N-acetyl aspartate ratio (Lac/NAA) in the thalamus and fractional anisotropy (FA) in white matter tracts measured within 15 days of birth. To confirm that these biomarkers are qualified to predict long-term outcome after neural rescue therapy we assessed surviving participants at 2–3 years of age.The TOBY-Xe proof of concept randomised trial found no effect of xenon combined with hypothermia after birth asphyxia on the lactate to Of the 92 infants in TOBY-Xe, one was omitted from the study, 69 survived and we assessed 62 participants, 32 in the hypothermia and xenon and 30 in the hypothermia only groups. We examined the relation between Lac/NAA and FA and the scores of the Bayley Scales of Infant and Toddler Development III and calculated their predictive accuracy for moderate or severe disability or death.Fifteen of 62 participants (24%) developed moderate/severe disability, and 22/92 (24%) died.The Lac/NAA ratio  and FA  differed significantly between participants with or without moderate or severe disability or death and were significantly related with development scores in both groups. Adverse outcomes were correctly identified in 95.65% of cases by Lac/NAA and 78.79% by FA, with adequate mean calibration of the model.The results confirm the qualification of the cerebral magnetic resonance biomarkers employed in the TOBY-Xe study as predictors of outcome after neuroprotective therapy.The Centre for the Developing Brain, King's College London, UK. We searched Pubmed without language restrictions from 1st January 1990 to 1st January 2019 with the terms (xenon AND hypothermia AND outcome) and again with the terms ((magnetic resonance imaging) OR (magnetic resonance spectroscopy) AND newborns AND asphyxia AND encephalopathy).We found just two completed randomised clinical studies of adjunct treatment with xenon and hypothermia to prevent brain injury: One was our study in newborns following birth asphyxia (The TOBY-Xe study); the other was in adults following out of hospital cardiac arrest. Both studies used magnetic resonance biomarkers for early therapeutic assessment. In the study in adults, global cerebral fractional anisotropy (FA) on magnetic resonance tensor imaging was slightly preserved in the xenon plus hypothermia group compared to the hypothermia only group, but clinical outcomes assessed six months later were similar in both groups.N-acetyl aspartate (Lac/NAA) ratio and the NAA metabolite concentration were reported to be the optimal predictors of neurodevelopmental outcome at 2–3 years but no study has prospectively qualified these biomarkers for rapid assessment of adjunct neural rescue therapy with hypothermia following birth asphyxia.Several single centre studies and one large multicentre prospective study assessed brain injury following neonatal encephalopathy by magnetic resonance spectroscopy and/or tensor imaging. In these studies, the thalamic peak area lactate/ Studies in animals using a perinatal asphyxia model assessed potential neural rescue therapies including therapies adjunct to moderate hypothermia using magnetic resonance techniques. In such studies the Lac/NAA ratio is an excellent biomarker of the therapeutic effect and consistently associated with the number of dead cells on brain immunohistochemistry and with the recovery of neurophysiological status after hypoxia ischaemia.The present study aimed to confirm prospectively the qualification of the thalamic Lac/NAA ratio and FA in the posterior limb of the internal capsule after an adjunct neuroprotective treatment with therapeutic hypothermia after birth asphyxia and neonatal encephalopathy. The study confirmed the high accuracy of the cerebral biomarkers chosen in the TOBY-Xe study for predicting neurodevelopmental outcome following birth asphyxia in each treatment group, and supports their use to evaluate a therapeutic effect on clinical outcomes, and estimate the power of the study to detect clinically significant changes in the cerebral biomarkers.Clinical trials of neuroprotective therapies initiated very soon after birth with clinical outcomes require large numbers, have a long duration and are costly. Statistically powerful qualified biomarkers measured soon after cerebral injury could enable rapid assessment of potential therapies in proof of concept studies. The present results confirm that cerebral magnetic resonance biomarkers, such as used in our study, provide a rapid and accurate surrogate outcome that can be used to identify useless interventions early and select promising neuroprotectants for further study.Alt-text: Unlabelled Box1Xenon, a monoatomic gas that is approved for inhalational anaesthesia, showed promising neuroprotective effects when combined with moderate hypothermia following asphyxia in studies in animals and in a preliminary clinical study in adults following cardiac arrest . These pNCT00934700), between 2012 and 2014 , or no useful vision).We examined the relation between the Lac/NAA in the thalamus measured by 2.2Stata (version 11) statistical software was used for the statistical analysis.Assessment of the relationship between early cerebral biomarkers and neurodevelopmental outcome: Lac/NAA values were skewed so we used the natural logarithm, where appropriate. We performed linear regression to assess the relation between the Lac/NAA peak area ratio in the thalamus and FA in the posterior limb of the internal capsule to the cognitive, language and motor scale development scores, in the whole study population and by treatment subgroup. We included in the analyses the Full IQ, Verbal and Performance scores of the two children that were assessed by the WPPSI-III, as these scores have the same mean and standard deviation as those of the Bayley-III scales. We compared mean or median values of the biomarkers in the normal outcome/mild disability group and the group with moderate or severe disability or death. We analysed the receiver operating characteristic curve (ROC) and calculated the area under the curve (AUC), sensitivity, specificity, and likelihood ratios of the prediction by Lac/NAA and FA of moderate or severe disability, and repeated the analysis including deaths in the adverse outcome group. We assessed mean calibration of the prediction models by the Hosmer-Lemeshow test.In the TOBY-Xe study, the Lac/NAA ratios were not corrected for post menstrual age at scan, therefore, we tested for a relation between these measures by linear regression.Analyses of clinical data of participants: Since all continuous outcomes had non-Gaussian distributions, we present the median and interquartile range and the difference in medians with 95% confidence intervals between participants in the xenon combined with hypothermia and hypothermia only group. Wilcoxon rank-sum test was used to test the null hypothesis. We calculated relative risks and 95% confidence intervals for categorical outcomes between the two groups.3The clinical characteristics at birth of the study infants are shown in Relationship between early cerebral biomarkers and neurodevelopment: The Lac/NAA ratio in the thalamus and FA in the posterior limb of the internal capsule measured within 15 days of birth were significantly related with the composite cognitive, language and motor developmental scores assessed at 2–3 years of age in the whole population and in each treatment group .The Lac/NAA ratio and the FA values differed between the normal outcome/mild disability and moderate/severe disability or death groups . Both meP = .272, r2 0.020, There was no correlation between the Lac/NAA ratios and post menstrual age at scan  The present study thus aimed to confirm prospectively the qualification of the cerebral biomarkers after an adjunct neuroprotective treatment with therapeutic hypothermia. Studies in animals have shown that the thalamic Lac/NAA ratio is a sensitive biomarker of the therapeutic and biological effects of hypothermia and of adjunct treatment with hypothermia following asphyxia, and we have previously shown the value of MR imaging as a biomarker after therapeutic hypothermia in a retrospective analysis of the TOBY randomised trial of therapeutic hypothermia . In suchThe MARBLE study reported that the NAA metabolite concentration in the thalamus was the optimal predictor following neonatal encephalopathy, but another recent study reported a similar predictive accuracy for the thalamic Lac/NAA ratio . The pre1H MRS confirmed in this study indicate that this is potentially a clinically useful measure that could be incorporated into clinical practice. However, since 1H MRS studies in newborns have been in specialist centres, further clinical studies are needed to determine the feasibility and cost/benefits of introducing this measure routinely in infants with neonatal encephalopathy.Although standard magnetic resonance imaging with visual assessment is now commonly used to assess the severity of cerebral injury and guide management following birth asphyxia and neonatal encephalopathy, the high accuracy for predicting later neuro-developmental outcome and the feasibility of measuring the Lac/NAA ratio on Two infants, one from each allocation group, had zero Lac/NAA values on proton MRS, and both infants developed severe disabilities. Absence of a lactate signal following severe asphyxial encephalopathy is highly unusual and we cannot exclude that the infants had an alternative pathology. These two data points are dropped following log normal transformation as log normal transformation of zero values is not possible.Studies in animals have suggested that there are several potential neuroprotectants that might augment the modest therapeutic effect of moderate hypothermia following birth asphyxia. However, clinical trials of adjunct neuroprotective therapies initiated very soon after birth with clinical outcomes require large numbers, have a long duration and are costly. There is a critical need for statistically powerful qualified biomarkers measured soon after cerebral injury for rapid assessment of potential therapies in proof of concept studies. The present results confirm that cerebral magnetic resonance biomarkers, such as used in our study, provide a rapid and accurate surrogate outcome that can be used to identify useless interventions early and select promising neuroprotectants for further study.Neurological and neurodevelopmental outcomes at 2–3 years of age were very similar in the xenon plus hypothermia and hypothermia only groups, mirroring the closeness of the results between groups of the cerebral biomarkers measured soon after birth, visual analysis of conventional MRI and neurological assessment at hospital discharge in the neonatal period. There was no difference in deaths and loss to follow-up in the two randomised groups, so the randomisation property still broadly applies to the 2–3-year outcomes, but this study was not designed to detect an effect of xenon on neurodevelopmental outcomes and was underpowered to do so because TOBY-Xe was powered to detect changes in the cerebral biomarkers. However, the near identical results of the clinical outcomes in the two treatment groups, and the close concordance with the neonatal outcomes suggest a low probability that the results would materially change with a larger study.The results also confirm that a definitive clinical trial of xenon gas combined with moderate hypothermia after birth asphyxia would not be appropriate using the protocol defined in the TobyXe study. The absence of a beneficial effect of xenon could be for a number of reasons, such as: suboptimal dose, duration and timing of administration of xenon ; the severity of encephalopathy in the participants; low sensitivity of the cerebral biomarkers used in the study; and low power of the follow-up study. Neuroprotective therapies are less likely to be successful following more severe injury, as was demonstrated in a recent study in animals that found no cerebral protection with xenon following a severe asphyxial insult whilst previous studies found beneficial effects following milder injury . HoweverThe UK Medical Research Council funded the TOBY-Xe study, and participating hospitals and The Centre for the Developing Brain, King's College London, UK, supported the follow-up study.The funder of the TOBY-Xe study had no role in study design; data collection, analysis, or interpretation; or writing of the report. The corresponding author had full access to all the data in the study and the final decision to submit for publication was made by the authors. All authors approved the final version of the manuscript submitted for publication.Prof D Azzopardi and Prof AD Edwards originated and designed the study, analysed the data and wrote the first draft of the manuscript. Prof NJ Robertson, Dr. AT Chew, Dr. A Huertas, Dr. A Deierl, and Dr. N Tusor contributed to the study design, data analysis and data collection. All authors contributed to the writing of the final version of the manuscript.The authors report no financial interest of potential conflict of interests


Phlebotomy is an error-prone process in which mistakes are difficult to reveal. This case report describes the effect on laboratory results originating from a blood sample collected in close proximity to an intravenous catheter.A 69-year-old male patient was referred to the Emergency department where pneumonia was suspected. Phlebotomy was performed to collect blood samples to assess electrolytes, renal function, liver function, infection and haematological parameters.The laboratory analysis showed reduced potassium and calcium concentrations. To prevent life-threatening cardiac failure the clinician decided to correct those electrolytes. Remarkably, the electrocardiogram showed no abnormalities corresponding to hypokalaemia and hypocalcaemia. This observation, in combination with an overall increase in laboratory parameters with the exception of sodium and chloride, led to the suspicion of a preanalytical error. Retrospectively, an intravenous catheter was inserted in close proximity of the puncture place but no continuous infusion was started prior to phlebotomy. However, the intravenous catheter was flushed with sodium chloride. Since potential other causes were excluded, the flushing of the intravenous catheter with sodium chloride prior to phlebotomy was the most probable cause for the deviating laboratory results and subsequently for the unnecessary potassium and calcium suppletion.This case underlines the importance of caution in the interpretation of laboratory results obtained from specimens that are collected in the proximity of an intravenous catheter, even in the absence of continuous infusion. The preanalytical phase includes procedures concerning sample collection prior to laboratory analysis such as patient identification, phlebotomy and transport of specimens to the laboratory  of our university hospital. The past medical history mentions pleuropneumonia and tuberculous meningitis 21 years prior to presentation. A follicular lymphoma was diagnosed 8 years later for which he was treated with chemo-immunotherapy and allogenic stem cell transplantation. Subsequent immune suppression therapy to minimize graft obtained .per minute, but was not in acute respiratory distress. Percussion dullness was noticed at the lower right thorax during pulmonary examination. The chest X-ray was markedly abnormal with flattening of the left hemi-diaphragm and pleural effusion and atelectasis in the right hemithorax was observed, but this was in accordance with previous observed pleurodiaphragmatic adhesions . A Cobas C-8000 automated modular analyzer  was used to perform chemical analysis. No technical errors during laboratory analysis were reported. Strikingly reduced concentrations of potassium were observed . TherefoThe results of the ECG recording combined with the elevated potassium and calcium concentrations measured from the sample post-suppletion , raised The suppletion of potassium and calcium was ceased immediately and fortunately the patient suffered no adverse effects from the wrong treatment.Phlebotomy should be performed by well-trained personnel according to well-established valid procedures (Therefore, in addition to accuracy during phlebotomy, assessing the entire dataset of laboratory results instead of focusing on the aberrant results are both essential to track down phlebotomy related preanalytical causes of unreliable laboratory outcomes. Communication between treating medical staff and the laboratory department is essential to track errors in the preanalytical phase.Introduction of a stopping interval of at least two minutes not only in case of a continuous infusion but also between flushing the infusion and the procedure of phlebotomy.Regularly inform the clinicians and nurses how to track down preanalytical causes of unreliable laboratory outcomes.


This Research Topic collects different contributions on nanotechnology-based strategies for controlling and fine-tuning biomaterials' properties at the nanoscale. Such modification allows the production of 3D environments with improved cell compatibility and ultimately functional tissue repair. In this Research Topic, we also present new insights on nanoengineered drug delivery systems.Casanellas et al.), introduces the recent advances in 3D nanoengineered biomaterials for musculoskeletal tissue regeneration, highlighting the different methodologies used to process those. The authors show both conventional and non-conventional technologies to manufacture 3D scaffolds with a fine control of the nanoarchitectural and compositional template for improved tissue integration. Nanofibers in particular had a high surface area, which is optimal for cell adhesion, allowing an interconnected porosity for assisting nutrient transfer and cellular waste. Nanofibrous scaffolds can be produced by conventional electrospinning technology which represents a versatile and widely used method to manufacture nanofibrous scaffolds. Within the non-conventional technologies, 3D printing allows controlling the design and manufacturing of scaffolds with complex structures and intricate geometries that can better mimic the nano- and micro- architecture of the tissues. Furthermore, the addition of nanomaterials during or after the bioprinting process can enhance the scaffold cytocompatibility, tune the physico-chemical and mechanical properties, and direct cellular behavior. Direct nanoscale bioprinting therefore represents a new interesting scenario that better mimics the nanofeatures and nanostructure of the musculoskeletal tissue.The first article in this Research Topic . Hickey and Peeling then highlight the influence of different nanostructures between bacterial and plant-based cellulose on the biological response of cells. These materials therefore have great potential to become the next standard in biomaterial generation due to their versatility and the diversity of biochemical and physical properties.Within the proposed nanoengineered biomaterials, the use of cellulose has recently caught the attention of researchers, due to its tuneable physico-chemical, and mechanical properties, allowing the use of an ideal candidate for scaffold manufacturing. As discussed by Liverani et al. who demonstrates the feasibility of different nano-functionalization strategies to modify the surface of electrospun membranes obtained using non-toxic solvents. Their outcomes show suitable results for all the functionalized polycaprolactone (PCL)-based meshes, with respect to the bare PCL, with better cell behavior on the membranes functionalized with the surface entrapment (after hydrolysis) of fibronectin. This extracellular matrix protein is fundamental for nanoscale ligand-integrin affinity, and is largely used for the functionalization of electrospun meshes as well as for coating cell culture plates in order to enhance cell adhesion and spreading, in products already available on the market.Continuing with the application of nanotechnologies, it is extensively accepted that nano-textures applied on construct surfaces can strongly influence some biomaterial characteristics, such as wettability, protein absorption and cellular and/or bacterial adhesion. The importance of the surface functionalization is tackled by Al-Azzawi et al. propose the potential improvement of drug uptake through the design and synthesis of low generation lysine dendrons with further functionalization with an ApoE-derived peptide (AEP) ligand. This methodology intends to enhance cellular uptake and drug delivery targeting to the brain in the treatment of neurodegenerative diseases . The high density of the terminal functional groups of the dendrimers is a key characteristic, as it allows several attachment sites at the nanoscale for drugs or other biomolecule complexation. In their study, the dendrimers as nanoscale carriers show a strong ability to be internalized by brain endothelia within a receptor-mediated transcytosis (RMT) approach. This type of internalization represents the first step of carrying bioactive molecules into the brain and has an attractive potential for novel therapeutics in the central nervous system.In another approach, to nano-functionalization with protein and peptides, Ferraris et al. who produced and characterized a Ti-oxide layer. Such a surface has a high density of the hydroxyl group, present in the form of a sponge like nanotexture. The treated titanium-based surfaces: (1) present enhanced bioactivity in simulated body fluid solution, encouraging the precipitation of new apatite crystals, and (2) determines an increase in sample anti-adhesive properties; in particular, a substantial inhibition in terms of bacterial viability and metabolism is evidenced for two different bacterial strains, S. Aureus and A. Actinomycetemcomitans, without compromising the material cytocompatibility.Finally, a chemical surface treatment for titanium and its alloys is presented in We hope that readers find this Research Topic to be a useful collection of articles in the emerging field of nanoscale functionalization and the manufacturing of medical systems in tissue engineering and drug delivery applications.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The influence of irradiation on mechanical properties of polymer foils used in spacecraft applications has widely been studied via macroscopic tensile samples. An increase in the local resolution of this investigation can be achieved by reducing the sample’s dimensions. A femtosecond laser enables a fast fabrication of micro-samples with dimensions from tens of  Polymer foils used in spacecrafts, e.g., as thermal control foils, are usually exposed to multiple types of radiation and severe thermal cyclic loading ,2,3. TheA femtosecond (fs) laser enables a fast and reproducible way for the fabrication of such micro-samples. This technique offers optimal properties for material processing on a scale from tens of micrometers up to a few millimeters. Most importantly, using a fs-laser for processing impedes melting of the specimen material during the ablation due to ideally no thermal diffusion into the material. This allows precise and reproducible fabrication of structures on the micro-scale . An incrThe processing of micro tensile samples by means of a fs-laser has rarely been studied. Works by Slaughter et al. , SeverinThe polymer foils were exposed to electron irradiation with typical dose levels seen by spacecraft in the low earth orbit to asses the capability of the micro-tensile experiments to study the influence on the material. Other influencing factors of the space environment like, thermal cycling, high vacuum, electromagnetic irradiation or further types of charged particle irradiation ,21 have Micro tensile specimens allow to evaluate the mechanical properties on a scale of a few hundred micrometer, hence, this study provides a technique, which can yield insights into the local irradiation damage of polymer foils. Additionally, the determination of damage gradients across the thickness of polymer foils can be of interest. It is particularly interesting to investigate the depth of embrittlement zones due to (space) irradiation. The fs-laser processing combined with the capability of precise positioning allows to locally slice the foils into thinner sections. This depicts a promising technique to enable the acquisition of depth-resolved mechanical data.This study is structured as follows: The first part deals with the experimental details of the work. In In this study a recently developed system, which combines a fs-laser with a FIB and a scanning electron microscope (SEM) was used . Details of the system can be found in a previous study . The intPolyimide Upilex-S VDA  (127 FEP (Fluorinated ethylene propylene) VDA  thinfilm (with 100 nm-thickness) on one side. The PET foil is not coated.The three types of polymer foil materials exhibit distinctively different tensile properties, ranging from high ultimate strength to high ultimate strain, therefore, this materials are ideally suited to assess experiments with fs-laser fabricated micro-tensile specimens. Furthermore, Upilex-S VDA and FEP VDA foils are commonly used in multilayer insulation of spacecraft ,23, hencThe electron irradiation doses of the outer layer of thermal blankets of the Hubble Space Telescope in the low Earth orbit roughly range from 100 kGy to about 1 MGy for the shortest servicing missions up to the defined end-of-life duration respectively ,24. The The irradiation was performed in a van de Graaff-type electron accelerator producing an electron beam with The focal plane was determined by selecting the ablation spot with minimum diameter via varying the distance of the beam expander lenses. The samples were placed in the middle of the scan field to ensure a normal incidence of the laser beam onto the foil.In 2 ,25. The The scan repetitions define how often each laser pattern, shown in Prior to the laser processing a piece of the foil with a size of about The final cross-section geometry of the samples shows a trapezoidal shape due to a certain taper angle resulting from the laser processing. The resulting mean values of the taper angles for the respective processing parameters of each sample material are listed in The uni-axial tensile experiments were performed on a Kammrath & Weiss fibre tensile module . This deFemtosecond laser processing is a fast and versatile method for the fabrication of micro-samples, nevertheless, especially in the case of polymers the influence of heat and effects due to air ionization see  need to Specifically, in the case of polymers the repetition rate needs to be carefully chosen. The excessive energy of each laser pulse, which is not used to ablate material generates a small amount of heat . If the To evaluate the heat accumulation effect on the sample quality an experiment, varying the time of energy input, was performed on the three investigated materials. For this, five parallel lines with a length of 600 The of 10kHz c still aPronounced melting was also found for the PET foils up to The damage of the FEP VDA foils showed less signs of damage due to melting, but an increase in debris deposition next to the processed structure compared to Upilex-S VDA and PET foils. Additionally, another critical issue occurred when compared to Upilex-S VDA and PET films. The use of high pulse repetition rates and respective small numbers of scan repetitions yields a small material removal rate. Therefore, a cut through the 1kHz see e. The goAccording to the results of these experiments on the variation of the pulse repetition rate, a rate of  cut see .The tensile properties of the three investigated non-irradiated materials show large differences in both, the maximum strength and the maximum elongation see . While UThe resulting tensile curves of Upilex-S VDA samples are shown in The stress-strain curves of the tensile experiments on the PET foils are shown in found in . The UTSfound in .Regarding the electron irradiation samples with a dose of 0 kGy , 250 kGy (4 MD), 500 kGy (3 MD) and 750 kGy (2 TD) were tested. Electron irradiation lead to a slight reduction of the yield strength. A significant decline in the maximal tensile strain and stress was found for both orientations. This is in contrast to the results in , which sIn contrast to the Upilex-S VDA foils the FEP VDA foils are strongly affected by the electron irradiation. Further the yield strength of The fs-laser processing atmosphere can play a critical role. Using atmospheric conditions the high energy density in the focal spot can lead to an ionization of the surrounding air . In a stFor the Upilex-S VDA and PET micro-samples, processed under ambient pressure conditions, no change in tensile properties for increasing fluence values was found see . The FEPd in air .An effect of using atmospheric processing conditions, as well as increasing fluence values was not found for irradiated FEP VDA samples. In this case, the influence of the electron irradiation dominates the decrease of the UTS and the maximum strain.Due to the very high energy electron beam used in this study and the small sample thickness, a constant electron irradiation damage across the thickness of the foils can be assumed. This will not be the case for foils used in space missions, hence, these samples may exhibit a gradient in irradiation damage across the foil thickness. A technique to evaluate the extent of this gradient as well as its influence on the mechanical properties has not been established yet. Due to the high material removal rate combined with the high precision, the fs-laser system allows to locally thin such foil samples. Taking into account the accuracy of the sample positioning, the thickness of the sample can be gradually reduced with a step-size of about The necessary preparation geometry is sketched in Femtosecond laser processing of polymer micro-samples was demonstrated for Upilex-S VDA, FEP VDA and PET foils. The structural quality of the samples is strongly influenced by the femtosecond laser pulse repetition rate due to heat accumulation effects. A repetition rate of 1 kHz yielded a minimal influenced zone, while ensuring a sufficient material removal rate.The evaluation of tensile properties by means of the femtosecond laser processed micro-samples shows a good agreement with macroscopic data found in literature. No degradation of the samples due to laser processing was found for the PET and Upilex-S VDA specimens. However, the FEP VDA samples exhibited a sensitivity of the tensile properties on the ambient atmospheric conditions as well as the fluence of the fs-laser. Electron irradiation up to 1000 kGy did not influence the tensile properties of Upilex-S VDA foils. PET foils revealed a distinct orientation dependence and showed a minor degradation due electron beam irradiation, observable for all investigated doses from 250 to 750 kGy. FEP VDA foils exhibited a pronounced degradation already for an irradiation dose of 250 kGy. Besides a lower ultimate tensile strength, the ultimate tensile strain was reduced by a factor of about 6.The study showed that femtosecond laser processing allows a fast and reproducible fabrication of polymer micro-samples with sizes of up to multiple hundreds of micrometers, therefore, enabling a high resolution for the investigation of local mechanical properties of polymer foils.


Thoracic injuries occur frequently in minivan-to-pedestrian impact accidents and can cause substantial fatalities. The present research work investigates the human thoracic responses and injury risks in minivan-to-pedestrian impacts, when changing the minivan front-end design and the impact velocity, by using computational biomechanics model. We employed three typical types of minivan model of different front-end designs that are quite popular in Chinese market and considered four impact velocities . The contact time of car to thorax region (CTCTR), thorax impact velocity, chest deformation, and thoracic injury risks were extracted for the investigation. The results indicate that the predicted pedestrian kinematics, injury responses, and thoracic injury risks are strongly affected by the variation of the minivan front-end design and impact velocity. The pedestrian thoracic injury risks increase with the increasing vehicle impact velocity. It is also revealed that the application of the extra front bumper is beneficial for reducing the thoracic injury risk, and a relatively flatter minivan front-end design gives rise to a higher thoracic injury risk. This study is expected to be served as theoretical references for pedestrian protection design of minivans. Pedestrians are typical vulnerable road users (VRU) in road traffic accidents, who sustain extremely high injury risk –3. As reHuman head and lower extremity were the body regions most frequently injured in pedestrian impact accidents, which have caused extensive concerns as identified in related studies –16. HoweHowever, thoracic injuries have not attracted enough research concerns and no test procedure exists , 23. FroTherefore, the purpose of the current study is to investigate the thoracic kinematics, injury responses, and injury risks when struck by minivan fronts of different designs at different impact velocities via numerical modelling of minivan-to-pedestrian frontal impacts using a previously developed and validated pedestrian computational biomechanics model. The findings of this study are expected to serve as references for minivan front-end structure design in terms of pedestrian thoracic injury prevention.The pedestrian model of an existing HNU-HBM (Hunan University Human Body Model) was employed in our study see  using thTo investigate the thoracic responses in frontal impact with different types of minivan, three minivan finite element (FE) models of typical front-end designs in Chinese market were employed, which have been previously developed and validated in detail against crash experimental data , 38. In It has been identified that about two-thirds of pedestrians were hit from the side by a vehicle when walking across a road in real-world accidents , 39; thuThus, in total, 12 simulations were conducted, and the thoracic kinematics and injury parameters of the pedestrian model were extracted from the simulations for a comparative study of pedestrian thoracic injury biomechanical responses.The contact time of car to thorax region (CTCTR) is defined as the time from the initial contact  to the moment when thorax firstly contacts with the vehicle exterior. CTCTR was used in the current study as a parameter to assess the pedestrian kinematics, since it helps to determine the level of thorax impact velocity.Thorax impact velocity, that is, the resultant translational velocity of the pedestrian thorax relative to the vehicle exterior at the moment of CTCTR, has been identified to be a direct factor in the determination of the thoracic injury responses [esponses . TherefoChest deformation, defined as the maximum difference between the initial and minimum left-right distance of the deformed thorax contours in transverse plane in side impact, is a critical injury parameter to evaluate thoracic injury severity/risk in vehicle safety assessment as well as the research field of human thoracic injury biomechanics under impact loading conditions [nditions , 43. In Thoracic injury risk: various injury criteria have been proposed in the literature for the evaluation of human thoracic injury risk/severity in impact loading conditions, some of which were used in legal regulations of vehicle crash safety performance in terms of occupant injury prevention. TTI (thoracic trauma index) was a widely used thoracic injury criterion (a standard thoracic injury index employed in the US regulation for assessing side impact crashworthiness and occupant injury prevention), which was developed based on a series of side PMHS (postmortem human subject) experiment data carried by Eppinger et al. [r et al.  and accor et al. , it was r et al. .The relationships between the CTCTR and the impact velocity for the three minivan models were built, as shown in With regard to the effects of the vehicle velocity, differences in the CTCTR distribution for the three minivan models were found when changing the level of the vehicle velocity from 20 km/h to 50 km/h, see The chest deformations of all the impact simulations when varying both minivan model and vehicle impact velocity were described in The calculated TTI values of all the simulation cases were collected to demonstrate the effects of minivan front-end design and impact velocity on pedestrian thoracic injury risks, see The effects of minivan front-end design and impact velocity on pedestrian kinematics were assessed by contact time of car to thorax region (CTCTR). As seen in As demonstrated in Figures The pedestrian thoracic injury risk induced by model I (with extra bumper) was slightly lower than that by model II (without extra bumper), which implies that the application of the extra bumper would mitigate the pedestrian thoracic injury risks of both AIS3+ and AIS4+, but only resulting in minor difference, especially for impacts at a speed lower than 30 km/h. To the best of the authors' knowledge, such investigation has not been carried out before.In the current study, TTI and chest deformation were used to represent the severity of thoracic injury; however, there are other injury parameters which were also used as thoracic injury predictors. It should be noted that all the injury parameters/criteria, employed in the current study or not, were proposed for the evaluation of vehicle crash safety regulations in terms of occupant protection rather than regarding the pedestrian injury assessment due to vehicle impact. Such particular injury parameter suitable for pedestrian thoracic injury evaluation is pended on further study.The limitations of this paper mainly rely on two aspects. The primary limitation is that the current study focuses on the evaluation of pedestrian thoracic injury risks, but in actual fact, pedestrian head and lower extremity pose more significant fatal and severe injuries, which has been identified in vast of related researches , 46, 47,Another limitation of this study is that the potential influence of the modifications of the minivan front-end shape, found to be conductive to reduce pedestrian thoracic injury risk in the current study, on the pedestrian lower extremity injury is not investigated. Since such influence has been analyzed in sedan-to-pedestrian impact accident scenarios , 48, furCTCTR (the contact time of car to thorax region) of the pedestrian is more sensitive to the change of the minivan front-end design in low speed impacts than that in high speed impacts.The effects of vehicle impact velocity on thorax impact velocity and chest deformation are more appreciable than when changing minivan front-end design.The pedestrian thoracic injury risk increases with the increasing vehicle impact velocity, and the application of the extra front bumper is beneficial for reducing pedestrian thoracic injury risk.A relatively flatter minivan front-end, that is, the highest windshield slope in the current study (model III), may lead to a higher thoracic injury risk to pedestrian.The effects of minivan front-end design on pedestrian thoracic injury risks are particularly significant for high speed impacts (40 and 50 km/h), but such effects for low speed impacts (20 and 30 km/h) are much less important.The current study reveals that the pedestrian may sustain a high thoracic injury risk when struck by a minivan. The results indicate that the analyzed parameters  as well as the thoracic injury risks of the pedestrian are strongly affected by the variation of the minivan front-end design and the vehicle impact velocity. The main findings are as follows:


Synovial sarcomas are soft tissue neoplasms mostly located in the lower extremities of young adults.A case of synovial sarcoma of the thigh in a 35-year-old male with the predominant epithelial component is reported. Microscopically the tumor showed variable-sized well-differentiated glands lined by the cuboidal cells with small foci of spindle cell component between glandular structures. Immunohistochemically glandular components showed positivity for the pan CK and EMA while CD99 and TLE1 were positive in both glandular and spindle cell components.This type of synovial sarcoma could be indistinguishable from metastatic adenocarcinoma and malignant adnexal tumor, thus, immunohistochemistry and molecular studies play an essential role in the exact diagnosis of this type of tumor. Synovial sarcoma is a distinct aggressive neoplasm that occurs most often in teenagers and young adults mean age:35) . The eti5 . The eA 35-year-old male referred to our center with a painful thigh mass. He had first noticed the mass 8 years ago after minor trauma. The tumor was growing slowly during these years, until about 6 months ago that started to grow rapidly and became painful. On physical examination, a 10 cm, well-defined, firm movable and mildly tender mass was palpated in the medial aspect of the right thigh. Magnetic resonance imaging (MRI) revealed a large lobulated hypervascular mass lesion in the deep portion of the right rectus femoris muscle . ComputeSynovial sarcoma is an aggressive neoplasm that occurs at any age but it is most prevalent in teenagers and young adults.In spite of its name, the involvement of joint cavities and the synovial membrane is rare , 9 and tImmunohistochemical analysis and finding the specific chromosomal translocation is necessary for the exact diagnosis of this tumor. Most synovial sarcoma show immunoreactivity for the cytokeratins  and EMA. There is focal positivity for S100 and immunoreactivity for CD99 and CD56 .In a case report by Ishida T et al., a case of synovial sarcoma with predominant epithelial component was reported. In this case, they stated that presence of a biphasic pattern, even with few scattered spindle cell component has an essential role in the correct diagnosis of synovial sarcoma and its distinguish from carcinoma .In another case report by Salgaonkar G et al., a case of synovial sarcoma with the primary manifestation of the chronic non-healing ulcer of the foot was presented. By histopathologic examination and IHC study of this case, the diagnosis of epithelial predominant biphasic synovial sarcoma was made .Synovial sarcoma is aggressive soft tissue tumor with poor prognosis , 5 . SomWe report a rare case of predominant epithelial synovial sarcoma in a young man presenting as painful thigh mass with the previous history of minor trauma. It is considered that this tumor could be mistaken with other malignant tumors such as metastatic adenocarcinoma, malignant adnexal tumor, and malignant melanoma. Thus, the role of immuno-histochemistry and molecular study for the exact diagnosis of this tumor is important.


Malnutrition affects a third of the global population with low- and middle-income countries (LMICs) being the most affected. Most of those affected by malnutrition have limited means of determining their nutritional status. Recent developments of point-of-care (POC) diagnostics promise to enable early diagnosis of nutritional deficiencies or disease risk through biochemical indicator assessment. This provides potential opportunities for relatively simple interventions before the emergence of clinical symptoms. The main objective of this systematic scoping review is to map evidence on accessibility to POC diagnostic tests for the assessment of nutritional biochemical markers as an integral part of maternal health services in LMICs.We will search for relevant literature from the following databases: PubMed, Science Direct, EBSCOhost , Google Scholar and World Health Organization library database. We will also search reference lists of included studies and existing networks such as organisations and conferences to source relevant literature. Primary research articles, published in peer-reviewed journals; review articles and grey literature that address the research question will be included. We will also search clinical trial registers to find relevant studies. Two independent reviewers will screen abstracts and full articles in parallel, from the included studies, using specific inclusion and exclusion criteria. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines will be used for reporting the screening results. NVivo version 10 will be employed to enable content thematic analysis of the review findings. A narrative summary of the results will be presented according to the emerging themes.We anticipate finding relevant literature on point-of-care diagnostic services for assessment of biochemical indicators as part of maternal services in low- and middle-income countries. The evidence obtained from the included studies when summarised will help to guide future research. Malnutrition is a major health risk associated with increased healthcare-related costs estimated prevalence of 30–50% globally , 2. In lMaternal malnutrition increases the risk of poor pregnancy outcomes including obstructed labour, premature or low birth-weight babies and postpartum haemorrhage . PostparDelayed disease diagnosis, as a consequence of poor access to laboratory infrastructure, has been demonstrated as one of the major problems in LMICs , 12. TheA recent systematic review and meta-analysis provided evidence on the effectiveness of POC diagnostics on maternal health outcomes in HIV-infected women, globally . TherefoThe proposed scoping review will be guided by Arksey and O’Malley’s scoping review framework , 17 whicThe main research question for this systematic scoping review is as follows: What is the evidence on accessibility to POC diagnostic tests for assessment of nutritional biochemical markers as an integral part of maternal health services in LMICs?What is the accessibility of POC diagnostic tests for nutritional biomarkers in maternal healthcare?The research sub-question is:The study will use an amended PICO  framework to determine the eligibility of the research question Table .Table 1FPrimary research articles, published in peer-reviewed journals, review articles and grey literature that address the research question will be included in this study. All study designs will be included for review. We will search literature from the following databases: PubMed, Science Direct, EBSCOhost , Google Scholar and the World Health Organization library database. We will include searching clinical trials registers to find relevant ongoing studies. We will also search the reference lists of included studies and conferences websites to source relevant literature.The search terms will include “nutritional,” “biomarkers,” “maternal health,” “point of care testing, point of care diagnostics, nutritional biomarkers, performance, and effectiveness”. MeSH  will be included in the search. Boolean terms, AND and OR, will be used to separate the keywords. We have conducted a pilot search using the above keywords to determine the feasibility of this study . The seaGuided by the study research question, we developed the inclusion/exclusion criteria to ensure correct identification and selection of relevant studies.Primary studies published between 2008 and 2018Studies reporting evidence of POC testing for nutritional status biomarkers of maternal health services in LMICsStudies reporting evidence of screening and management of nutritional status biomarkers for maternal health services in LMICsTo be included, studies must meet the following criteria:Evidence on POC diagnostics for other diseases other than nutritional statusEvidence of POC diagnostics aimed at men and childrenEvidence of laboratory-based POC diagnosticsEvidence from high-income countriesWe will exclude publications reporting the following:This study will be conducted using a three-stage mapping strategy. The first stage will include comprehensive title screening which will be done by one reviewer. All eligible studies will be uploaded onto Endnote X7.4 software and duplicates removed. The final Endnote library will be shared among the review team. The second and third stages which will comprise of an abstract and full-article screening, respectively, will be conducted by two independent reviewers guided by the inclusion and exclusion criteria. In an event where a study/article could not be retrieved from the databases, we will request for the assistance from the University of KwaZulu-Natal library services and contact the authors to request for the article. Disagreement at the abstract screening stage will be resolve through discussions among the reviewers until consensus is reached. However, a third reviewer will be engaged to resolve disagreement at the full-article screening stage. Screening results will be reported using the adapted Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines  Fig. 1)1).Fig. 1A data charting form will be developed and piloted Table . The datThe primary aim of the study is to map evidence on the scope and effectiveness of POC diagnostics for nutritional biochemical indicators as an integral part of maternal health services in LMICs. The study will provide a narrative account of findings from existing literature through thematic content analysis of the extracted literature. The themes will be structured around the following interned outcomes: accessibility, effectiveness, availability of POC, nutritional status, screening of nutritional status and related health conditions. The themes will be coded in correspondence to the respective authors. NVIVO software version 13 would be used collectively to organise the data extracted from the included studies.CodingCategorise codes into major themesBuild theme-related themes (cut-and-paste technique)Display dataIdentify key patterns in the data and identify sub-themesSummariseThe below process will be followed:We will carefully interrogate the resulting themes and critically examine their relationship to the research question. Authors will also scrutinise the meanings of the findings as they relate to the overall aim of the study and address the implications for practice and for future research. We will analyse the resulting themes and critically examine their relationship to the research question. The reviewers will also analyse the meanings of the findings in relation to the aim of the study and the implications of these research, policy and practice.We will include the quality appraisal step to assess the quality of the included studies, as recommended by Levac et al. . The quaThe current scoping review will be conducted to provide evidence of the existence of POC diagnostic services for nutritional status markers in maternal services in LMICs. The Sustainable Development Goals (SDGs) focuses on increasing equitable coverage of quality health care and provision of integrated services as a means to reduce maternal mortality . ReductiThe proposed systematic scoping review will include primary studies published from 2008 to 2018 and publications reporting evidence of POC testing for nutritional status biomarkers. Furthermore, publications reporting evidence of screening and management of nutritional status biomarkers and published and unpublished reports reporting on nutritional status biomarkers for maternal health services in LMICs will be included. The proposed systematic scoping review will exclude studies that report evidence of other POC diagnostics that are not aimed at screening or management of nutritional status in maternal health services. Evidence from high-income countries reported by studies, as well as, laboratory-based studies will also not be considered in this review. It will be essential to have a comprehensive and balanced account of previous work to provide a sound background of the research. Hence, this study will include evidence from articles that has been published from the past 10 years, 2008 to 2018.It is anticipated that the results of the study will help identify requirement priorities for primary research in this area. The findings of the study may be of interest to stakeholders involved in the provision of maternal health services in LMICs. The findings of this study will be disseminated through peer-reviewed journal publications and conference presentations.


Background: Ameloblastoma is a rare head and neck tumor characterized by a high incidence of BRAF mutation providing a rationale for the use of BRAF inhibitors in patients with advanced disease.Methods: We report the case of a 26-year old female presenting with metastatic ameloblastoma. A molecular screening of the tumor revealed a BRAF V600E mutation.Results: The patient started treatment with dabrafenib and trametinib and experienced complete response which is still ongoing 30 weeks after treatment onset.Conclusions: The complete response observed here illustrate the role of molecular profiling in complicate clinical situation of rare head and neck cancer and the potential benefit of BRAF-targeted therapy in ameloblastoma carrying BRAF V600E mutation. Precision oncology aims to tailor the therapeutic strategy based on tumor's molecular alterations. Previous studies have suggested the validity of such approach in rare and ultra-rare tumor subtypes, including rare head and neck cancers; with the identification of targetable alterations in up to 93% of cases . AmeloblIn November 2018, a 26-year old female was referred for hemoptysis and cough of several weeks' duration. Her past medical history was significant for the diagnosis, at the age of 13 years, of an ameloblastoma of the right mandible (tooth 48) treated by surgery with clear margins and no evidence of locoregional relapse since then. A CT scan was performed which showed numerous bilateral nodules. The patient underwent a CT-guided percutaneous lung biopsy of one of these nodules. Histological examination was in favor of lung metastasis of ameloblastoma.BRAF gene V600E mutation [The patient was enrolled in our molecular screening program after signature of informed consent  and gave also written informed consent for the publication of this case report. Next-generation sequencing of the metastatic tumor sample was performed as previously described and revealed the presence of a The ameloblastoma is a histologically almost always benign odontogenic tumor of the jaw bones with a potential of locoregional recurrence . DistantBRAF mutation (BRAF V600E mutation.Anecdotal response has been reported with platinum salts agents but there is no standard of care in this setting . A seminmutation . In melamutation . The toxmutation . The comAll datasets generated for this study are included in the article/supplementary material.This study was approved by the institutional review board of Institut Bergonié.AI: conception and design. EK and AI: collection and assembly of data. All authors: data analysis, interpretation, manuscript writing, and final approval of manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Drosha and Dicer are RNase III family members of classes II and III, respectively, which play a major role in the maturation of micro-RNAs. The two proteins share similar domain arrangement and overall fold despite no apparent sequence homology. The overall structural and catalytic reaction similarity of both proteins, on the one hand, and differences in the substrate and its binding mechanisms, on the other, suggest that both proteins also share dynamic similarities and dissimilarities. Since dynamics is essential for protein function, a comparison at their dynamics level is fundamental for a complete understanding of the overall relations between these proteins. In this study, we present a dynamical comparison between human Drosha and Giardia Dicer. Gaussian Network Model and Anisotropic Network Model modes of motion of the proteins are calculated. Dynamical comparison is performed using global and local dynamic programming algorithms for aligning modes of motion. These algorithms were recently developed based on the commonly used Needleman-Wunsch and Smith-Waterman algorithms for global and local sequence alignment. The slowest mode of Drosha is different from that of Dicer due to its more bended posture and allow the motion of the double-stranded RNA-binding domain toward and away from its substrate. Among the five slowest modes dynamics similarity exists only for the second slow mode of motion of Drosha and Dicer. In addition, high local dynamics similarity is observed at the catalytic domains, in the vicinity of the catalytic residues. The results suggest that the proteins exert a similar catalytic mechanism using similar motions, especially at the catalytic sites. Sequence and structure alignment algorithms are long standing techniques to study proteins. Sequence alignment algorithms –3 identiDynamical comparison relies on analysis of low-frequency normal modes from coarse-grained elastic network models (ENM) such as the Gaussian Network Model (GNM)  or the AThe Ribonuclease III (RNase III) family is a group of endoribonucleases that specifically degrades double-stranded RNA (dsRNA) at selected target sites, producing typical staggered ends containing 2-nt 3′-overhangs . The cleRecent studies have found that human Drosha and Giardia Dicer  share a similar domain arrangement and overall fold, besides the C-terminal component, despite no sequence homology , 36. BotDrosha and Dicer act as "rulers" and "scissors" since they measure and cut at a fixed distance of each substrate , 36. DroThe overall structural and enzymatic reaction similarity of both proteins, on the one hand, and differences in the substrate and its binding mechanisms, on the other, suggests that both proteins share dynamics similarity and dissimilarities related to their common and unique functions. In this paper, we examine the dynamics similarity and dissimilarities of human Drosha and Giardia Dicer  by comparing their GNM and ANM modes of motions, using recently developed global  and locaα atom and a cutoff distance of 15Å was used  to fit the B-factor scale of the protein structures. The PDB file B-factor values are replaced by the RDSS and best dynamically matching areas are visualized by the B-factor coloring option of the used viewer, Pymol [For each pair from the bination . The finr, Pymol . The abir, Pymol  and showr, Pymol .Human Drosha and Giardia Dicer are not apparent homologous proteins . However, recent studies , 36 founSuperimposing of Drosha and Dicer structures with SPDBV is depicted in GNM analysis was used to calculate the slowest  motions of Drosha and Dicer. The two slowest modes of motions are presented in The above analysis enabled us to identify slow modes hinge regions. A complementary analysis of mean square fluctuations (MSF) indicates the mobility of each residue as calculated from all modes . The MSFThe above calculation was performed using modes predicted by GNM, which are isotropic. More detailed dynamical information can be obtained by ANM modes of motion, which are anisotropic. ANM modes of the proteins were calculated and global mode alignment between the forty slowest modes of the two proteins were performed. The AAS matrix for alignments of the five slowest modes is presented in The first two or three slowest modes usually describe global functional motions that are to great biological interests . TherefoDrosha and Dicer’s motion according to their second mode is similar . DespiteGlobal alignments revealed dynamical similarity between Drosha and Dicer of only one slow mode of each protein, although local similarities may still exist. Local mode alignments of the three, twelve, and forty slowest modes of the two proteins were performed. The higher the mode number, the higher the energetic cost of the protein to move along this mode, and the motions become more local and less global. Each of the examined local mode alignments has a slightly different local dynamic similarity profile, although the three alignments show dynamical conservation at the same domains . In the first three modes, very high dynamic similarity is observed at the top part of the RIIIDb domain, while the RIIIDa helix located at the cleft between the two catalytic domains and, in the case of Drosha, the following helix, have very low dynamic similarity. At the twelve modes alignment, the dynamic similarity level of the top part of RIIIDb slightly declined, whereas the dynamic similarity of its lower part as well as the RIIIDa helix, that is in the cleft between the two RIIIDs, increased. Local mode alignment of forty modes shows that the highest RDSS residues concentrate at the areas containing the catalytic residues at each of the RIIIDs, parallel to rising of the dynamic similarity level of RIIIDa. Despite the few differences in the dynamic conservation profile of the three alignments, all three alignments show higher conservation in the vicinity of the catalytic residues for each catalytic domain at the processing center.Drosha and Dicer are classes II and III members, respectively, of the RNase III protein family that play a key role in miRNA biogenesis , 31. FunThe GNM analysis shows that the least mobile region for both proteins is the substrate binding cleft . In addiGNM modes comparison can be viewed as a low-resolution dynamical comparison, since these modes provide information on the size of the fluctuations but not their directions. ANM modes provide both the direction and size of the motion, hence, can be viewed as a high-resolution dynamical comparison. Furthermore, each mode vectors {U→} see  describiAlthough no significant global similarity was found, both Drosha and Dicer exhibit similar global motion trend, of bending the upper and lower domains toward each other, while moving in a semi-circular manner. Since this kind of movement is observed in the different modes of the two proteins it is probably of a functional significance of assisting the cleavage of each substrate. Rotating the substrate can impair its stability by generating high torsional stress or by stretching chemical bonds. Bending of the upper and lower domains towards each other together with the substrate can physically assist the cleavage mechanism.As members of RNase III family, Drosha and Dicer catalytic domains are highly conserved and function with the same mechanism of dsRNA cleavage, although they have different substrates (pri- and pre- miRNA). Therefore, it is expected that the two proteins will have similar but not identical local dynamics. Local mode alignments show higher dynamic conservation at both RIIIDs, in the vicinity of the catalytic residues and at the Connector domain. The high dynamical conservation of the processing center indicates that Drosha and Dicer use similar local dynamics for the catalytic mechanism.In this study, we present relatively new methodologies for dynamical comparison of proteins and exemplified the use of comparative dynamics as a new layer to study proteins by comparison. Sequence, structure, and dynamical comparison algorithms are three complementary layers to study proteins, and together give a more complete and accurate view of the relation between related proteins.S1 Fig(PDF)Click here for additional data file.S2 Fig(PDF)Click here for additional data file.S1 File(MP4)Click here for additional data file.S2 File(MP4)Click here for additional data file.


Concept of neuro-cardiovascular diseases (NCVD) is one fruitful approach that enables the comprehension of the pathological processes raising along the brain-heart & blood vessel axes from the integrative prospective. That is the reason why multidisciplinary and interdisciplinary approaches result in novel insights into pathophysiological processes bringing new directions for therapeutic development, both at the laboratory bench and at the clinical bedside. NCVD comprises the group of pathologies that have as a primary pathological substrate the changes in neurochemical, neurophysiological and neuroanatomical levels of the autonomic nervous system (ANS) and its regulated organs .A striking fact is that “cardiovascular disease is the leading cause of death in the world today and will remain so by the year 2020”  and the sympathetic-adrenomedullary axis (SAM)  in generating behavioral and autonomic responses to real and perceived emotional stressors. Central position and integratory function of this structure, between higher cortical regions , qualifies it as a crucial, emotional stress mediator neural hub. Though the review reports, parallel and comparative results obtained in different species, the guiding theme is the enlightening of the understanding of the morpho-functional substrate affiliated with emotional stress response in humans. Crucial for understanding of the behavioral response to the perceived emotional stress are the inputs from the MPC to the dlPAG. The species-specific MPC subregion of the primate brain, the area 10 m, has the largest volume in humans with respect to other primate species. Allman and collaborates , and chemical phenotyping for the purpose of pharmacological intervention, and the role of tonic pre-stimulus sympathetic neural activity, for the development of the hemodynamic profiles that are susceptible to progression of the compartment syndrome.The impact of peripheral information on neural mediation of the cardiovascular (CVS) response can be crucial to the development of pathologies initiated by physical stressors like injury. When a physical stressor is recognized by the brainstem through pain, inflammation and other signals, both fast SAM and sluggish HPA responses are activated , a virtual spectroscopy method for studying the long-range interactions between biological macromolecules  and also 12 repurposed antimuscarinic drugs potentially could be efficient in VVS treatment. Follow up with in vitro and in vivo studies will test the therapeutic capacities of drug candidates identified by ISM.Neurogenic hypertension (NH) and vasovagal syncope (VVS) are NCV entities representing an unsolved pathophysiological puzzle. Novel data exists about the central molecular mechanisms regulating the tonic activity of preganglionic sympathetic neurons  and pathophysiology  represents one of the central research topics of NCV physiology in the last few decades  estimation for short (20–30's) time segments. The proposed method uses the oscillations of ABP and HP instead of their original values. The method provides reliable estimates of BRS without regard to posture change during the short data segments of 20–30 s in length. The proposed method solves several shortcomings of the sequence method by increasing the accuracy and validity of BRS estimation  and intrinsic components (ganglionated plexus) that innervate the heart, as fundamentally contributing to positive feedback mechanism of AF. The ganglionated plexus, is the network of acetylcholine and other neurochemically distinct neurons, which play an important role in the modulation of cholinergic transmission and can be the site of maladaptive changes including arrhythmogenesis. These maladaptive changes could be based on both short-term and long-term plasticity mechanisms, with engagement of 5HT3 receptors, acetylcholine release and NO signaling in sympathetic neurons, and nicotinic expression, NO-cGMP signaling and NMDA receptor expression in vagal neurons. The neurochemical profile of synaptic plasticity of both sympathetic and vagal ganglionic transmission is promising target for future pharmacological studies aiming to intervene in AF that is morpho-functionally stabile as its persistent form. Traditional ECG and HRV linear and nonlinear indexes  presents NCVD events typically triggered by sympathovagal discharge  analysis of RR interval was proposed as a sensible method for distinction of AF from healthy subjects. GPP revealed for the first-time different system dynamics for large time scales in AF and healthy subjects. In the special case when GPP analysis was performed between 100 preceding and 100 following RR intervals, distinct regimes could be observed in healthy subjects, reflecting hypothetical different set-points of the blood pressure-heart rate baroreflex loop. In AF patients the GPP profile of RR intervals were scattered. This result suggests that AF patients have smaller adaptive capacity to internal and external perturbations. Four cluster profile of correlation maxima and their absolute values for different correlation scales were also different in healthy and AF patients. These results supported the hypothesis that regulatory regimes in healthy subjects operate in fine tuned superimposed regimes acting on different time scales-parasympathetic, sympathetic and slow regulatory mechanisms like thermoregulation, rennin-angiotensin-aldosterone-sodium system, hormones etc. The AF cluster pattern was highly distorted, shifted toward higher frequencies and with increased randomness. The new GPP methodological approach for detection and profiling cardiovascular regimes need future pharmacological evaluation and potential translatory development as a diagnostic tool for AF and other NCVD.This was the focus of the research of Guarino et al. Even though this comprehensive overview emphasizes the potential vagal route for neuromodulation and pharmacological intervention, the sympathetic route was also evaluated. This, more complex and differently structured subsystem presents itself as less understood and consequently is a significantly diminished path for obesity and related NCVD treatment. Its anatomical characteristics, i.e., approachability by external manipulations imply that the pharmacological approach should be investigated in the future, while the vagal route offers a good basis for both neuromodulatory and pharmacological strategies. Vagal modulation, in specific transcutaneous auricular vagus nerve stimulation is a promising method for body weight reduction in obese patients, also resulting with significant improvements of cardiometabolic profile. Sympathetic modulation, with inconsistent results on body weight reduction and partial cardiometabolic effects, from a results prospective, is a less promising strategy.ANS is coupled directly to the cardiovascular system, but also through the interface of an energy regulating system. This is why an imbalance of energy regulation, as it is the case in obesity, often represents the first step, or the initial trigger of a neurally and metabolically mediated cascade of cardiovascular complications . Digestion, absorption and neuroendocrine activity associated with the adoption of food has a direct effect on cardiovascular regulating centers  is also associated with different morpho-functional remodeling of left ventricle, specific for its ejection functioning. This interesting association, widely recognized as a valuable prognostic and diagnostic parameter , the clinical endpoint of the number of CVD Marwick, . Toschi-Marwick,  seeks foCosta et al. studied the prognostic significance of perioperative arterial blood pressure (ABP) variability for the occurrence of respiratory depression following CABG. The finding of Costa et al. that ABP variability parameters have prognostic value for respiratory depression has both pathophysiological and clinical significance.A number of surgical and pharmacological interventions manifest NCV disturbances as an important caveat. For that reason, detailed and comprehensive NCV evaluation becomes a constituent part of pre-interventional evaluation of the patient and postintervention follow up. Coronary artery bypass graft (CABG) surgery can induce disbalance of sympathovagal ratio and, consequently respiratory depression, approximately 5 days after the surgery  the independent or accompanying autonomic co-morbidity of the main PD pathological process, (b) the procedures associated to the surgery . Significant predictor potential has only pre-operative ABP, with diastolic BP as the marker most associated with hemodynamic event. Hypertension, predisposing factor of cerebral hemorrhage was noted during electrode placement and nuclei stimulation. A prospective study is needed for detailed hemodynamic evaluation (a) during the DBS surgery and the estimation of (b) pre- and (c) post-operative autonomic status of the PD patients. This approach would potentially change protocols of presurgical evaluation and postsurgical treatment of PD patients subjected to DBS. After heart transplantation, the autonomic reinnervation of the transplanted heart has important consequences on its reactivity and hemodynamical adaptability  represents an invasive, frequent and developing intervention for the treatment of a spectrum of neurological diseases, with Parkinson's disease (PD) as the most common. As reported by Li et.al. applied their method  combined with conventional liner parameters of HRV as a tool for predicting fingolimod-induced bradycardia in patients with multiple sclerosis (MS). On the basis of their analysis they report an increased pre medication parasympathetic activity as the predisposing factor for fingolimod induced bradycardia, with pretreatment HR as the only predicting factor. Yuen et al. performed the meta-analysis on clozapine induced autonomic dysfunction in patients with schizophrenia. They conclude that the most frequent complications were myocarditis, orthostatic hypotension and tachycardia, prevalently due to sympathetic overactivity. This report emphasizes the need for introduction of post-medication NCV evaluation autonomic tests for prevention and therapeutic coping with clozapine-induced side-effects. In accordance with Li et al., an intuitive direction for future investigations would be the identification of NCV predicting parameters for clozapine induced autonomic side effects.Pharmacological interventions in neuropsychiatric patients often disturb autonomic balance. A growing corpus of data supports the standpoint that besides the cerebral autoregulation  is an issue of the upmost importance for understanding the NCVD, from two aspects:Dang et al. report “two phase” change of basal ganglia glutamate level after HIBD, that is significantly and negatively correlated to the brain perfusion fraction. Even though this association is suggestive for negative electrochemical coupling of cerebral activity (glutamate) and brain perfusion in HIBD, further investigations are necessary for elucidating the mechanism(s) of brain activity-blood flow coupling in HIBD. Special emphasis should be on the role of sympathetic nervous system in cerebral activity-blood flow regulation in HIBD . Ainslie, . An impoIn conclusion, the presented physiological, methodological and pathophysiological aspects of NCVD point to the importance of consideration of NCVD from integrative point of view and as a constitutive part of different pathophysiological entities. Application of novel mathematical methods for molecular targeting and systemic characterizing of NCVD enounce promising lines of future research in the translational science. Neurocardiovascular side-effects of surgical and pharmacological interventions emphasize the importance of ANS evaluation before and after the intervention as the routine procedure in the clinical work. Finally, an intriguing role of autonomic networks, traditionally considered the cardiovascular neural subsystem, in the regulation of cerebral blood flow both in physiological and pathophysiological conditions is about to open a novel aspect of cerebro-cardiovascular integration.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


A 43-year-old woman was referred from her general practitioner to the department of radiology because of a progressive painless right-sided proptosis that had developed slowly over at least several months. There was no diplopia and thyroid function was normal. A non-contrast-enhanced Computed tomography (CT) of the brain was performed which showed an aggressive appearing sclerotic bony expansion of the right greater and lesser sphenoid wing Figure . The bonorbitosphenoid meningiomas and represent about 15–20% of all meningiomas [Meningiomas arise from the arachnoid cap cells of arachnoid villi and are the second most common primary brain tumors after gliomatous tumors. Sphenoid wing meningiomas are a specific subtype of meningiomas arising from the dura overlying the sphenoid wing bone. They are also known as Sphenoid wing meningiomas may be associated with very extensive hyperostosis, as was the case in our patient. The most accepted cause of hyperostosis associated with sphenoid wing meningiomas is direct tumor invasion, reactive bony changes, or a combination of the both. In our own patient, anatomopathology revealed islands of meningioma cells in the trabecular bone of the surgically removed right lateral orbital wall.The most common signs and symptoms associated with sphenoid wing meningiomas are visual deterioration, proptosis and cosmetic deformity. Treatment consists of surgery and can be complex, depending on the size and extension of the tumor, with different chances of complete removal and often requiring both extensive intra- and extradural surgery. In our own patient partial resection did not lead to an improvement of clinical symptoms and in the end total resection of the right orbital wall had to be performed.


Head and neck cancers are common in Southern China including Hong Kong. Intensity modulated radiotherapy has been the treatment of choice for these patients. Although radiotherapy provides good local control, radiotherapy treatment side-effects are still inevitable due to close proximity of the organs at risk from the target volume. Xerostomia, which is caused due to the damage of salivary glands, is one of the main radiation induced toxicities in post-radiotherapy head and neck patients. This review article discusses the methods for the assessing of radiation induced salivary gland changes including the gland morphology and saliva flow rate. The discussion also includes the recovery of the salivary gland after radiotherapy and how it is affected by the dose. It is expected that the future direction in monitoring the recovery of salivary glands will focus in cellular or molecular levels, and the development of imaging biomarker. Head and neck cancers are common cancer in Hong Kong that registers about 2,000 new cases annually . Owing tXerostomia is one of the common radiation induced complications in head and neck patients after radiotherapy –8. The cIn radiotherapy of head and neck cancers, although the detail mechanism of radiation induced xerostomia is not fully known, it is understood that high radiation dose to the salivary glands causes loss and atrophy of acinar cells and granules , 13, whiThe onset of radiation induced xerostomia usually starts at the later part of the radiotherapy course in head and neck patients . Timely In the 1980's, computed tomography was commonly used to image salivary glands, which was effective to demonstrate duct calculi, diffuse sialectasis, and enlarged lymph nodes . To avoiComparing between MRI and UI for the assessment of post-radiotherapy salivary gland changes, UI is a comparatively affordable solution and has been used in research studies. It is particularly useful in assessing superficial soft tissues. Bialek et al. reported that ultrasonography was useful for detecting acute and chronic inflammation of salivary gland . InformaAnother imaging technique for ductal condition of main salivary gland assessment is sialography which employs the use of contrast injection and radiographic technology. It is useful to detect blockage of the salivary ducts. During the procedure, the patient is instructed to hold the catheter which is placed at the opening of salivary duct, through which the contrast agent is injected, followed by the imaging of the gland by x-ray. Recently, more advanced imaging using MRI has been introduced instead of x-ray to provide 3-dimensional images of the salivary glands in post-radiotherapy patients .The flow rate of saliva is an indicator of xerostomia. The accepted range of normal flow for unstimulated saliva and stimulated saliva are above 0.1 and 0.2 mL/min, respectively . The calFor accurate measurement of flow rate, the method of saliva collection should be reliable and efficient. Before salivary collection, subjects are instructed to refrain from eating, drinking and smoking , 36, 37.A more detail assessment of salivary gland function is the “salivary gland scintigraphy,” which employs positron emission tomography (PET) technology . DynamicWhereas, the differences in pre-radiotherapy SEF and post-radiotherapy SEF of a patient can be evaluated with SEF ratio (rSEF) using the following equation:A reduction of more than 25% in rSEF would indicate salivary gland toxicity.Salivary glands have been demonstrated to show recovery after the completion of radiotherapy. Braam et al.  and Li eChen et al. followed up a group of 31 post-radiotherapy head and neck patients treated by IMRT up to 24 months. Measurements were performed using scintigraphy and observer Quality of life (QoL) grading. They demonstrated an improvement of 5% in rSEF in the second year measurement (78%) compared with that in the first year (83%) . Gupta emean was <26 Gy at one parotid gland. The volume of irradiation and Dmean were indicators of saliva flow and gland recovery  causes permanent xerostomia, parotid-sparing radiation therapy (PSRT) ensured recovery of saliva quantity over time. Twelve months after PSRT, parotid glands produced substantial amounts of salivary epidermal growth factor (EGF) and other proteins, eventually approximating pre-radiotherapy levels, with recovery of salivary function . In addiRadiation induced xerostomia has been a common complication in radiotherapy of head and neck cancer patients despite of the advancement in radiotherapy techniques. It is logical to expect lower risk of xerostomia if the mean dose to the salivary glands is lowered. Methods to assess the gland condition and xerostomia severity are useful to monitor the progress of the toxicity, where appropriate management can be provided to the affected patients. Our review has discussed the common ways to assess the morphology of the gland mainly using imaging modalities, such as ultrasound, MRI, CT, and scintigraphy using x-ray. Each of them can contribute useful information of the gland condition and their uniqueness in imaging the salivary gland has been identified.The assessment of the salivary gland function lies mainly on the measurement of saliva flow, which requires a reliable and convenient method of collecting the saliva from patients. The flow volume and flow rate are common indicators of the severity of xerostomia in patients. The details of saliva collection procedure and the parameters for measurement (such as rSEF) have been introduced, which are useful to assess the radiation induced changes in post-radiotherapy patients. In addition, questionnaires for collection patients' subjective feelings on various life aspects related to xerostomia are available. EORTC QLQ-C30 is a questionnaire based on a list of functional measures and symptom measures to assess the QoL of cancer patients. Another cancer-specific questionnaire established by EORTC is the H&N35 which measures QoL based on symptoms . Some stResults of several longitudinal studies on salivary gland recovery have been discussed in previous section . Apart fAssessing saliva gland changes in post-radiotherapy of head and neck cancer patients can be on three main aspects: morphology of the gland, saliva flow rate and saliva content including biomarkers. Imaging modalities play an important part in the monitoring of the morphology of the salivary glands. Ultrasound imaging is advantageous for its convenience whereas MRI is superior in providing details gland textures. In assessing the saliva flow rate, salivary gland scintigraphy can offer more reliable results in which the residual saliva excretion fraction (rSEF) is used. Several studies have proved that salivary recovery took place after completion of radiotherapy. Many of them reported that a greater improvement in salivary function was observed between 1 year and 3 years post-radiotherapy , 42, 50.KL collected information and drafted the manuscript. VW designed the outline and edited the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Peer-assisted learning is well established in medical education; however, peer tutors rarely act as assessors for the OSCE. In the compulsory, near-peer teaching programme covering basic medical skills at the University of Heidelberg, peer tutors serve as assessors on a formative OSCE. This study aimed to investigate the feasibility and acceptance of peer assessors and to survey the perceived advantages and disadvantages of their use.In 2016 and 2017 all OSCE peer assessors  and all of the peer-assessed students in 2017  were invited to participate in a survey. Both groups were asked to complete a tablet-based questionnaire immediately after the OSCE. Peer assessors were asked to rate eight statements and the peer-assessed students to rate seven statements on a five-point Likert scale. Both were asked to comment on the advantages and disadvantages of peer-assessors.Overall, 74 of 76 peer assessors and 307 of 308 peer-assessed students participated in the study. 94% (67/74) of peer assessors and 90% (276/307) of the peer-assessed group thought that it is important to have peer tutors as assessors. Of the peer assessors, 92% (68/74) felt confident in giving structured feedback during the OSCE and 66% (49/74) felt they had improved their teaching skills. Of the peer-assessed students, 99% (306/307) were satisfied with their peers as OSCE assessors and 96% (292/307) considered the peer feedback during the OSCE as helpful. The participants mentioned structural benefits, such as lower costs, and suggested the quality of the OSCE was higher due to the use of peer assessors. The use of peer assessors was found to be beneficial for the learners in the form of high-quality feedback and an overall reduction in stress. Furthermore, the use of peer assessors was found to be beneficial for the peer assessors .From a learner’s perspective, the use of peer assessors for a formative OSCE that is part of a near-peer teaching program aimed at junior medical students is favourable for all. A broad implementation of peer assessment in the formative OSCE should be encouraged to investigate effects on quality and stress-reduction. The Objective Structured Clinical Examination (OSCE) aims to examine the medical student’s clinical competence . In genePeer-assisted learning, also known as (near-)peer tutoring or (near-)peer teaching, represents an educational approach in which more experienced students teach younger and less experienced ones , 11. Theplus) imparts basic medical skills in history-taking, physical examination and practical skills to all medical students (approximately 320 per year) and culminates in a formative OSCE at the end of the second year. As of 2013, peer tutors in AaLplus have been deployed as assessors for the OSCE . The peer assessors and peer-assessed students agreed that deploying peer tutors as OSCE assessors improves quality because peer assessors undergo more in-depth training than the professional staff and that because they have served as peer tutors within the 2 years prior to the OSCE, peer assessors have better knowledge of the course content. Furthermore, peer assessors claimed that they can easily judge a student’s level of knowledge and that they understand how to answer students’ questions [“We are more familiar with the curricular material and can often better understand the problems students are having.”]. Peer-assessed students mentioned that peer assessors are often more aware of and refer to current standards.Both the peer-assessed students and their peer assessors identified structural benefits for the AaLsense of transparency about own OSCEs”].The benefits for peer assessors include the improvement of teaching, feedback and clinical skills. They also gain personal benefits such as the improvement of social skills and the opportunity to assume responsibility. Finally, the experience of serving as an assessor provides peer assessors with useful knowledge regarding their own upcoming examinations and, especially, OSCEs [“student-focused feedback”]. Third, “peer feedback is better because students find it easier to ask follow-up questions about the feedback and therefore get clearer takeaways.”In regard to the benefits for peer-assessed students, they along with peer assessors often mentioned the provision of high-quality feedback, the creation of a pleasant atmosphere and an overall reduction in stress. First, both groups suggest that peer-assessed students accept feedback from peer assessors more easily because they are on the same level academically and they have established a personal relationship. Second, it was reported that the peer assessors’ feedback is of a higher quality because peer assessors are mindful of the students’ personal situations and take more time to provide feedback. Their recommendations are more useful because they personally understand what students are going through .Another main advantage mentioned by nearly all in the peer-assessed group was the overall reduction in stress; nearly every peer-assessed student reported that peer assessors create a comfortable atmosphere. This was due to the presence of the peer assessors and the more minimal difference in academic and social hierarchy. Some peer-assesses even considered the pleasant atmosphere as a fun learning environment . One student wrote, “Peer assessors can remove the fear of failure, for both the OSCE and medical study.” Finally, the close social and academic standing between peer-assessed students and peer assessors resulted in behaviour that improves the overall atmosphere of the OSCE and enabled high levels of knowledge transfer [“Peer assessors are more focused  and are not bored during the examination”].In addition, peer assessors and peer-assessed students often highlighted valuable information regarding future OSCEs and the knowledge gained during the OSCE . For peer assessors this could be caused by a difficulty maintaining an atmosphere appropriate to a compulsory examination, as was mentioned by one peer assessor.The structural disadvantages reported by the two groups included the limited professional competencies of peer assessors and a possible lack of objectivity on the part of peer assessors. In general, both groups identified less obligation and limited professionalism on the part of peer assessors. Less experience as assessors, a lower level of medical skill and limited clinical knowledge were all identified as disadvantages to using peer tutors as assessors. Furthermore, peer assessors may not be as objective as professional staff due to the relaxed atmosphere and personal relationship. Furthermore, personal relationships between peer assessed students and peer assessors can lead to awkward situations [“The disadvantage for the peer-assessed students is that they might not take the OSCE seriously enough. Finally, 65 peer-assessed students (22%) and 15 peer assessors (20%) responded that there are no disadvantages to having peer tutors act as assessors for the OSCE.In this study we found an overwhelming approval of using peers as OSCE assessors by both the learners and the peer assessors. We found that the implementation of peer assessment in the compulsory medical curriculum is feasible. From the learner’s perspective, peer assessed students benefit greatly from the use of peer assessors because the feedback is detailed and precise, making it more helpful than feedback from professional staff. Peer assessors benefit personally from improved clinical, social and teaching skills. Finally, from learner’s point of view peer assessors contribute to a profound reduction in stress within the formative OSCE, which is felt to be pivotal for individual success in learning.To the best of our knowledge this is the first study to report on broad implementation of a formative OSCE with peer-assessors in routine. We have more than 5 years of experience in the mandatory curriculum and more than 1500 medical students have passed the formative peer-led OSCE within the last 5 years. Our results indicate that medical students generally accepted peers as examiners in a formative OSCE. First published in 2010, a mock OSCE was found to be beneficial for student nurses . In 2014The benefits for peer assessors, including improvement in feedback and teaching skills and the consolidation of knowledge through teaching and administering examinations, has also been summarised in a scoping review by Khan et al. . Those aInterestingly, both peers assessed students and peer assessors claimed that there is an improvement in quality connected to the use of peer assessors compared to professional staff. Surprisingly, the few studies on peer tutors as OSCE assessors found only little difference between peer tutors as OSCE assessors compared to professional staff as OSCE assessors , 36–38. Finally we have shown that peer assessors in a formative OSCE at the conclusion of a mandatory near-peer teaching programme imparting basic medical skills could be successfully implemented in the curriculum of a large medical school with 320 students annually. The hidden curriculum of the formative OSCE at the end of the second year is to familiarise students with the OSCE’s format and decrease negative expectations or even fears of the OSCE in subsequent years of medical school. Our study indicates that we have fulfilled this goal. We have learned that if students have been previously trained as peer tutors, they are able to perform successfully as OSCE assessors. Other medical schools should be encouraged to implement peer assessments in near-peer teaching programs for junior medical students in routine.In this explorative study we showed that deploying peers as assessors remains a successful practice. One limitation of this study is that the close relationship between the peer assessors and the peer-assessed students may have resulted in less critical responses from peer-assessed students relating to the performance of peer tutors as OSCE assessors (effect of benignity). Second, this study was implemented as part of the routine evaluation. An extended study design, such as interviewing key actors, might have supplied further information. Finally, many participants are convinced that utilising peers as assessors reduces the level of stress for peer-assessed students, whereas the formative nature of the OSCE itself might also reduce stress levels. Therefore, the belief in the beneficial effect of stress reduction caused by the use of peer assessors may be a biased point of view and the amount of stress-reduction by peers as assessors could be overemphasised. Future studies and broad use of peers as assessors in qualifying OSCE are necessary to improve our understanding on the effect of stress-reduction.The use of peer assessors in the OSCE in a near-peer teaching programme for junior medical students is feasible and could be successfully implemented into medical curricula. Furthermore, over 90% of the peer assessors and peer-assessed students believe it is important to have peers as assessors. From an organisational point of view, deploying peer assessors enables the implementation of compulsory formative OSCE training for a high volume of medical students while reducing the impact on faculty resources. For peer assessors, the experience of acting as OSCE assessors provides valuable knowledge and improves physician competencies . Peer-assessed students respect peer assessors and appreciate the high quality of feedback they provide and the relaxed atmosphere during their first and formative OSCE. In contrast to this clear and self-confident point of view of the learner’s, it remains to us to prove or refute the equivalence or even improvement of quality as well as the effect of stress-reduction by student led peer assessment in the (mock) OSCE .Additional file 1. Questionnaire for peer assessors.Additional file 2. Questionnaire for peer-assessed-students.