings of the patients. The dental findings are useful diagnostic aid for the early diagnosis of this debilitating disorder. Glycosaminoglycans (GAGs), formerly known as mucopolysaccharides, are long-chained carbohydrates that are vital for the formation of bone, cartilage, tendons, corneas, skin, and connective tissue. The deficiency of lysosomal enzymes required for the metabolism of the various mucopolysaccharides results in the accumulation of the respective substrate in the cells, leading to progressive cellular damage and clinic pathological changes. Mucopolysaccharidosis (MPS) is comprised of at least seven recognized phenotypes that are assigned by numbers and eponyms.Two siblings, a 13-year-old girl  is a rare disorder which presents with a number of musculoskeletal defects. The clinical condition was first described independently in 1929 by Morquio and Brailsford. Matalon et al. in 1974 identified the deficiency of enzyme N-acetyl-galactosamine-6-sulfatase causing intracellular accumulation of keratan sulfate responsible for Morquio's syndrome type IVA .The parents did not belong to different ethnicity, yet they were not consanguineously related  . MorquioGAGs and proteoglycans provide the extracellular polyanionic macromolecules for the biomineralization process of several biologic systems. GAGs regulate the enamel maturation during the transitional and maturation stage of amelogenesis. Typical dental changes are characterized by surface pitting and thin hypoplastic enamel resulting in altered shape and discoloration . The maxInclination of the distal ends of the radius and ulna towards each other, hand bones being short, and squat help in radiological diagnosis. Convergence of proximal surfaces of metacarpals gives a “bullet-”shaped appearance –7. OtherDiagnostic methods available are blood and urine analysis to quantify the keratan sulfate level, direct enzyme assay in leukocytes or fibroblasts, and the wide range of radiographic views to demonstrate the skeletal abnormalities. Although the elevated urinary keratan sulfate is diagnostic of MPS, mucopolysaccharide excretion reduces with age and cases of Morquio with absence of excessive keratan sulfate in the urine have also been reported , 7. OdonIn conclusion, MPS IVA is a rare type of mucopolysaccharidosis associated with highly specific dental abnormalities. As there is no cure for Morquio's syndrome, periodic monitoring and intervention are mandatory. Bone marrow transplant and enzyme replacement therapy (ERT) have been used with some success. This case illustrates the importance of systemic evaluation and inclusion of MPS type IVA in the differential diagnosis of enamel hypoplasia. As both the primary and permanent dentitions are affected, an early diagnosis is possible even in the clinically atypical cases. Early systemic evaluation and follow-up will help in improving the quality of life of the patients.