The aim of this study was to evaluate & compare the wetting ability of five saliva substitutes & distilled water on heat-polymerized acrylic resin. Contact angle of the saliva substitute on denture base can be taken as an indicator of wettability. Good wetting of heat-polymerized acrylic resin is critical for optimum retention of complete dentures.Two hundred & forty samples of heat-polymerized acrylic resin were fabricated using conventional method. 240 samples divided into 6 groups with 40 samples in each group. Advancing & Receding contact angles were measured using Contact Angle Goniometer & DSA4 software analysis.Anova test was carried out to test the significance in difference of contact angle values in the six groups. The mean of advancing angle values & mean of receding angle values of all the six groups has shown statistically significant difference between the groups. The mean of angle of hysteresis values of all the six groups are statistically not significant between the groups. A multiple comparison using Bonferroni’s test was carried out to verify the significance of difference between the contact angles in a pair of groups. Statistically significant difference was seen when Aqwet (Group II) was compared to Distilled water (Group I), Wet Mouth (Group III), E-Saliva (Group IV), Biotene (Group V), and Moi-Stir (Group VI).The contact angles of five saliva substitutes and distilled water were measured and compared. Group II (AQWET) has the lowest advancing and receding contact angle values and the highest angle of hysteresis on heat-polymerized acrylic resin. Based on contact angle values, Group II (AQWET) has the best wetting ability on heat-cured acrylic resins. The ability of saliva to wet the denture surface is one of the most important properties for complete denture retention in dry mouth cases. Retention of complete dentures can be affected by physical, physiological, psychological, mechanical, and surgical factors. The physical factors are further divided into adhesion, cohesion, interfacial surface tension, and atmospheric pressure. These physical factors operate in the fluid film between the denture base and the mucosa. The salivary mucins possess rheological properties that include elasticity and adhesiveness, which aid in retention of dentures. Saliva is essential to the function and protection of the oral cavity and contiguous gastrointestinal epithelium. Common functions of the fluid component of the salivary secretions include cleansing and lubrication of oral soft and hard tissues, solubilization and bolus formation of food, facilitation of taste perception, mastication and speech and retention of removable prosthesis . Saliva Kawazoe and Hamada 1978)  stated t8  statedFive saliva substitutes and Distilled water were used in this study . They arSample distribution: Two hundred & forty samples of heat-cured acrylic resin were made. 240 samples were divided into 6 groups each containing 40 samples  was used. Processing was done according to the manufacturer’s instructions. Two hundred & forty samples were made by following the above method  was carried out for 240 acrylic samples. The study comprised of 240 acrylic samples of which 40 samples were used to measure advancing and receding contact angles of Distilled water which were considered as Group I, 40 samples were used to measure advancing and receding contact angles of Aqwet which were considered as Group II, 40 samples were used to measure advancing and receding contact angles of Wet Mouth which were considered as Group III, 40 samples were used to measure advancing and receding contact angles of E-Saliva which were considered as Group IV, 40 samples were used to measure advancing and receding contact angles of Biotene which were considered as Group V, 40 samples were used to measure advancing and receding contact angles of Moi-Stir which were considered as Group VI. The angle of hysteresis was calculated as the difference between the advancing and receding contact angle values. The data was subjected to analysis using IBM SPSS 19.0 PACKAGE. A p-value of (< 0.05) was considered statistically significant. Means of contact angle values were as follows . Anova tThe wearing of dental prosthesis causes discomfort in xerostomic patients. A lack of salivary buffering action also leads to increased risk of caries. Qualitative and quantitative deficiency of the saliva causes an unhealthy and painful environment. In addition, saliva plays an important role in the retention of complete dentures and protecting oral health. A factor that would affect the magnitude of contact angle of a fluid on a solid surface is the roughness of the adherent surface, which differs with respect to the solid. Surface roughness, even in test specimens of the same group of denture base material, was an uncontrollable variable. The variability in surface roughness of denture base materials must be considered when contact angles are evaluated. Ozden et al (1999)  said thaContamination of the studied surfaces may produce a change in the water surface tension that, in turn, would induce an error in the measured contact angle values. The origin of this contamination may be of chemical nature  or of microbial nature (formation of metabolites). However, in the application of angle measuring techniques, the liquid drop was left in contact with the polymer surface for less than 2 min. Moreover, the extremely careful rinsing procedure made it highly improbable that either chemical or microbial contamination occurred. Surface heterogeneity may play its role in increasing contact angle hysteresis. In this case, the advancing contact angle would depend on the fraction of the surface occupied by a low surface-energy phase; the receding angle would be influenced by a high surface-energy phase. O’brien & Ryge (1965)  said thaThe existence of continuous salivary layer is extremely important for two reasons: 1) Salivary contact angle on the mucosa i.e. equal to zero. 2) The volume of the saliva beneath the denture may not be considered as constant because of the salivary flow. The contact angle hysteresis and denture geometry at the meniscus contact lines are determinant factors of denture retention , 10. Themg is the weight of the denture, ∂R is the receding angle and ∂A is the advancing angle. From this equation, it is clear that force required for separating the two surfaces increases with increase in hysteresis angle. The capillary force, which helps restrain any dislodging force on the denture, is increased by complete wetting of the surface, high surface tension of the saliva and large tissue contact area of the denture. The capillary force F, responsible for retention of a denture, can be expressed by the following equation:Where D is the film thickness, and g is the gravitational force. Thus, contact angle hysteresis and denture geometry at the meniscus contact line are the determinant factors of denture retention. A large number of important conditions influencing denture retention in mouth may be taken into account while choosing denture base materials and denture shape. For example, retention might be improved in cases of denture base surfaces with high values of advancing angles and low values of receding angles. Good wetting of the acrylic denture base resin by saliva substitutes is of clinical importance. The quality of life for xerostomia patients may be improved by the use of a suitable saliva substitute. According to wettability studies the measurement of contact angles, the primary data indicates the degree of wetting when a solid and liquid come into contact. Small contact angles (< 90°) correspond to high wettability, while large contact angles (> 90°) correspond to low wettability. More specifically, a contact angle less than 90° indicates that wetting of the surface is favorable, and the fluid will spread over a large area on the surface, it is considered as hydrophilic; while contact angles greater than 90° generally means that wetting of the surface is unfavorable so the fluid will minimize its contact with the surface and form a compact liquid droplet, it is considered as hydrophobic. For example, complete wetting occurs when the contact angle is 0°, as the droplet turns into a flat puddle [Where γ˜ is the surface tension of saliva, A is the area of tissue surface of the denture, ∂1 is the advancing contact angle, ∂2 is the receding contact angle, t puddle . AdvanciThis study was done to compare wettability of distilled water and five saliva substitutes on heat cure acrylic resin using contact angle goniometer. The mean advancing angles of all the groups were compared. Aqwet showed lowest contact angle which indicates the wettability is more on heat polymerized acrylic resin. Good wetting of the heat polymerized acrylic resin by the saliva substitute is critical for optimum retention of the upper complete denture. Statistically significant difference was seen when the mean advancing angle measurement of aqwet (group II) (76.6750) was compared to the remaining five groups in a pair wise test. This could be because the contact angle of aqwet is less than remaining five groups as lesser the contact angle more the wettability. Comparison result of aqwet with distilled water and wet mouth are similar to those found by Sharma and Chitre . MathrawSaliva plays a substantial role in the retention of complete dentures. To create sufficient denture adhesion to the bearing tissues, saliva must wet the contact surfaces and flow easily over the surfaces. The ability of saliva to wet the denture surface is one of the most important properties for complete denture retention. The contact angle of a liquid on a substrate is an indication of its wettability: the smaller the angle, the greater the wettability. With a contact angle of 0°(degree) complete wetting is said to occur; therefore the retention would be expected to be greatest with an angle of 0°(degree). The purpose of this in vitro study was to determine the wetting ability of different artificial saliva substitutes on heat-polymerized acrylic resin samples using contact angle measurements, to present suitable saliva substitute for best wetting in dry mouth (xerostomic) denture wearers. The contact angles of distilled water and five saliva substitutes were measured and compared. Despite several limitations of this study, the following conclusions can be drawn: Group II (AQWET) has the lowest advancing and receding contact angle values and the highest angle of hysteresis on heat-cured acrylic resin . Based on contact angle values, Group II (AQWET) has the best wetting ability on heat-cured resin acrylic dentures fabricated with DPI heat-cured denture material.Flow and contact angles plays important role in wetting ability of saliva substitutes;Necessary need of saliva substitute for the dry mouth denture patients;There is diminished production of natural saliva in xerostomia patients  and cancer patients.This study presented suitable saliva substitute for best wetting in dry mouth (xerostomic) denture wearers;In depth study of flow and wetting of saliva to the oral bearing tissues;This study adds to the use of best available saliva substitute for the cancer patients.The authors declare no competing intererst.


Equus that inhabited the different regions of the continent and on their taxonomic nomenclature. In this study, we investigated cheek tooth morphology and ancient mtDNA of late Pleistocene Equus specimens from the Western Interior of North America, with the objective of clarifying the species that lived in this region prior to the end-Pleistocene extinction. Based on the morphological and molecular data analyzed, a caballine (Equus ferus) and a non-caballine (E. conversidens) species were identified from different localities across most of the Western Interior. A second non-caballine species  was recognized from southern localities based exclusively on the morphological analyses of the cheek teeth. Notably the separation into caballine and non-caballine species was observed in the Bayesian phylogenetic analysis of ancient mtDNA as well as in the geometric morphometric analyses of the upper and lower premolars. Teeth morphologically identified as E. conversidens that yielded ancient mtDNA fall within the New World stilt-legged clade recognized in previous studies and this is the name we apply to this group. Geographic variation in morphology in the caballine species is indicated by statistically different occlusal enamel patterns in the specimens from Bluefish Caves, Yukon Territory, relative to the specimens from the other geographic regions. Whether this represents ecomorphological variation and/or a certain degree of geographic and genetic isolation of these Arctic populations requires further study.Horses were a dominant component of North American Pleistocene land mammal communities and their remains are well represented in the fossil record. Despite the abundant material available for study, there is still considerable disagreement over the number of species of  Equus have been named from the Pleistocene of North America )Dry Cave , U-bar CDry Cave , and BlaDry Cave , 31. At ralensis  and receralensis . The resEquus ferus and E. conversidens, are identified for the late Pleistocene of the Western Interior of North America, based on molecular and morphological analyses of the cheek teeth. A third species, E. cedralensis, is provisionally recognized based exclusively on the morphological analyses of the cheek teeth. Equus ferus is a caballine equid that appears to have been distributed throughout much of the Western Interior of North America. It was identified from Cedral, Mexico, the American Southwest , Natural Trap Cave (where it is represented by relatively few specimens), Alberta , and the Bluefish Caves, Yukon Territory. Geographic variation in morphology in this species is indicated by statistically different occlusal enamel patterns in the specimens from Bluefish Caves relative to the specimens from the other geographic regions. Whether this represents ecomorphological variation and/or a certain degree of geographic and genetic isolation of these Arctic populations requires further study. Equus conversidens is a non-caballine equid which was previously identified based on ancient mtDNA as the New World stilt-legged clade [E. conversidens come from northeastern Mexico , the American Southwest , Natural Trap Cave, and Alberta . Specimens assigned on morphological grounds to a different non-caballine species are provisionally identified as E. cedralensis. We were unable to recover ancient mtDNA from teeth assigned to this species to corroborate its identification as a distinct species. Equus cedralensis appears to have been restricted during the late Pleistocene to the southern latitudes of the Western Interior of North America, as the specimens assigned to this species come from Cedral, Mexico, and the American Southwest .Two equid species, ed clade . The assed clade , 21, 22)E. occidentalissensu Merriam, 1913, which is commonly identified in late Pleistocene sites from the Pacific Coast of North America  is considered a separate species from the ones described here based on the morphology of the upper P3/P4 premolars [The analyses of tooth morphology and ancient mtDNA reported in this study have provided new insights into the taxonomy of late Pleistocene equids from the Western Interior of North America. Nevertheless, additional work is needed to validate the patterns presented in our study. Of particular importance is the application of a mtDNA genomic approach to better resolve the phylogenetic relationships within the caballine and stilt-legged clades. Equally relevant is the morphological and, if possible, genomic assessment of several holotypes that consist of isolated teeth or partial tooth rows. Another important aspect is to increase the geographic coverage of the equid sample. Some late Pleistocene morphospecies identified in previous studies appear to be restricted to areas outside of the Western Interior of North America. For example, remolars  as well remolars , 12, 124S1 FileLinear measurements of horse teeth studied (Tables A–H).(XLSX)Click here for additional data file.S2 FileResults of principal component analysis , upper and lower horse teeth included in the geometric morphometric analyses (Tables A and B), landmarks used in the geometric morphometric analysis of the upper P3/P4 teeth (Table C), equid teeth sampled for ancient mtDNA (Table D), primers used (Table E), and horse mtDNA sequences compiled from the literature used in the Bayesian phylogenetic analysis (Table F).(PDF)Click here for additional data file.S3 File(TPS)Click here for additional data file.S4 File(TXT)Click here for additional data file.


Therapy with mesenchymal stem cells exhibits potential for the development of novel interventions for many diseases and injuries. The use of mesenchymal stem cells in regenerative therapy for vocal fold scarring exhibited promising results to reduce stiffness and enhance the biomechanical properties of injured vocal folds. This study evaluated the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring.PubMed, Embase, the Cochrane Library and Google Scholar were searched.Controlled studies that assessed the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring were included. Primary outcomes were viscoelastic properties and mucosal wave amplitude.Seven preclinical animal studies  were eligible for inclusion. Evaluation of viscoelastic parameters revealed a decreased dynamic viscosity (η’) and elastic modulus (G’), i.e., decreased resistance and stiffness, in scarred vocal folds treated with mesenchymal stem cells compared to non-treated scarred vocal folds. Mucosal wave amplitude was increased in scarred vocal folds treated with mesenchymal stem cells vs. non-treated scarred vocal folds.The results from these studies suggest an increased regenerative effect of therapy with mesenchymal stem cells for scarred vocal folds and are encouraging for further clinical studies. Parts of normal vocal fold (VF) tissue are often replaced with scar tissue during the healing process after trauma, inflammatory disorders, iatrogenic lesions after surgery, and as a well-known side-effect of the treatment of head and neck cancers with radiotherapy.The tissue in the wound healing process after any type of insult may be replaced by fibrous scar tissue, which primarily consists of an excessive, disorganized extracellular matrix. The scar tissue matrix is generally stiffer than the extracellular matrix it replaces. This matrix is of particular concern in areas surrounding and including the vocal folds because the normal functions of these tissues depend on their elastic and vibratory properties.True VFs are one of the most important structures used during normal phonation because of their unique anatomic structure, which is essential for regulating the phonatory output. The mucoHowever, the surgical and medical treatments to ameliorate the reduced functions of the vocal folds after scarring produce limited effects. Therefore, the potential for regenerative therapy using stem cells is of growing interest in the field.Mesenchymal stem cells (MSCs), which were first described in the bone marrow to support hematopoiesis, are so-cSeveral clinical trials with MSCs in various fields of regenerative medicine were performed, and promising results with minimal side effects of the treatment were demonstrated., 14–16Some studies used non-expanded cells from the fat-derived stromal vascular fraction (SVF), which included a heterogeneous cell population of endothelial, hematopoietic and pericytic origin and only a minor fraction of adipose stem and precursor cells.Several types of therapies were evaluated to ameliorate the effects of scar tissue formation in the VF, such as implantation of scaffolds and injection of growth factors. No cliniControlled animal studies that evaluated MSCs as a treatment for vocal fold scarring and included biomechanical measures were eligible for inclusion, regardless of the publication date. Only publications in English were included. Unpublished clinical trials were accessed via ClinicalTrials.gov. The outcome variables of interest were any type of viscoelastic or mucosal wave measurement of the VFs after MSC treatment.An electronic search was performed on PubMed, Embase, the Cochrane Library and Google Scholar. The following keywords (MeSH terms included) were used: vocal folds or vocal cords and stem cell or MSC or mesenchymal stem cell or processed lipoaspirate cell or stromal vascular fraction cell. The Search strategy appendix in The following data were extracted from the included studies: study design, randomization, blinding, study participants, graft donor, source of graft, intervention, control groups, persistence of the stem cell, statistical tests, biomechanical method, time after stem cell injection and results from measurements of dynamic viscosity, elastic modulus and amplitude.The electronic searches identified 118 potentially eligible studies, only seven of which –25 met tThe species, source of the stem cell graft, evaluation time, disease model, intervention and statistical tests varied significantly across the studies, and a meta-analysis would be meaningless.Five of the studies reported biomechanical measures, e.g., dynamic viscosity and elastic modulus, after the induction of VF scarring. Two of these five studies reported a statistically significant improvement in dynamic viscosity in the MSC-treated group versus a saline-treated control group. The difference in dynamic viscosity was only marginally significant in one study (P = 0.07), but it was insignificant in the other study (P = 0.2). The last study did not report a comparison between the MSC-treated and saline control groups.Five studies compared elastic modulus measurements in an MSC-treated group versus a saline-treated control group. Three of these studies demonstrated a significant improvement in elastic modulus in the MSC-treated group versus the saline control group, but one study did not demonstrate an improvement (P = 0.34). The last study did not report the statistics of this comparison.None of the studies reported a measure of the magnitude of the difference, such as a fold-change or percentage difference, in dynamic viscosity or elastic modulus in the MSC-treated versus saline control group. Two of the studies that compared the viscoelastic results in an MSC-treated group versus a normal control group that was not VF scarred demonstrated that neither the elastic modulus nor the dynamic viscosity between the scarred VFs treated with MSCs and a group of animals with normal unscarred VFs was significantly different. These results suggest that most or all of the negative impact of scarring on the biomechanical properties of the VFs was ameliorated. However, this outcome was not always reported or measured.Three studies reported measurements of the mucosal wave amplitude after induction of VF scarring. MSCs were injected into animal VFs on the same day as the scarring was performed in six of the seven studies. Therefore, these studies include the possibility of reducing scar tissue formation from the onset of healing, when a known insult to vocal fold tissue is performed. Only one study investigated the possibility of reducing already manifested scar tissue. The VFs in this model were scarred and left to heal with scarring for 9 weeks before surgically removing the scar tissue and injecting MSCs into the VFs during the same procedure. It is difficult to know in advance whether a given insult to human VFs will result in significant scar tissue formation. Therefore, this last model represents a more relevant model for the treatment of VF scarring using MSCs.Six of the studies used surgical instruments to induce scarring. However, the procedure was not described in detail regarding the extent of the insult, but most of the studies suggest that the entirety of the mucosa and lamina propria was removed. Some or most of the thyroarytenoid muscle was also surgically removed in four studies. Scar tissue formation was induced using an electrocoagulator in one study. The healing process during inflammatory disorders or after radiotherapy is different than surgically induced scars, but whether the treatment of scarred VFs after these types of insult would result in the same outcomes as these studies cannot be assessed.The injected cells were detected at the evaluation time in four of the seven studies. Two of the seven studies detected no MSCs at the evaluation time, and no measurement of the persistence was performed in one study. Whether the presence or absence of the MSCs correlated to the effect of the injected stem cells is not known because of the largely unknown mechanism of action.The electronic search identified two on-going clinical trials, , 27 but To the best of our knowledge, this study is the first systematic review of functional outcomes after mesenchymal stem cell treatment of VF scarring. No clinical trials have evaluated the effect of stem cell injections, and therefore, our results are based on preclinical animal studies. The use of MSCs in the treatment of vocal fold scarring is a complex research field, and several factors must be considered when evaluating the effect of MSC in the treatment of VF dysfunction after scarring. These factors include the type and dose of MSCs (adipose-derived or bone-marrow derived), the origin of MSCs , the study design (acute or chronic scarring), and the disease model (surgery or electro coagulation to induce scarring). Three of the studies primarily examined a combined approach with MSCs and a type of scaffold or ECM protein, but these studies did not report the statistics of the comparison between an MSC-treated group versus saline-treated group although these experiments were performed. These methodological differences make it difficult to summarize the findings into a coherent conclusion. Potential biases in the studies were also a concern because only a few of the studies reported the randomization of animals into treated or control groups, and none specified how the randomization was performed. Only one study reported blinding.Five of the seven studies evaluated the biomechanical properties of excised VFs, and most of these studies reported improvement in the MSC-treated group. However, not all of the studies reached statistical significance. Whether this difference in statistical significance was related to the low power used to detect a difference or methodological differences cannot be evaluated.Three of the studies examined mucosal wave patterns after an intervention with MSCs, and most of these studies reported an apparent improvement. However, only one study reported the statistics (P < 0.01) for the comparison between the MSC- and saline-treated control groups. The significance of the comparisons in the two remaining studies was not reported.Taken together, the above-mentioned findings are encouraging for further studies. There are some fundamental limitations in the animal studies that will make it difficult to evaluate whether human trials with MSCs will lead to clinically relevant improvements in phonation following an MSC treatment. First, six of the seven studies evaluated the reduction of scar tissue formation in the acute phase of healing. It is unlikely that this timeframe represents a relevant model of the treatment of human VF scarring. A relevant model would require the administration of MSCs during a planned insult to the VFs, which may be relevant in some, but not all clinical scenarios. It is unlikely that MSC treatment would be given before an observation period to assess any spontaneous improvement in phonation before offering any treatment because of the relative complexity of the current autologous MSC treatments. Only one study investigating the effect of MSC treatment of chronic scar tissue formation has been published, and this study reported encouraging improvements in biomechanical properties following MSC treatment. Studies comparing time perspectives of the injection of stem cells in relation to the specific trauma should be performed to obtain a treatment regimen focused on the exact cause of the VF lesion.We identified one other review of vocal fold regeneration. This review primarily focused on histological changes following MSC treatment with various types of scaffolds and growth factors. The corrThe results of the two uncompleted clinical trials, one using expanded MSCs and the other using the heterogeneic SVF cell population, should provide useful results in the field, especially for assessments of safety concerns and feasibility. However, the limited number of clinical studies indicates that much more research is necessary to provide evidence of MSC therapy for the treatment of scarred vocal folds. The authors are currently designing a prospective, blinded clinical trial of the injection of mesenchymal-derived stem cells perioperatively in Reinke’s edema patients.In conclusion, animal studies of MSC treatment of scarred vocal folds reveal encouraging results for biomechanical and mucosal wave measurements. These results should be viewed cautiously with the limitations in the included studies, such as statistical insignificance, great intervention variance and the existence of potential biases. Whether these results will translate to improved phonation in human trials with MSC treatment for vocal fold scarring is currently not known. The results from the two on-going clinical trials with MSCs for VF dysfunction should answer some of these questions and are awaited with great interest.S1 Appendix(DOCX)Click here for additional data file.S1 File(DOC)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.


Capítulo de Kinesiología Intensivista of theSociedad Argentina de Terapia Intensiva conducted anarrative review aiming to show the available evidence regarding conditioning ofinhaled gas in patients with artificial airways, going into detail on conceptsrelated to the working principles of each one.Instrumentation of the airways in critical patients  prevents them from performing their function of humidifyand heating the inhaled gas. In addition, the administration of cold and drymedical gases and the high flows that patients experience during invasive andnon-invasive mechanical ventilation generate an even worse condition. For thisreason, a device for gas conditioning is needed, even in short-term treatments,to avoid potential damage to the structure and function of the respiratoryepithelium. In the field of intensive therapy, the use of heat and moistureexchangers is common for this purpose, as is the use of active humidificationsystems. Acquiring knowledge about technical specifications and the advantagesand disadvantages of each device is needed for proper use since the conditioningof inspired gases is a key intervention in patients with artificial airway andhas become routine care. Incorrect selection or inappropriate configuration of adevice can have a negative impact on clinical outcomes. The members of the Under normal conditions, the upper airway and respiratorytract are responsible for humidify and heating inspired air, a process defined asconditioning of inhaled gas. For this reason, the use of an external device forconditioning the delivered gases is required, even in short-term treatments.Instrumentation of the airways  preventsthe conditioning of inspired gas. In addition, the administration of cold and drymedical gases and the high flows that patients experience with invasive (iMV) ornon-invasive mechanical ventilation (NIV) lead to an even worsecondition.Capítulo deKinesiología Intensivista of the Sociedad Argentina deTerapia Intensiva (SATI) to develop the present narrative review. Thesearch was performed using the following databases: LILACS, MEDLINE, Cochranelibrary and SciELO, and the following terms and combinations of words:"randomized controlled trial" OR "controlled clinical trial" OR "trial"OR "groups" AND "humidifiers" AND "heat and moisture exchangers" OR "heat andmoisture exchangers filters" AND "heated humidifiers" OR "heated humidified" AND"mechanical ventilation" AND "noninvasive ventilation" AND "spontaneousbreathing". The most relevant articles were chosen according to theauthors' criteria.A literature search was performed by the -10 The temperature ofthe gas is very important because its water vapor content depends on gastemperature. Relative humidity is the percentage (%) of water vapor contained ina gas relative to its maximum carrying capacity. Absolute humidity is the totalamount of water vapor contained in a gas, expressed in milligrams of watersuspended in liters of gas (mg/L). Absolute humidity is directly related to thegas temperature and is important in terms of humidification since at lowtemperatures, the relative humidity can be 100%, while the absolute humidity canbe far below the recommended value,9 , with 100% relative humidity and 44mg/L absolute humidity.The point where the gas acquires these conditions is known as the isothermalsaturation limit; this limit is usually close to the 4,8 because these medical gases are cold anddry.The presence of an artificial airway prevents inspired air from contacting themucosa of the upper airway affecting gas conditioning . MoreoveTwo types of devices for conditioning inspired gases in the presence or absenceof an artificial airway are available: heat and moisture exchangers (HME) andactive humidifiers.Regardless of which device is chosen, it should infallibly meet the minimumrequirements to replace the function of the upper airway, which, according theAmerican Association for Respiratory Care, are:- 30mg/L absolute humidity, 34ºC and 100% relative humidity forHME.- Between 33 and 44mg/L absolute humidity; between 34ºC and 41ºC;100% relative humidity for active humidifiers.-22The working principle for these devices is based on their capacity to retain heatand humidity during expiration and to deliver at least 70% of them to theinhaled gas during subsequent inspiration. This "passive" function can beachieved by different mechanisms, and the classification of these devices isbased on their mechanisms.,16,23,24Heat and moisture exchangers are simple condensers constructed with elements madeof disposable foam, synthetic fiber or paper, with a significant surface areathat can generate an effective temperature gradient through the devicedelivering heat on each inspiration. From the field of filtration, hydrophobicHMEs were made to repel the humidity and to retain the heat of the expired gas,delivering it in the next inspiration ., whichabsorbs expired water vapor and delivers it to the inspired gas, optimizing thedelivery of humidity. The synthetic fiber also helps to decrease theaccumulation of condensation in a device-dependentposition.These devices are made with materials needed for moisturizing and heating basedon their working principle (hydrophobic or hygroscopic); in addition, theycontain an electrostatic filter. Filters are flat layers of fiber material(modacrylic or propylene) that act as a barrier to the gas flow; at the sametime, the filtration performance is optimized by applying material withelectrostatic charge.The available types of filters are: heat and moisture exchanger filters (HMEFs),hygroscopic condenser humidifier filters (HCHFs) or hygroscopic heat andmoisture exchanger filters (HHMEFs).,26Hygroscopic and hydrophobic elements are used combined to create a combined HME.The performance in terms of absolute humidity is better in HCHs than in HMEs.However, the performances are similar between HCHs and combinedHMEs.The working principle of passive humidifiers implies that a higher volume ofcondenser material will yield better device performance . For thiT) increases and with supplementaryO2.-30This dead space does not represent a disadvantage for patients with iMV becausethe dead space can be compensated for in the programming of the ventilator.However, in patients with artificial airways, without the requirement of iMV,the increase in the ventilatory minute volume as a compensatory mechanism forthe dead space could generate a hard-to-tolerate load in patients with lowventilatory reserve. Therefore, passive humidifiers with 'small volume' weredeveloped . AlthougT). Studies conducted by Prat andHinkson account for this, demonstrating significantchanges in arterial carbon dioxide partial pressure (PaCO2) (and inpH) under these circumstances.The instrumental dead space added by the passives humidifiers during iMV becomesrelevant when the pathology requires strategies for lung protection , resistance can vary under changes in theconditions . Althoughsome studies,34,35 have shown that the presence of 'humidity' in adevice does not lead to significant changes in resistance, excessivecondensation or impaction (due to secretions or blood) can alter it.Although the resistance of an unused device could be considered negligible.However, in 2014, Lellouche et al. investigated the impact of minuteventilation (10 versus 20L/minute) and the room temperature onthe new generation of HMEs, reporting no significant effects on the performanceof these devices [absolute humidity delivered with a minute volume >10L/minute was 30.9mg/L]. For this reason, these authors recommend not takinginto account the minute ventilation as a limitation of the new generation ofhumidifiers. Since the minute volume is composed of the respiratory frequencyand the VT, it might be worth investigating this issue thoroughly.The increase of the VT in the study was a modest 150mL , whereas the increase in respiratory frequency was greater,from 20 to 30 resp/minute (50%). The question becomes one of which of these 2components of the minute volume [VT or respiratory frequency] has agreater effect on a humidifier performance.The humidification performance of an HME decreases when minute volumeincreases.,18 the performance in terms of humidification ofthe HMEs using methods and test conditions based on the ISO 9360:1992 standard.In both studies, a more significant effect on performance was observed whenchanging the VT from 500mL to 1000mL (increase of 100%) compared withchanging the respiratory frequency from 10 to 20 resp/minute (increase of 100%),which suggests that VT has a primary effect.,18 Nevertheless, dueto the unusual use of a VT of 1000 mL, the results should beconsidered with caution.Two studies compared assessed the time of contact of the inspiredgas, and the authors did not find significant differences in delivered absolutehumidity when comparing 1 second versus 2 seconds. Branson etal. suggested that the expiratory flow could be avariable to consider since as the expiratory flow increases, the time of contactbetween the gas and the HME decreases along with the absolute humiditydelivered.Eckerbom et al.Although manufacturers provide general specifications for the changing of thesedevices, we could consider an 'ideal' recommendation that the change isperformed:- Due to excessive condensation that increases the resistance.- Due to visible impaction with secretions or blood.- Each 48 hours in patients with chronic obstructive pulmonarydisease.-39- Each 96 hours and up to 1 week in the remainingpatients.Active humidifiers are devices composed of an electric heater on which is placed aplastic casing with a metallic base in which sterile water is stored. When the baseis warmed, the water temperature increases by convection. Some active humidifiersare self-regulated by a mechanism consisting of a heating wire (heated-wirebreathing circuit) that keeps the gas temperature constant during its passagethrough the circuit and a wire with two temperature sensors connected to the exit ofthe heater  and to a part of the circuit (close to the patient) to controlthe system temperature.It should be taken into account that while heated-wire breathing circuit keep thetemperature stable throughout its route and decrease the condensation, the lack ofcontrol exposes the patient to risks such as a higher incidence of occlusion of theartificial airway.The flow of entering air is forced to pass through a tube that leads it to thelower part of the casing. The gas exiting from the distal end of the tube (underthe water surface) form bubbles that gain humidity and temperature as they riseto the water surface. The amount of water in the container and the flow rate arefactors affecting the humidity content of the gas. Simply expressed, if thewater column in the container is taller, the gas-water interface will increase.Inversely, as the circulating flow increases, the device performance drops.These types of devices are no longer used. In comparison with the previously describeddevice, pass-over humidifiers have lower resistance. It is important to considerthat the water temperature in the enclosure will be a determining factor forhumidity.,43The air flow passes over the water surface, which is hot, and the circulating gasgains heat and humidity from the gas-water interfaceformed.A variant of the pass-over humidifier is the 'wick' humidifier, in which a porousmembrane that absorbs humidity (such as blotting paper) is dipped into watersurrounded by the heating element, keeping the membrane constantly saturatedwith water vapor. The dry gas enters the chamber, makes contact with the wickand is loaded with more water vapor than in the basic system because thegas-liquid interface is larger.Another variant is the hydrophobic membrane humidifier, where dry gas passesthrough the membrane, and, due to the membrane properties, only water vaporpasses through. The dry gas is loaded with water vapor and exits thechamber.Active humidifiers are placed in-line in the inspiration branch of therespirator. The circuit exiting the inspiration valve is connected with theentry hole of the plastic casing, which should be always filled to the levelindicated by the manufacturer. Subsequently, a second section of the circuit (ofstandard length) is connected with the exit hole of the casing and to the "Y" ofthe circuit responsible for delivering gases to the patient. With this type of humidification device, it is necessary to use water traps,reservoirs with unidirectional circulation systems that allow the deposition ofsurplus condensation without leaking air. Among other problems, the excessiveaccumulation of water in the circuit can lead to auto-triggering, misreading ofthe ventilator monitoring or even draining of contaminated material into thepatient's airway.- Observe that the tubing drains the water downwards and not towardthe artificial airway or the ventilator.- Place the water traps correctly to receive drained water.- Frequently monitor the active humidifier device .- Never fill above the recommended level.- Do not drain the condensation toward the humidifier chamber.- Comply with the manufacturer's specifications.® is an HME thathas the property of remaining in-line during the application of aerosols inmechanical ventilation, avoiding the opening of the circuit and potentiallyreducing the contamination of tubing and the exposure of healthcare staff tocontaminated gases.The HME for aerosol therapy Gibeck Humid-FloT of 1000mL. This type of humidifier has 2 modes: "HME and AEROSOL", which can be selected byrotating the central axis of the device. By choosing HME, the device acts as aconventional passive humidifier. In AEROSOL mode, the humidifier part isskipped; therefore, the aerosol goes directly to the patient without coming intocontact with the humidifier material. However, the absolute humidity deliveredwith this device is at least questionable since it delivers 30.4mg/L, but with aV assessed the performance ofseveral HMEs to be used in combination with aerosol therapy. Those authors didnot find significant differences in drug  deposition in theartificial lung without HME (control) versus with HME, using amoisturized circuit .Although the study was only laboratory-based, the HME modified for aerosoltherapy seemed to not interfere with drug deposition.Recently, in a bench study, Ari et al.® is a type of hybrid active humidifierconsisting of a passive humidification system and a 'T' connector containing aself-regulated heater and a small-volume chamber for continuous infusion ofdistilled water (consuming approximately 250mL every 3 days). The upper part ofthe device has a hydrophobic membrane that only allows the passage of water whenit has evaporated toward the tubing. Therefore, the humidity from the waterevaporated on the membrane is aggregated during inspiration, improving the gasconditions by approximately 3 - 4mg/L . During the expiratory phase, heat andhumidity are retained by the passive properties of the humidification system.The dead space of the device is approximately 9mL.The HME-BoosterAdvantages: easy to use, eliminates excessive condensation in the tubing, couldbe useful for hypothermic patients and has a bacterial filter .Disadvantages: it does not include temperature monitoring, increases resistanceand requires a source of electrical energy .This device consists of an HHME in a heated casing in the shape of a cone with aradiator and an electronic controller. There is a line between the device andthe water source, another line between the radiator and the controller and athird heating line between the device and the controller. The casing contains apaper element that provides a surface for humidity transfer to the gas. A watersource drips continuously on the paper element, and the casing heat makes theliquid evaporate, increasing the humidity of the inhaled gas. The device iselectronically controlled through a water and temperature control unit used toprogram the volume per minute of the patient.2O/L/s.Some of the proposed advantages are eliminating condensation from the inspirationbranch and avoiding the use of water traps. In addition, if the water source isdepleted, this device continues working like an HHME (providing approximately 28- 31mg/L absolute humidity). The active HHME provides temperatures of 36 - 38ºCand 90 - 95% relative humidity. The absolute humidity provided by the device issimilar to the HME or active humidifiers but with lower water use and lesscondensation. The dead space of the device is 73mL, and the resistance is1.7cmHThe disadvantages of this product are the possibility of skin burns and greaterdead space compared with a heated humidifier or only an HHME.,49 Although there are some data that favor the useof HMEF (or HCHF) over active humidifiers for the prevention of pneumoniaassociated with mechanical ventilation, the choice of the device should not bebased only on infection control. An algorithm for the selection of thehumidification device is proposed in Taking into account the humidification capacity and the advantages anddisadvantages, both passive and active humidifiers are suitable for theconditioning of inhaled gas . To simplify the checks that should be performed when choosing a humidificationsystem, we have provided this short list containing the main points to beconsidered  and 9.,43,51-61 Given below aresome clinical situations that should be considered:When deciding which humidification system should be used, one should take intoaccount the different clinical scenarios since each device features particularproperties that can affect the clinical situation of the patient ., which implies the risk of generating hypercapnia due tohypoventilation. It becomes rational to decrease the instrumentaldead space as much as possible to counteract this adverse effect. Aneasy strategy to implement is the use of active humidifiers in thesesituations.,32,53,54- Acute Respiratory Distress Syndrome: The ventilatory strategy oflung protection uses low V,52- Ventilator associated-pneumonia (VAP): Decreasing the VAP rate isachieved by the adoption of a series of measures; humidificationsystems are not part of these measures (CDC 2014). For this reason,it is recommended to not choose the humidification device based oninfection control.,61- NIV: The high flows achieved by the devices and leaks predisposethem to heat and moisture loss during the respiratory cycle.Humidification increases the chances of success in the applicationof NIV since it is related to the capacity of managing respiratorysecretions and increases the feeling of comfort. The device ofchoice for gas conditioning in NIV would be the active humidifier,with continuous flow ventilators and a one-branch circuit. Inmicroprocessor-controlled ventilators with a two-branch circuit,this recommendation could be debated.,43- Spontaneous ventilation and artificial airways: In patients withtracheostomy (without iMV), it is advised to use the correspondingHME (considering their limitations) as the first-line treatment. Incase it is contraindicated, then active humidification systems witha water temperature in the casing not below 53ºC should beused.Knowledge of the technical specifications and the advantages and disadvantages ofeach of the humidification devices is essential for professionals who provide careto patients in the intensive care unit. The conditioning of inspired gases is a keyintervention in patients with artificial airways and has become a routine carestrategy. The incorrect selection of the device or an inappropriate configurationcan negatively affect the clinical outcome by damaging the airway mucosa, increasingrespiratory effort or prolonging invasive mechanical ventilation.


Hippocampal rhythms are believed to support crucial cognitive processes including memory, navigation, and language. Due to the location of the hippocampus deep in the brain, studying hippocampal rhythms using non-invasive magnetoencephalography (MEG) recordings has generally been assumed to be methodologically challenging. However, with the advent of whole-head MEG systems in the 1990s and development of advanced source localization techniques, simulation and empirical studies have provided evidence that human hippocampal signals can be sensed by MEG and reliably reconstructed by source localization algorithms. This paper systematically reviews simulation studies and empirical evidence of the current capacities and limitations of MEG “deep source imaging” of the human hippocampus. Overall, these studies confirm that MEG provides a unique avenue to investigate human hippocampal rhythms in cognition, and can bridge the gap between animal studies and human hippocampal research, as well as elucidate the functional role and the behavioral correlates of human hippocampal oscillations. The hippocampus is an important brain region for various cognitive processes, including spatial navigation  measures the brain magnetic fields induced by synchronous neuronal populations, with superconducting sensors in a heavily shielded room Cohen, . CompareHowever, with the advent of whole-brain MEG systems in the 1990s . Some researchers further subdivide CA3 into CA3 and CA4 regions. The basic morphology of the mammalian hippocampus proper is an elongated, curved and rod-like structure . The MEG gain matrices (MEG forward model) for the hippocampus and neocortex were computed in a spherical head model in accordance with a CTF whole-head 151-channel system configuration . Results showed that average cortical activation increased linearly as a function of patch size, whereas hippocampal fields reached a plateau (saturation) for patches greater than about 2 cm2. This is likely due to the geometry of the hippocampus causing partial cancellation of the signal, similar to that seen during activation of large areas of the folded neocortex . The activity at each location was modeled as an equivalent current dipole. Orientations of the current dipoles at neocortical areas were constrained to the local normal of the cortical mantle at each vertex location of the gray-white matter interface. Current dipoles were placed randomly in the inner volume grid in the thalamus, striatum, and the amygdala because the cells in those structures do not have preferred orientation. The hippocampus was modeled as the external envelope due to the difficulty of differentiating the precise inner structure based on 3T MRI images. The current dipoles were placed perpendicular to the local surface.Detailed simulations of deep brain areas, such as the hippocampus, the amygdala, and thalamus were carried out by Attal et al. , dynamic statistical parametric mapping (dSPM) and standardized low-resolution electromagnetic tomography (sLORETA)], to localize the sources. DLEg (the Euclidian distance of a solution's gravity center from the reconstructed source location to the true location) and DLEm (the Euclidian distance of a solution's maximum from the reconstructed source location to the true location) were to assess the ability of the three inverse operators.Simulation of activation from each region of interest in seven participants was performed for patch sizes ranging from 1 to 5 cmg was lower using wMNE than the two noise-normalized depth-weighted MEG inverse operators (dSPM and sLORETA) with errors < 8 mm in the majority of the hippocampus and the amygdala. Conversely, better DLEm was obtained by dSPM and sLORETA, but the spatial patterns for the two inverse operators were not the same. sLORETA had a lower DLEm in the deeper central regions, such as the thalamus, whereas dSPM had a very good estimation over the hippocampus but strong errors in the thalamus. Interestingly, activations of large patches give stronger DLEg, whereas large patches of 4 and 5 cm2 produce the strongest currents. This might be due to the cancellation of oppositely-directed currents as described above. For concurrent activation of two sources, one in the hippocampus and one in the visual cortex, when the two activations had little overlap (25%), hippocampal generators were well-estimated by the three inverse operators, but only dSPM maintained the local maximum in the hippocampus. With increasing overlap of the activation of the two areas, the performance of all of the methods decreased. wMNE had good detection of hippocampal activation when the overlap was up to 50%, whereas sLORETA and sSPM had good estimation of hippocampal activation even when the two sources were simultaneously activated, but created a local maximum in the thalamus (a deep ghost source).With a single subcortical activation, DLEThe authors also computed point-spread functions to quantify the distortion of the source reconstruction by the inverse operators, namely, the spread of hippocampal sources to other cortical and subcortical areas. The resulting point-spread function maps of hippocampal sources showed that highest values were localized in the lateral and medial  and temporal lobe. Compared to wMNE point-spread function map, sLORETA point-spread function map of hippocampal sources showed a significant decrease in values in the neocortex but still significant values in the parahippocampal areas; however, the deeper regions in the thalamus and the nearest amygdala part showed a point-spread function value increase. dSPM point-spread function map of hippocampal sources showed small values in the neocortex and other subcortical structures. To quantify the distortion that is induced from other source locations, cross-talk functions were computed. No significant difference was found in the cross-talk function maps for the three inverse operators and the strongest values of the cross-talk function maps were located in the lateral temporal lobe, especially in the superior temporal sulcus, which suggests that activity in this region is most likely to influence the reconstructed hippocampal sources.Simulation studies were carried out by Quraan et al.  to estimIn a follow-up study, Mills et al.  comparedhttps://surfer.nmr.mgh.harvard.edu/) based on individual MRIs at 3T. A single dipole perpendicular to the surface of the hippocampal curvature or cortical surface was simulated in either the hippocampus or the cortical areas with a 300 ms segment of a sinusoidal waveform of 20 Hz and a dipole moment of 20 nAm. Gaussian white noise was added to simulated MEG fields. Two different realistic forward models were compared, one which included both the cortical surface and the hippocampus and one which only included cortical surface using three different inverse methods, namely, MNE, empirical Bayes beamformer (EBB), and multiple sparse priors (MSP). Free energy —was concordant with the results using free energy values and the cortical model gave higher DLE values than the combined model.Activity in a nearby medial cortical area, 2.14 mm from the hippocampus, was then modeled to see whether the model comparison would return false positive results. The two models did not return significantly different results. These researchers also tested the influence of SNRs and MEG-MRI co-registration error on the model comparison. It was found that the more co-registration error and noise are, the harder it is to differentiate the two models. Most interestingly, poor SNRs were less harmful to the ability to differentiate models than co-registration error. When the co-registration error was > 3 mm, accurate model comparisons could not be achieved, indicating that minimizing head motion, and improving the accuracy of MEG-MRI co-registration will be important for MEG studies of hippocampal activity.The results of the simulation studies reviewed above confirm that magnetic fields emanating from the hippocampus can be detected by MEG sensors at the surface using both planar and axial gradiometers. Cancellation occurs when hippocampal subfields and dentate gyrus are activated together but is only partial. Whether the hippocampal magnetic fields are visible or not on the global field power plot depends on the relative magnitude of background brain “noise,” including whether there are strong magnetic fields simultaneously arising in other cortical areas . However, even in cases where the signal is not visible at the sensor level, source localization algorithms can potentially localize hippocampal sources at the group level. Thus, SNRs at the sensor level may not reflect the ability to localize weak hippocampal sources  and familiar (r = −0.57) environments  shown with iEEG  signals related to neuronal activities . Using simulation data, David et al.  showed tTaken together, the evidence reviewed above strongly supports the contention that MEG can reliably detect signals from the hippocampus. We can draw on three converging lines of evidence:Physiological considerations. The principal neurons of the hippocampus are uniformly aligned with their dendrites in parallel in the same direction perpendicular to the hippocampal surface , MEG systems with axial gradiometers with appropriate baselines may have a slight advantage to detect hippocampal activity  and numerical  forward models can be used to reliably localize hippocampal activities. In principle, the more accurate the forward modeling is, the more accurate the reconstructed source activities will be.Inverse operators. A variety of inverse operators have been successfully used to image the hippocampus, provided methods are used to suppress stronger signals from other brain regions. Beamforming is good at suppressing the activity outside the region of interest without compromising the signal from the region of interest. If the interest is in hippocampal rhythms, SAM (Robinson and Vrba, Finally, although this review focuses on current MEG methodology, it should be noted that recent hardware advances such as the introduction of new types of MEG sensors may further improve MEG measures of deep sources. For example, optically pumped magnetometers (OPMs; Boto et al., To conclude, we have reviewed evidence indicating that MEG is capable of detecting hippocampal signals reliably and provides sensitive and behaviorally-relevant measures of hippocampal functions across a variety of experimental paradigms in both normal healthy participants and patients. It opens a unique window for us to study the functional and behavioral correlates of hippocampal rhythms and the neurophysiological mechanisms of inter-regional connection between the hippocampus and other brain regions without depending on the limited opportunities for recordings from pre-surgical patients. This advantage will thus allow us to bridge the gap between animal studies and human hippocampal studies and between the computational models and human neurophysiological data in routine experimentations.YP conducted the review; YP, DC, BC, and BJ wrote the paper.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.


Obstetric haemorrhage, sepsis and pregnancy hypertension account for more than 50% of maternal deaths worldwide. Early detection and effective management of these conditions relies on vital signs. The Microlife® CRADLE Vital Sign Alert (VSA) is an easy-to-use, accurate device that measures blood pressure and pulse. It incorporates a traffic-light early warning system that alerts all levels of healthcare provider to the need for escalation of care in women with obstetric haemorrhage, sepsis or pregnancy hypertension, thereby aiding early recognition of haemodynamic instability and preventing maternal mortality and morbidity. The aim of the trial was to determine whether implementation of the CRADLE intervention (the Microlife® CRADLE VSA device and CRADLE training package) into routine maternity care in place of existing equipment will reduce a composite outcome of maternal mortality and morbidity in low- and middle-income country populations.The CRADLE-3 trial was a stepped-wedge cluster-randomised controlled trial of the CRADLE intervention compared to routine maternity care. Each cluster crossed from routine maternity care to the intervention at 2-monthly intervals over the course of 20 months (April 2016 to November 2017). All women identified as pregnant or within 6 weeks postpartum, presenting for maternity care in cluster catchment areas were eligible to participate. Primary outcome data  were collected at 10 clusters . This trial was informed by the Medical Research Council guidance for complex interventions. A process evaluation was undertaken to evaluate implementation in each site and a cost-effectiveness evaluation will be undertaken.All aspects of this protocol have been evaluated in a feasibility study, with subsequent optimisation of the intervention. This trial will demonstrate the potential impact of the CRADLE intervention on reducing maternal mortality and morbidity in low-resource settings. It is anticipated that the relatively low cost of the intervention and ease of integration into existing health systems will be of significant interest to local, national and international health policy-makers.ISCRTN41244132. Registered on 2 February 2016.Prospective protocol modifications have been recorded and were communicated to the Ethics Committees and Trials Committees. The adapted Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Checklist and the SPIRIT Checklist are attached as Additional file The online version of this article (10.1186/s13063-018-2581-z) contains supplementary material, which is available to authorized users. Approximately 800 women die in pregnancy or childbirth every day . ObstetrThere are simple, cost-effective and established interventions to save lives for each of these pregnancy-related conditions, but the barrier to initiating treatment lies in recognition of maternal haemodynamic compromise and access to interventions , 4. AccuThe CRADLE Research Group proposes that the introduction of the CRADLE Vital Sign Alert (VSA) device, a vital-sign-measuring device and alert tool, integrated with the CRADLE training package, will aid the early recognition of haemodynamic instability secondary to haemorrhage, sepsis and pre-eclampsia in LMICs. The CRADLE VSA device has been validated as accurate for use in pregnancy, including in women with pre-eclampsia  and is tThis protocol describes the stepped-wedge cluster-randomised controlled trial to assess the implementation and clinical usefulness of the CRADLE intervention in LMICs.The trial was preceded by a mixed-methods feasibility phase. The aim was to explore the acceptability and feasibility of the CRADLE intervention and its implementation strategies in three non-trial sites representative of the 10 main trial clusters . Simultaneously, the 10 main trial clusters collected primary outcome data to evaluate the methods of data collection, and to inform the randomisation programme and the sample size calculation. Results were used to optimise the final CRADLE-3 protocol including training materials and implementation strategy for the main trial.The primary aim of the trial was to determine whether implementation of the CRADLE intervention to community and facility maternity care reduces a composite of  maternal mortality or major morbidity by ≥ 25%.The trial is complemented by simultaneous process evaluation informed by the Medical Research Council (MRC) guidance. The aim of the process evaluation is: (1) to explore if the CRADLE trial was delivered as intended ; (2) to understand whether, how and why the intervention had an impact, through exploring healthcare provider (HCP) perspectives of their usual care and of the intervention and (3) to explore if the results are likely to be scalable and sustainable. This will include an evaluation of cost-effectiveness.The CRADLE-3 trial was a pragmatic, mixed-methods, multicentre, stepped-wedge cluster-randomised controlled trial of the introduction of the CRADLE intervention (CRADLE VSA device and CRADLE training package) to routine maternity care settings in LMICs. It was informed by the MRC guidance for evaluation of complex interventions .Gokak, Belgaum, IndiaHarare, ZimbabweNdola, ZambiaLusaka, ZambiaFree Town, Sierra LeoneMbale, UgandaKampala, UgandaCap Haitien, HaitiSouth West, MalawiAddis Ababa, EthiopiaTen clusters were identified to take part in the trial. Each cluster comprised a secondary or tertiary health facility with multiple satellite primary care centres that referred to the central hospital:Each randomisation cluster crossed over from control to the CRADLE intervention at 2-monthly intervals Figs. . At the Women identified as pregnant or within the 6-week postpartum period, presenting for antenatal, intrapartum or postpartum care in cluster catchment areas* within the trial time frame.*Catchment areas were defined in collaboration with local principal investigators, and included the major outreach facilities that result in women being assessed and referred to a defined central facility/ies. These were defined prior to randomisation and remained constant throughout the study period.There were no exclusion criteria.The CRADLE intervention consisted of two components and is described according to the TIDieR Checklist .The Microlife® CRADLE VSA is a hand-held, upper-arm, semi-automated device that measures blood pressure and pulse. The device has undergone extensive testing for accuracy and is one of few blood pressure devices to have been validated as accurate in pregnancy, including in pre-eclampsia and hypotension , as wellThe device incorporates a traffic-light early warning system that alerts all levels of HCP to abnormalities in blood pressure and pulse secondary to obstetric haemorrhage, sepsis and pregnancy hypertension. The thresholds that trigger the traffic lights were determined through prediction studies , 15. TheThe production costs are less than US$20 per unit and has been designed to be simple to use, even by unskilled personnel after minimal training. The device fulfils the World Health Organisation requirements for automated devices used in low-resource settings . Other dAs part of the CRADLE-3 trial intervention, the CRADLE VSA was incorporated into routine maternity care. Primary, secondary and tertiary facilities were allocated devices according to their delivery rate, staffing numbers and number of beds per ward. Pre-existing blood pressure measurement devices were removed from clinical areas unless existing equipment had functionality designed for that area, e.g. repeated automated measures in an operating theatre or a high dependency area, and this was left to the discretion of the lead clinician.The intervention users included every cadre of healthcare professional involved in maternity care within the cluster. This included community healthcare providers (cHCPs) where they were supported at district level and involved in provision of routine maternity care. The CRADLE research group created a simple CRADLE training package for prospective CRADLE VSA users.The training package consisted of short animated films, an interactive session, action prompt cards attached to the CRADLE VSA and posters. There were two sets of training materials available, one for facility HCP (fHCPs) and one for cHCP with very limited resources or no formal training. All materials were translated into local language where required.How to use the CRADLE VSAMaintenance of the CRADLE VSABasic overview of clinical assessment and management of pre-eclampsia/eclampsia and shock in relation to the traffic-light alertsThe CRADLE package content covered:At the randomised time point the local implementation team  attended face-to-face one-off training with the research team lasting approximately 5 h. The implementation team and research team subsequently delivered one-off group training sessions lasting 2–4 h to local stakeholders and representative HCP from each of the clinical areas in the cluster.Attendees were given training materials and CRADLE VSA to disseminate to their clinical areas. The implementation team continued to visit clinical areas regularly to collect outcome data therefore providing ongoing support to HCP.The core components of the intervention  were standardised across all clusters. Delivery of the core components could be adapted to meet the needs of the cluster.This intervention was compared to routine maternity care. This involved blood pressure monitoring with a variety of blood pressure devices that were available locally and management according to local guidelines.The rate of a composite of maternal mortality or major morbidity . We will report the effect of the intervention on the primary endpoint, on each of the three components, and on each of the secondary endpoints.Maternal death was defined as death during pregnancy or within 42 days of delivery (or last contact day if contact not maintained to 42 days).Eclampsia was defined as occurrence of generalised convulsions with increased blood pressure during pregnancy, labour or within 42 days of delivery in the absence of epilepsy or another condition predisposing to convulsions.Emergency hysterectomy was defined as surgical removal of all or part of the uterus.Maternal deaths from all causes were collected with additional information regarding the cause of maternal death collected to determine the potential for impact of the CRADLE VSA. The percentage of deaths that occurred as a result of obstetric haemorrhage, pregnancy-related sepsis and hypertensive disorders of pregnancy will be presented across all clusters pre and postintervention with adjusted risk ratios (RRs). If there are other large groups of other clinically important causes of death, e.g. early pregnancy complications, these will also be defined.Intensive care unit admission, defined as any admission to a specific intensive care unit or an equivalent highest-level care environment within the trial area  in areas where an intensive care unit does not existStroke, defined as hemiparesis and/or blindness developed during pregnancy or in the 42 days postpartum lasting longer than 48 hCause of intensive care admissionCause of maternal deathCause of emergency hysterectomyPlace of eclamptic fitPlace of maternal deathMaternal secondary outcome measures:Number of stillbirths per 10,000 deliveries per month.Number of neonatal deaths per 10,000 deliveries per month.The duration and content of training and whether it was adapted in different contexts (structured observation of training)The proportion of HCPs working in maternity services that were trained to use the CRADLE deviceThe proportion of facilities with access to working blood pressure devices prior to and after implementationThe number of CRADLE VSA deliveredThe proportion of women attending maternity services that had their blood pressure measured (subset of clusters for a 4-week period immediately prior to implementation and the same duration 3 months after implementation)The implementation and impact of the intervention in each site was evaluated by both quantitative and qualitative measures. The fidelity, dose, reach and adaptation  was determined by measuring:n = 3–5 in each cluster) at 3 months following implementation explored the experience of triage, intervention, referral and transportation and reception at the higher-level facility, as well as information on the escalation process and barriers to women attending higher-level careSemi-structured interviews of a purposive sample of HCPs (n = 5–8 in each cluster) at 3 months elicited how the CRADLE VSA influences the process of referrals and work loadA focus group discussion with a purposive sample of stakeholders The proportion of clinical areas using the CRADLE VSA post implementation Costs of implementation n = 5–8 in each cluster) at 6 to 9 months and interviews with the implementation team at 12 months to elicit contextual change over time and sustainability of the interventionA focus group discussion with a purposive sample of stakeholders  over the trial will be quantified, thereby evaluating the financial sustainability of the interventions. Research costs will be excluded from the costs of the intervention.Each cluster was described according to the number of primary, secondary and tertiary facilities and their referral distances. Details on staffing levels and availability of key resources, such as intensive care beds, blood transfusion and magnesium sulphate use, was collated. In addition, major changes to the trial catchment, such as changes to infrastructure, policy, patient payment requirements or environmental conditions, were systematically reviewed each month.Methods of data collection were discussed and optimised based on the existing resources available in each site. Outcomes were triangulated across multiple sources  to ensure data completeness and all outcomes checked to avoid double counting.Outcome data were recorded over the 20-month period. Consistency and quality of source data was monitored by the research midwife/assistant at each cluster (monthly). Data were entered onto an online database (MedSciNet). This allows for extensive monitoring and query processing features, as well as a comprehensive alerting system to identify missing data. The trial coordinator will monitor data entry continuously on MedSciNet. Ten percent of the source data were validated by the primary investigator and a proportion of this was reviewed by the trial coordinator. Patient records are identified with a unique identification number generated sequentially and no identifying data are stored.The unit of randomisation is the cluster (or clusters), rather than individual women. Large variation in the primary event rate was anticipated between clusters; therefore, a restricted method of randomisation was used with zero rank correlation between events per month and order of randomisation. The sequence of timing for receiving the CRADLE intervention was determined by computer-generated random numbers by the CRADLE statistician. The clusters were masked to the order of implementation until they are informed of their allocation 2 months prior to their implementation date (to enable training to be arranged).Sample size estimation has been carried out by the CRADLE statistician, using Stata version 13.1 and the methods of Hemming and Girling . This waThe effect of the intervention on the primary outcome, on each of the three components, and on the secondary outcomes specified above, will be reported. Results will be reported firstly as odds ratios (ORs), with risk ratios (RRs) as a secondary comparison if the appropriate models converge. Within the stepped-wedge cluster design it remains appropriate to analyse outcome data from clusters individually, despite randomising cluster time points with some clusters paired .The main statistical analysis method will be by logistic regression, using generalised estimating equations with a population-averaged model   to maternity care settings in LMIC communities and facilities reduces maternal mortality and morbidity. A stepped-wedge cluster-randomised controlled trial design has been chosen to evaluate the intervention in a pragmatic fashion. Individual randomisation would be logistically difficult and would not measure impact and transferability at a population level. The stepped-wedge design is useful where phased implementation is preferable because of logistical and practical constraints.The CRADLE intervention is intended to be beneficial to all types of practice in a wide variety of settings. In keeping with the pragmatic trial design, and to ensure that results are generalisable, efforts were made to ensure that participating clusters represented diverse settings, at both a country level with different healthcare systems and at a facility level. Our study clusters, therefore, included academic/specialist facilities, private facilities and primary and secondary-level government facilities. We hypothesise that the intervention will work by facilitating earlier detection, referral and treatment of pregnancy complications.A composite of maternal mortality or morbidity  was chosen as the primary outcome as powering a trial for maternal death alone would require a prohibitively large sample size. These are robust and meaningful clinical endpoints that are unambiguous and, therefore, feasible to collect in these environments. Maternal complications were selected, each of which is associated with significant acute and chronic morbidity. Therefore, a reduction in this composite would be highly desirable. Each component of the primary outcome will be individually interrogated to ensure no paradoxical effects within the composite, i.e. an increase in morbidity may be associated with a reduction in mortality, as a consequence of intervention. Therefore, should the CRADLE intervention result in appropriate referral and intervention (e.g. hysterectomy) this will be recognised as beneficial even though the overall effect on the composite outcome may be neutral. We have ensured that all primary outcome measures are feasible to collect at primary to tertiary facilities, as determined through the feasibility study. It is, therefore, not necessary to conduct costly household surveys. In the unlikely event that a primary outcome occurs without HCP contact, this is likely to be unchanged pre and post intervention and should not affect our ability to assess the impact of intervention implementation.It is recognised that the CRADLE intervention may reduce perinatal mortality and morbidity. Perinatal outcomes have not been included as primary outcomes as the intervention is designed specifically to identify maternal health complications. Many of these occur postpartum and will not directly influence perinatal outcomes. Acquisition of detailed perinatal data within LMIC settings would be a substantial additional cost. However, the secondary perinatal outcomes will be collected in women who experience a primary outcome.The potential for this trial to demonstrate reductions in maternal mortality and morbidity and a positive impact on the working lives of HCPs will be of interest to local, national and international health-policy makers. The CRADLE VSA could become a key tool in achieving the post-2015 global maternal health goals, as well as facilitating a basic recommended standard of care, i.e. accurate blood pressure determination in all pregnant women. Given the low cost, reliability and accuracy of the device, if the trial is successful, a low regulatory hurdle and rapid progression to adoption is anticipated. The trial results will be generalisable beyond the immediate research setting, as the trial will be carried out in a variety of countries and at both at community and facility levels. A robust scale-up strategy will be required to support international scale-up to allow widespread and equitable access to the innovation. This will require appropriate resourcing to include commercial expertise and facilitate partnership between inventors, manufacturers and governments to maximise effective and efficient marketing, supply and distribution through appropriate channels and fair pricing.OngoingAdditional file 1:SPIRIT Checklist. (DOC 122 kb)


Mallet fingers with an avulsion fracture of the distal phalanx or rupture of the terminal tendon of the extensor mechanism is known as a common injury, while mallet thumb is very rare. In this paper, the case of a 19-year-old woman with a sprained left thumb sustained while playing basketball is presented. Plain radiographs and computed tomography revealed an avulsion fracture involving more than half of the articular surface at the base of the distal phalanx. Closed reduction and percutaneous fixation were performed using the two extension block Kirschner wires' technique under digital block anesthesia. At 4 months postoperatively, the patient had achieved excellent results according to Crawford's evaluation criteria and had no difficulties in working or playing basketball. Various conservative and operative treatment strategies have been reported for management of mallet thumb. We chose the two extension block Kirschner wires' technique to minimize invasion of the extensor mechanism and nail bed and to stabilize the large fracture fragment. Injury to the tip of a finger, such as an avulsion fracture of the distal phalanx or a rupture of the terminal tendon of extensor mechanism, often occurs during sports activity . HoweverA 19-year-old woman sprained her left thumb while playing basketball and presented with tenderness and swelling around the dorsal side of the interphalangeal (IP) joint. On physical examination, she could not actively extend the joint but neither passive extension nor active flexion of the joint were disturbed. There was no instability of the IP joint against radial and ulnar stress. Radiographs and computed tomography showed an avulsion fracture at the base of the distal phalanx involving more than half of the articular surface Figures . A reducMallet finger due to avulsion fracture of the distal phalanx or rupture of the terminal tendon of the extensor mechanism is known as a common injury, but mallet thumb is rare. A series by Robb included mallet deformity of 149 digits, only one of which was a mallet thumb , and a sBecause of the rarity of mallet thumb, there is no consensus regarding the recommended treatment. Din and Meggit published a report that included 4 cases of mallet thumb without avulsion fracture and showed excellent results with operative treatment , while MVarious surgical treatments have been advocated for bony mallet fingers including tension band fixation, pull-in suturing, extension block with Kirschner wires, hook plate, external fixation, compression pins, and biodegradable device, with excellent results , 9–14. HAs a limitation, the follow-up period of this case was short; therefore, further follow-up will be needed for the long-term result.In conclusion, we encountered a rare case of bony mallet thumb that we repaired using the two extension block Kirschner wires' technique and the outcome was excellent.


In juvenile idiopathic arthritis (JIA), imaging is increasingly used in clinical practice. In this paper we discuss imaging of the knee, the clinically most commonly affected joint in JIA. In the last decade, a number of important steps have been made in the development of imaging outcome measures in children with JIA knee involvement. Ultrasound is undergoing a fast validation process, which should be accomplished within the next few years. The validation processes of MRI as an imaging biomarker for clinical trials in the JIA knee are at an advanced stage, with important data available on the feasibility, reliability and validity of the Juvenile Arthritis MRI Scoring system. Moreover, both US and MRI data are emerging on the normal appearance of the growing knee joint. The knee joint is the most commonly affected joint in juvenile idiopathic arthritis (JIA) . It can,Conventional radiography has played an important role in the management of JIA, but imaging techniques such as ultrasonography (US) and MRI are now considered more helpful for several reasons. First, the trend towards early suppression of inflammation to prevent irreversible damage of cartilage and bone has shifted the emphasis from detecting damage (using radiography) to detecting early joint changes of JIA. This drives the need for imaging techniques that are more sensitive than radiography in the evaluation of inflammatory processes as well as early osteochondral changes. In this regard, MRI and US play an increasingly important role in evaluating and monitoring disease activity . Second,In the clinical setting, conventional radiography still plays an important role, especially in narrowing the differential diagnosis and in establishing a baseline for disease follow-up. Although radiography provides important information on growth disturbances and damage to cartilage and bone, it does not show early changes suggestive of active inflammation . No valiAlbeit nonspecific, the presence of joint fluid and synovial thickening can be seen as increased density in the infrapatellar fat pad and suprapatellar region. In the Western population, bone erosions in knee joints in children with JIA are relatively rare. Because of the availability of more effective treatment options and the relatively large amount of epiphyseal cartilage in knees in growing children, erosive damage is usually only seen as a late complication of JIA. When present, bone cysts and bone erosions can be seen. Moreover, loss of articular cartilage can cause gradual joint space narrowing. Joint malalignment and ankyloses in the knee are extremely rare.Radiography does have an advantage over ultrasound and MRI in the determination of growth disturbances. Due to hyperaemia, overgrowth of extremities and disturbance of epiphyseal bone formation can be observed. Moreover, it is easier to compare bilateral joints using radiography compared to, for instance, MRI.In paediatric rheumatology, ultrasound plays an important role in narrowing the differential diagnosis and can be useful for treatment monitoring as well as for guidance for joint injections . It is sFor the application of US in paediatric rheumatology, both grey-scale B-mode and power/colour Doppler modes should be used in every examination. Also, standard scanning positions should be considered. For standard clinical paediatric ultrasound examination of the knee, the child is placed in supine position with a slightly flexed knee. The standard sagittal view includes the patella inferiorly, the quadriceps tendon, and the suprapatellar recess . An axiasynovial thickening and synovial effusion [The main US features characterizing pathology in JIA at this stage of the development of a US-based outcome measure are effusion . Synoviaeffusion .Fig. 1UlPower/colour Doppler is useful to acquire information about tissue perfusion. It is important to clarify that synovitis can be detected on the basis of B-mode findings  alone. Nevertheless power and colour Doppler have proved to be useful in differentiating active (hypervascular) from fibrotic (hypovascular) pannus . In growloss of cartilage thickness has been described. US has a strong correlation with MRI in the evaluation of cartilage thickness of the medial and lateral condyle and the intercondylar region, with a rho correlation of 0.70–0.86 [In children with JIA, .70–0.86 .We are currently developing a consensus-based US scoring system. The preliminary scoring system consists of three grades separated for synovitis and synovial perfusion Table . Its relAge-related US findings have been described in healthy children , 15. TheWithin the last decade, the use of MRI and advances in MRI techniques have substantially improved the evaluation of joint pathologies in children with JIA . MRI is In children with JIA and knee involvement, the main imaging features include synovial thickening, joint effusion and bone marrow oedema. Moreover cartilage loss and bone erosions — although relatively rare in paediatric patients — can be observed. Tendinopathy, enthesopathy, inhomogeneity of the infra-patellar fat pad and bone cysts can be seen, as well, but these abnormalities are relatively uncommon in the knee joint. Moreover, the reliability of scoring these secondary features is unsatisfactory . Table 3synovial thickening is the principal pathological process in JIA, and the presence of synovial thickening on knee MRI is associated with the clinical onset of JIA [Synovial inflammation leading to t of JIA . On MRI,t of JIA . The sigt of JIA . Omittinjoint effusion  in the articular cartilage or contour abnormalities, defects or thinning of the cartilage. Gradient-echo and proton-density-weighted sequences provide good contrast in the cartilage structure and can be used to evaluate the cartilage–synovial fluid interface and the subchondral bone.bone erosions. Bone erosions can be seen on T1-weighted images as loss of the normal low signal intensity of cortical bone and loss of the normal high signal intensity of trabecular bone  the Juvenile Arthritis MRI Scoring system for use in JIA  and (2) Recently the Outcome Measures in Rheumatology (OMERACT) special interest group on MRI in JIA conducted a reliability study evaluating both scoring methods . This stBesides this international reliability study, the intra-observer and inter-observer reliability of the original Juvenile Arthritis MRI Scoring system has been evaluated, and both proved to be reliable . These dAlthough MRI has some practical limitations such as limited availability in some regions/countries and the challenge of maintaining the same position for a prolonged period of time, it has proved feasible to perform contrast-enhanced knee MRI in children with JIA as young as 5 years old without the use of anaesthesia or sedation . MoreoveWithin the last few years, two studies have focused on the sensitivity to changes in disease activity using the original Juvenile Arthritis MRI Scoring system , 30. In Next to the responsiveness and discriminant validity, the clinical validity has also been evaluated. In a study focusing on whether clinical, laboratory or MRI measures were able to differentiate JIA with active arthritis from other causes of non-infectious arthritis in a group of patients with clinical signs of early arthritis, multivariate analysis showed that MRI-based synovial thickening was independently associated with JIA  .synovial membrane in children. As stated, an intravenous injection of a gadolinium-based contrast agent is warranted for reliable evaluation of the synovial membrane. Therefore data on normal values for the synovial membrane in healthy children are sparse. Two studies that focused on the contrast-enhanced appearance of the synovial membrane in children have been performed: (1) A study by Nusman et al. [Because synovial inflammation is the hallmark of disease activity in JIA, it is important to determine the normal appearance and thickness of the n et al.  looked an et al.  determinjoint fluid in the knee can be seen in the majority of healthy children. The largest pockets of normal joint fluid in healthy children are located in the central locations of the knee — around the cruciate ligaments and retropatellar region [Some r region . The mear region , 33.Bone marrow changes suggestive of bone marrow oedema in knees of healthy children are relatively uncommon. In a study of 57 healthy children, bone marrow changes suggestive of bone marrow oedema were observed in 3 healthy children only. In all three children, the bone marrow changes were located in the apex patellae [patellae . The preMoreover, zones of hematopoietic red bone marrow in the distal diaphysis and metaphysis of the femur might be seen as flame-like regions with signal characteristics fitting with bone marrow oedema. Typically, these marrow flames originate from the physis and have straight vertical margins . These hThe thickness of the normal articular cartilage in knees of growing children differs with age. As expected, the cartilage is normally thicker in younger children compared to older children. A study performed by Keshava et al.  clearly The validation process of US in children with JIA is moving forward. Despite the relatively easy applicability of US, until now there has been no specific US knee scoring system. Rather the US knee examination is part of a more global US score covering multiple joints with respect to disease activity. The Outcome Measures in Rheumatology paediatric ultrasound working sub-group has performed a number of steps towards the validation of US as an outcome measure in paediatric rheumatology. Next important steps of the work of the sub-group include multicentre reliability testing of the newly created score tested in a single-centre prospective study. In this case, sensitivity to change will also be tested. The sub-group has started its work in tendons and entheses and should follow the Outcome Measures in Rheumatology Filter 2.0 criteria for the validation process. Another important step will be to develop scores incorporating osteochondral changes, where US is expected to be beneficial in evaluating peripheral cartilage. Its utility in detecting erosive changes might also be tested, and compared to that of MRI and radiography. This underlines the importance of close collaboration between US and MRI working groups, which is planned to start in 2018 with a joint symposium.Although the first steps towards developing evidence-based guidelines for MRI data acquisition and interpretation have been made, further cooperation is necessary. The use of a juvenile arthritis MRI scoring system for the knee as an outcome measure in daily practice and clinical trials is promising. Thus far, juvenile arthritis MRI scoring has only been internationally tested in JIA patients visiting academic paediatric rheumatology centres in the Netherlands and Canada with full access to high-quality treatment. This has resulted in a population of studied JIA patients with only mild to moderate disease activity. Consequently, the presence of destructive changes of cartilage and bone has been relatively low in the studies performed until now. To evaluate the value of juvenile arthritis MRI scoring as a sensitive measure regarding destructive changes, further international collaboration is warranted, especially among research centres with access to more severely affected JIA patients. Furthermore, collaboration should focus on developing an MRI atlas of healthy joints in children, obtaining agreement on an optimal imaging protocol for the knee and further validating scoring methods. Interaction between researchers and health professionals in JIA imaging is essential to obtain international consensus and continuous improvement of MRI outcome measures. Such collaboration is expected to be very fruitful under the umbrella of an international, well-accepted collaborative international group such as the Outcome Measures in Rheumatology working group.According to the Quantification Imaging Biomarker Alliance of the Radiological Society of North America, quantitative imaging techniques covering the full spectrum of imaging have to be developed and validated to provide more objective tools to measure disease activity throughout all fields of medicine . With reForthcoming research is expected to shed more light on the suitability of advanced quantitative MRI techniques for evaluating inflammatory and destructive changes in the JIA knee, including dynamic contrast-enhanced MRI, T2-mapping and diffusion-weighted imaging –44. CurrIn this paper, we discussed the status of imaging the JIA knee. In the last decade a number of important steps have been made in the development of imaging outcome measures in children with JIA knee involvement. Ultrasound is undergoing a fast validation process, which should be accomplished within the next few years. The validation processes of MRI as an imaging biomarker for clinical trials in the JIA knee are at an advanced stage, with important data forthcoming from both single-centre as well as international multi-centre studies on the feasibility, reliability and validity of the Juvenile Arthritis MRI Scoring system. Moreover, data are emerging in both US and MRI on the normal appearance of the growing knee joint. However, future research is clearly needed, especially within the scope of evaluating the value of Juvenile Arthritis MRI Scoring as a sensitive measure for assessing destructive changes. The ultrasound score needs further validation, as well. Moreover, further validation is needed for promising advanced quantitative US and MRI techniques for the evaluation of inflammatory and destructive changes in JIA.