The behavior of neutrophils is very important for the resolution of inflammation and tissue repair. People have used advanced imaging techniques to observe the phenomenon of neutrophils leaving the injured or inflammatory site and migrating back into blood vessels in transgenic zebrafish and mice, which is called neutrophil reverse migration. Numerous studies have shown that neutrophil reverse migration is a double-edged sword. On the one hand, neutrophil reverse migration can promote the resolution of local inflammation by accelerating the clearance of neutrophils from local wounds. On the other hand, neutrophils re-enter the circulatory system may lead to the spread of systemic inflammation. Therefore, accurate regulation of neutrophil reverse migration is of great significance for the treatment of various neutrophil- mediated diseases. However, the mechanism of neutrophil reverse migration and its relationship with inflammation resolution is unknown. In this review, we reviewed the relevant knowledge of neutrophil reverse migration to elucidate the potential mechanisms and factors influencing reverse migration and its impact on inflammation in different disease processes. Neutrophils are the main component of leukocytes, accounting for 50 -70% of the total number of leukocytes and play an essential role in anti-infection. Neutrophils are known to be the first cells to reach the site of inflammation and their chemotaxis to the site of inflammation is the critical immune response process in the management of tissue infection and injury. Neutrophils have complex functions. They can eliminate pathogens through phagocytosis, degranulation, reactive oxygen species (ROS), and neutrophil extracellular traps (NETs) –3. HowevWhat are the effects of reverse migration of neutrophils on the organism? Some scholars believe that reverse migration regulates the resolution stage of inflammation, reduces neutrophils retention at the inflammatory site, and accelerates the resolution of local inflammation . HoweverThe form of neutrophil movement has attracted much attention. At the initial stage of inflammation, many chemokines will be released from the wound site , and neuSome scholars believe that neutrophils leave the inflammatory site due to the influence of chemotactic signals far away from the inflammatory site. Recent studies have shown that reverse migration is related to vascular permeability. When inflammation occurs, the vascular permeability increases, and the chemokines released by tissues and immune cells diffuse int the blood vessel wall. Endothelial cells bind to some of these chemokines and present them in the lumen of the vessel, resulting in a greater concentration of certain chemokines in the plasma than at the injury site, thus prompting neutrophils to migrate into the vessels. During the reverse migration phase, an increase in the concentration of CXCL1 in the blood can be detected, and the increased concentration of CXCL1 is sufficient to drive the reverse migration of neutrophils .Neutrophils have a variety of reverse migration patterns . One pathigh, CXCR1low, while neutrophils in resident tissue were CD54low, CXCR1low, and the circulating neutrophils were CD54low, CXCR1high [Compared with neutrophils in resident tissues and circulation, neutrophils undergoing reverse migration have a unique phenotypes. The neutrophil phenotype after reverse migration was cell adhesion molecule-1 (ICAM-1 or CD54) XCR1high . The expXCR1high , indicatXCR1high .Neutrophils reverse migration of neutrophils has been widely studied in the past decade, and there are many different views on this phenomenon. We still need more detailed and more convincing evidence to accurately explain the phenomenon of neutrophil reverse migration. At the same time, we also need to master many aspects of reverse migration, such as mechanism, influencing factors, and drug targets.The specific mechanism of neutrophils reverse migration is still unclear, so neutrophils have been observed to migrate from wounds through surrounding tissues , 8, 16 oReverse transendothelial migration was first observed in real-time imaging transgenic zebrafish models . NeutropWhy is the expression of JAM-C on endothelial cells decrease during an ischemia-reperfusion injury? It is related to the leukotriene B4-Neutrophil Elastase Axis. Nourshargh et al. confirmed that the LTB4 - NE axis is a promoter of reverse transendothelial migration: expression of the lipid chemotactic agent LTB4 was increased during ischemia-reperfusion injury in the cremaster muscle of mice. LTB4 binded to BLTR on intravascular neutrophils and stimulated neutrophils to produce excess neutrophil elastase (NE), then neutrophils delivered NE to EC-JAMC via Mac-1, and finally NE hydrolyzed endothelial JAM-C protein, resulting in loss of JAM-C as shown by ① in Fig. In addition, in some studies, we have found that the LTB4-NE axis is not only related to rTEM, but is also closely linked to secondary organ damage. It was found that intradermal injection of LTB4 into the cremaster, buccal muscle or ear skin of mice resulted in neutrophils accumulation in the lungs and distal organ damage  . We knowStudies have found that extracellular cold-inducible RNA-binding protein (CIRP) may induce the reverse migration of septic neutrophils by upregulating NE expression and down-regulating JAM-C expression in mouse lungs . Sepsis In addition, studies in zebrafish have shown that the HIF signaling pathway is associated with neutrophils reverse migration. HIF is a transcription factor that acts on a variety of immune cells, such as macrophages, T cells, B cells and neutrophils and plays an important role in the immune and inflammatory response of the body . The HIFThe presence of lipid mediators has also been associated with neutrophils reverse migration. Prostaglandin E2 (PGE2) is one of the critical cell growth factors and regulators. PGE2 is the most abundant prostaglandin in the body and has multiple effects on inflammation . It was Reducing the excessive retention of neutrophils at the site of inflammatory is critical to promote inflammation resolution. CXCL12 / CXCR4 signal axis retains neutrophils at the site of inflammation . RenshawMacrophages also play a specific role in promoting the reverse migration of neutrophils. Macrophages control neutrophils reverse migration through redox and Src family kinase signals, which are achieved by contacting neutrophils . HuttenlTo date, the exact mechanism of neutrophil reverse migration is unclear.The effect of some anti-inflammatory drugs is linked to the regulation of neutrophil reverse migration. If we could control neutrophils reverse migration through drugs, it would be greatly beneficial to improve the patients’ condition. Here we have listed some medications associated with reverse migration to provide a new idea for the treatment of inflammation.Tanshinone IIA is a Chinese herbal medicine with anti-inflammatory activity. The mechanism of tanshinone IIA accelerating inflammation in vivo is related to neutrophils. Some scholars evaluated the effect of tanshinone IIA on freshly isolated human neutrophils by morphology and Annexin V / PI staining and found a significant increase in apoptosis after 8 hours of incubation with tanshinone IIA in neutrophils . HoweverKuding tea is a kind of tea rich in chlorogenic acid, which has anti-inflammatory and anticancer effects. Recent studies have found that chlorogenic acid-enriched extract of kuding tea promotes neutrophil reverse migration by inducing phosphorylation of ERK and AKT proteins. ERK  and AKT The relative levels of different lipid mediators can also promote the resolution of inflammation and may be involved in the reverse migration of neutrophils. As mentioned previously, LTB4 is a neutrophil chemoattractant, but following a switch in lipid mediator class, the pro-inflammatory lipid mediator production pathway is altered in favour of pro-regressive mediators such as lipotoxins, abasicins, and protectins , 44. TheMany studies in mice and zebrafish have shown that reverse migration reduces the accumulation of neutrophils at the site of trauma and accelerates local inflammation resolution. However, neutrophils migrating back into the blood vessels may also lead to the spread of systemic inflammatory. That is to say, reverse migration is a double-edged sword. How to balance the resolution of local inflammation and the spread of systemic inflammation is a crucial issue for us. Here we explain the effects of reverse migration in different animal disease models to further understand reverse migration.In the zebrafish larvae caudal fin or ventral fin aseptic injury model, zebrafish neutrophils can be directly observed leaving the wound and migrating back into the blood vessels , 23, 46.highneutrophils with THP (a kidney-specific protein) [high neutrophils with THP in the blood and accelerated recovery renal function and tissue repair. It was confirmed that reverse migration accelerated the resolution of local inflammation.Reverse migration is also exist in mice during the recovery from acute renal ischemia-reperfusion injury. After acute renal ischemia-reperfusion injury, ICAM-1protein)  were detNeutrophils reverse migration also leads to the spread of pathogenic neutrophils to distal organs, thereby promoting the spread of systemic inflammation. We have previously explained that reverse migration is associated with the expression of JAM-C, which also plays a massive role in promoting the spread of systemic inflammation. In mice suffering from testicular I-R injury , 23 and high and CXCR1lowphenotypes in peripheral blood increased significantly, indicating that acute pancreatitis is closely related to neutrophils reverse migration. After BLT1 blockade by LY293111, the number of neutrophils returning to circulation was reduced, the percentage of neutrophils with the unique phenotypes of CD54 high and CXCR1low in peripheral blood decreased and the degree of lung injury was reduced [If the conclusion that reverse migration causes the spread of systemic inflammation is true, then blocking reverse migration could reduce the spread of systemic inflammation. We have previously explained that the LTB4-NE axis is related to reverse migration. In RA and LPS-induced acute pancreatitis mice, acute pancreatitis leads to an increase in LTB4 and its specific receptor BLT1, which aggravates the lung injury associated with acute pancreatitis . At the  reduced . These e reduced  and to t reduced , indicat+ neutrophils with reverse migration markers were detected in bone marrow and lung, and CXCR4 was upregulated in the lung. Interestingly, treatment with CXCR4 antagonist AMD3100 resulted in increased GFP + neutrophils in the lungs and decreased GFP + neutrophils in the bone marrow of mice. It is known that CXCR4 upregulation of neutrophils allows them to return to bone marrow via CXCL12 [Why does reverse migration lead to secondary organ damage and the spread of systemic inflammatory? The septic thermal liver injury experiment in mice  shows tha CXCL12 . This pha CXCL12 . Althouga CXCL12 . The desa CXCL12 .It is well known that activated neutrophils are prone to produce reactive oxygen species(ROS) and that excessive ROS can lead to tissue or organ damage. After reverse migration, neutrophils produce a large amount of ROS , 21. TheIn general, reverse migration is positive for local inflammation resolution, but neutrophils returning to the circulation can spread to secondary organs, causing secondary organ damage and leading to the spread of systemic inflammation. In particular, in infectious inflammatory diseases, the migration of large numbers of activated neutrophils back into the blood vessels can easily cause the spread of inflammation in distal organs, especially those with an abundant blood supply, such as the lungs, and it is therefore particularly important to rapidly upregulate the expression of CXCR4 on post-migrating neutrophils to reduce their residence time in the lungs and return them to the bone marrow for apoptosis.In recent decades, greater grogress has been made in our understanding of neutrophils with the help of in vivo imaging techniques and genetic technologies. However, neutrophil reverse migration remains a phenomenon to be investigated. While excessive and prolonged neutrophil infiltration can lead to the development of chronic tissue inflammation, the migration of neutrophils back into the circulation may lead to systemic inflammation and tissue damage in distal organs. It is likely that the answer to this question depends on the nature, magnitude, and location of the inflammation. In the case of infection, premature neutrophil reverse migration may result in failure to clear the infection and dissemination of intracellular pathogens to other sites. In the case of tissue injury, reverse migration might have positive effects at the local site of inflammation, as neutrophils depletion may promote wound healing, but may have negative effects systemically such as multiple organ failure. Therefore, by precisely controlling reverse migration, it is possible to improve the acute inflammation of patients and prevent the inflammation from developing into chronic inflammation and secondary organ damage. However, most of the reverse migration observed to date has occurred in zebrafish and mice, and the behavior of human neutrophils in vivo needs to be further studied.Recent studies have shown that inflammation resolution is an actively programmed process regulated by the production of a series of endogenous anti-inflammatory and pro-regressive mediators . The new


First Episode Psychosis (FEP) treatment is a critical element of mental health-care systems, which has been shown to improve outcomes in this patient group. Due to divergent historical and political trajectories, countries of Central and Eastern Europe have taken a different course in the development of mental health-care. Among these differences is the less advanced level of present FEP treatment networks. Traditionally mental health-care is more inpatient based in these countries, with a lesser emphasis on specialized outpatient services, and early intervention programmes have been only launched during the last 15 years. Despite the lag of the development of FEP services, a variety of models has been already started in our countries. In my lecture I will review the literature about the Central and Esteran European region. I will also present good practices of how the existing early intervention programmes can be integrated into the traditional mental health-care systems.No significant relationships.


Many people think that people with mental disorders might be dangerous or unpredictable. These patients face various sources of disadvantages and experience discrimination in job interviews, in education, and housing. Mental health-related stigma occurs not only within the public community, it is a growing issue among professionals as well. Our study is the first that investigates the stigmatising attitude of psychiatrists across Europe.We designed a cross-sectional, observational, multi-centre, international study of 33 European countries to investigate the attitude towards patients among medical specialists and trainees in the field of general adult and child and adolescent psychiatry.An internet-based, anonymous survey will measure the stigmatising attitude by using the local version of the Opening Minds Stigma Scale for Health Care Providers. Data gathering started in July this year and will continue until December 2020.This study will be the first to describe the stigmatising attitude of psychiatric practitioners across Europe from their perspectives.The study will contribute to knowledge of gaps in stigmatising attitude towards people with mental health problems and will provide with new directions in anti-stigma interventions.No significant relationships.


Transcatheter mitral valve replacement is a promising alternative to open-heart surgery in elderly patients. Patients with severe mitral annulus calcification (MAC) are a particularly high-risk population, where postprocedural complications can have catastrophic effects. Amongst these, obstruction of the left ventricular outflow tract can lead to ventricular hypertrophic remodeling and subsequent heart failure, while subclinical valve thrombosis can result in early bioprosthetic valve failure.To elucidate the mechanisms of left ventricular outflow tract obstruction and valve thrombosis following valve-in-MAC procedures, we used image processing and Computational Fluid Dynamics (CFD) software to generate patient- and device-specific models based on preprocedural CT data. Personalized computer simulations were performed to predict the left ventricular haemodynamics after implantation in three patients with severe MAC.The simulations have successfully captured the increased pressure gradient in the left ventricular outflow tract as a result of the partial obstruction due to the implanted valve. Regions of wall shear stress above the threshold value for platelet activation were also observed on the bioprosthetic frame as a result of the reduced outflow tract area, which led to increases in flow resistance and blood residence time inside the ventricle. Consistent with these findings, areas of slow recirculating flow and blood stasis formed near the valve frame, creating potential pro-thrombotic conditions.This study provides insight into the relationship between size and shape of the outflow tract post-implantation, pressure gradients and pro-thrombotic flow metrics such as wall shear stress and blood residence time. Results show the potential of CFD modeling to bring key functional metrics into preprocedural assessment for a comprehensive evaluation of post-procedural risks beyond anatomical factors. Following further validation and extension to the atrial chamber, this approach can provide an in-depth analysis of the likelihood of valvular thrombosis. Mitral annulus calcification (MAC) is the deposition of calcified material around the mitral annulus leading to a reduced orifice area and stiffening of the surrounding tissue, which can lead to concomitant valvular involvement . This ch2 is currently considered to lead to an unacceptable degree of obstruction  Global registry (30-day outcomes) were stroke 3.9%), mitral valve re-intervention 13.8%), persistent mitral regurgitation (13.2%), valve embolism (6.9%) and LVOT obstruction (39.7%) . A low dose non-contrast scan was used to reduce the range of retrospective scanning and to evaluate for mitral valve annulus calcification. Following this, a retrospective contrast enhanced ECG gated helical acquisition was performed in a single breath hold with bolus tracking in the ascending aorta to optimize contrast enhancement in the left atrium and over the mitral valve. Scanning parameters included a heart rate dependent pitch (0.2–0.45), gantry rotation time of 250 ms tube voltage of 100 or 120 kVp, depending on the patient’s body-mass index and a tube current of 125–300 mA. A biphasic contrast protocol was used with 90 ml of iodinated contrast at a flow rate of 5 ml/s followed by 40 ml of saline at 5 ml/s. The acquired cardiac CT data was reconstructed using a medium level of advanced model-based iterative reconstruction with the use of a 250 mm field of view, 512 × 512 matrix and a smooth reconstruction kernel. In the presence of significant ectopy, ECG-editing was performed using vendor-specific software. All ventricular measurements were taken at the peak systolic CT frame in line with previous protocols for evaluation of the LVOT obstruction , 16.The blood pool of the LV was segmented with manual contouring at the peak systolic-frame in the multiphase CT series using the software MITKWorkbench , as showWall motion tracking was performed using temporally sparse free-form deformation to create a vector field of displacement values, which were then applied to the surface mesh, deforming the initial mesh to match the wall motion at each time frame in the CT series . To valim3 and viscosity 3e−3 Pa.s.From the end-systolic surface mesh a polyhedral volume mesh was created using the commercial software STAR-CCM+ (Siemens PLM). A CAD model of the Sapien 3 was embedded into the fluid domain in the position of the mitral annulus prior to volumetric meshing . ComputaA mesh independence study was performed to assess the optimal size of the mesh. The final volumetric mesh for the LV blood pool comprised an average of 1,100,000 elements, depending on the size of the LV, with a base size in the range of 0.5 mm. Volumetric growth rate was 1.1, constricting the increase in element size toward the centre of the ventricle.Boundary conditions were derived from the preprocedural CT datasets. Specifically, the mass flow rate of blood through each of the mitral and aortic valves was derived from the change in mesh volume over each time step, and the deformation field extracted from the wall motion tracking was prescribed on the endocardial wall.Aortic jet peak velocity and the peak pressure gradient in the LVOT were measured from the simulation data and compared to post-procedural Doppler derived values for validation .Pressure gradients were measured over the systolic period in four locations, with mean and peak values reported in Wall shear stress magnitude was visualized on the device frame as a surrogate marker for platelet activation . All thrThe OSI quantifies the oscillatory nature of the flow with low values indicating predominantly unidirectional flow. OSI iso-contours were used in conjunction with streamline analysis to identify areas of blood recirculation on the device frame . All casThe BRT throughout two cardiac cycles was measured in the ventricular cavity  to identFinally, The principal findings of the current study are that a relationship exists between LVOT pressure gradient, size and shape of the neo-LVOT area and pro-thrombotic flow metrics such as WSS and OSI. Further, the size and shape of a bioprosthetic in relation to the ventricle wall impact ejection dynamics and BRT, and the WSS can reach values close to the threshold for platelet activation on the device frame during ejection.In line with previous findings from both clinical and computational studies, LVOT pressure gradient was inversely proportional to neo-LVOT area for all cases , 15, 40.Finally, in all of our models the combination of WSS magnitude and exposure times on the valve was found to be close to the threshold values for platelet activation measured in experimental settings shown in , suggestThis type of personalized modeling provides insight into blood flow metrics whose measurement is challenging to obtain in a clinical setting without the use of specialized sequences, currently applied in research settings only . Such approach has shown merit in displaying the potential of LVOT obstruction to exacerbate risks of thrombus formation on the device, as well as in informing which patients may require preprocedural septal modification prior to ViMAC procedures, such as with alcohol septal ablation or leaflet modification procedures with the LAMPOON technique.The CAD model of the bioprosthetic device is simplified and does not account for moving leaflets and details in the different frame components. Consideration was not made to the layers of device design including the cobalt-chromium frame, trileaflet bovine pericardial tissue valve, and polyethylene terephthalate (PET) fabric skirt, in which small particles may become trapped. A more realistic device model could therefore increase the amount of blood trapped by the different elements composing the device and hence our simplified approach could represent a “best case scenario.” Papillary muscles are excluded from the ventricle segmentation and the endocardium surface is smoothed to reduce likelihood of numerical instability. However, these approximations should result in an attenuation of the flow disturbances caused by the valve implantation, also suggesting that our value could underestimate the magnitude of pressure gradients and WSS, as well as the potential for blood flow to adhere to the valve structure. The accuracy of the ventricle motion is limited by the number of CT time-frames obtained at the time of capture, which is 10 frames for each case. Segmented surfaces are subject to interpolation between CT frames to a temporal resolution of 0.5 ms, therefore there may be loss of accuracy in the deformation field prescribed on the surface of the model (endocardium) and subsequently in the flow simulation. Finally, the sample size of the study is limited to three patients due to the availability of ViMAC patient data, not allowing the comparison between patients with significant LVOTO and those without.The methodology presented has successfully captured the increased pressure gradient and maximum WSS as a result of reduced neo-LVOT area, and also provided insight into the mechanistic interpretation of OSI, WSS and BRT on the underside of the valve leaflets that is increasingly observed in transcatheter bioprosthetic valves. This shows the potential of CFD analysis, once validated on a larger patient cohort, to complement image-based preprocedural assessment by providing important information on the patient-specific haemodynamics, as well as to shed light on mechanisms of potential thrombus formation on the valve.The original contributions presented in this study are included in this article/supplementary material, further inquiries can be directed to the corresponding author.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.SH, AD, and RR designed and wrote the study. SH and AD performed and analyzed the simulations. AY, BP, and SR contributed to the reviewing and editing of the manuscript. All authors contributed to the article and approved the submitted version.


Collectively, these articles provide multidisciplinary evidence that the ECM operates as a highly dynamic functional framework in physiology and pathology. Furthermore, they underscore the opportunities available for future explorations that can help develop more robust models of ECM structure and function for human health and disease.The current volume of articles focused on extracellular matrix (ECM) presents some recent developments in biology, bioengineering, and pathology that reiterate the central theme of our Petzold and Gentleman offer a comprehensive review of mechanical cues and their impact on stem cells and embryogenesis. Their article contrasts the effects of mechanotransduction from intrinsic cues vs. extrinsic cues for cell differentiation. ECM mechanical properties and topography take the central stage in their discussion of cellular response to mechanotransduction. The authors also provide a coherent summary of the bidirectional structural changes that occur in the cell and the ECM mediated by a robust cytoskeletal signaling network. Furthermore, their discussion extends to the mechanoregulation of embryogenesis and the novel methods that have emerged in this field for the measurement of embryonic stiffness.Korntner et al. test the capacity of chick embryos to offer a system for the study of craniofacial tendon development. Using the jaw-closing tendon of the musculus adductor mandibulate externus and the jaw-opening tendon of the musculus depressor mandibulae, they characterize the developmental trajectory of cell and ECM morphology. They discover that several markers implicated in limb tendon formation are also present in embryonic jaw tendon. Their morphological and molecular biological characterizations of the developmental program directing chick jaw muscle tendon assembly provide a basis for future modeling of the developmental program shaping human masticatory tendons.Few models of tendon developmental biology are available. Moreover, models of tendon development that allow investigation of craniofacial muscles have yet to be explored. López-Mengual et al. illustrates the critical role played by mechanical cues in the developing nervous system. Using the mouse embryonic explant system for the study of slices of developing brain in Matrigel preparations, the authors complement the methods of classical developmental biology with atomic force microscopy and traction force microscopy measurements to demonstrate differential tissue stiffness of the developing brain and its immediate effects on Cajal-Retzius cell migration and ultimate effect on neocortical development.The study by Scholp et al. present their design of a custom force-bioreactor that uses fibroblast-seeded fibrin gels to allow microscopy-based documentation of force generation in response to drug treatment. Lu et al. describe their findings on the use of pulmonary visceral pleura (PVP) as a potential biomaterial for tissue repair and reconstruction. They test PVP processed from both swine and bovine lungs to determine its structural characteristics, mechanical properties, cytotoxicity, and biocompatibility for rat sciatic nerve and skin repair.Bioengineering researchers have long provided an ever-expanding toolkit of methods to investigate cell and ECM mechanobiology. In that tradition, Despotović and Ćosić. Their work shows that the collagen fiber straightness quantified using theoretical methods as a measure of ECM remodeling can be a useful indicator of the early stages in the development of colorectal cancer.ECM structural organization has long remained a fertile ground for investigations from diverse scientific fields. An application of methods from condensed matter physics to detect changes in collagen fiber organization in colorectal cancer is tested by Knutsen et al. report on the therapeutic effects of KATP channel opener Minoxidil for the treatment of individuals with William-Beuren Syndrome (WBS), which occurs as a result of loss of one copy of the elastin gene ultimately causing large artery vasculopathy. After confirming the similarities in pathophysiological features of elastin heterozygous null mice with those of children with WBS they demonstrate partial remedy of cardiovascular features in mice. Their results provide the necessary evidence to suggest consideration of Minoxidil therapy under strict cardiac size monitoring as an adjunct to surgical intervention for humans with WBS cardiovascular pathology.Mammoto et al. describe the ECM changes that occur in aging aorta with a particular focus on the fragmentation of elastic fibers and excessive deposition and crosslinking of collagens as major drivers of aging-induced aortic dysfunction. Cardiac pathology is the focus of yet another investigation published in this Research Topic. Studying a rodent model of heart hypoplasia induced by congenital diaphragmatic hernia, Watson et al. suggest that changes in environmental cues such as ECM stiffness and mechanical force may underlie the pathological progression of heart hypoplasia by affecting the balance between cardiomyocyte cell proliferation and maturation.In addition to gene loss targeting the ECM architecture, defects of the cardiovascular system are also caused by the effects of aging on the ECM morphology. In their mini-review, in vitro collagen gel assay, David et al. report that simvastatin may be a suitable prophylactic drug therapy for preventing or mitigating post-traumatic joint contracture.From experiments showing the unexpected effects of prophylactically administered drugs on ECM functional organization in a rat model of elbow injury and Bauch et al., using a cerebellar slice culture model of demyelination/remyelination, provide evidence for the inhibitory effects of tenascin-C and tenascin-R on remyelination. Collectively, their results show the relevance of oligodendrocyte physiology and ECM dynamics for gaining a better understanding of debilitating pathologies, e.g., multiple sclerosis.In their study on the effects of ECM on nerve injury and regeneration, As co-editors of this Research Topic, we thoroughly enjoyed learning about the aforementioned recent developments in ECM dynamics. We hope the readers of this Research Topic would also feel the same way.


The radiology imaging community has been developing computer-aided diagnosis (CAD) tools since the early 1990s before the imagination of artificial intelligence (AI) fueled many unbound healthcare expectations and other industries. Today we see rapid growth in the number of FDA-approved AI imaging products, and some products have been adopted in clinical settings. However, overall clinical adoption of most of the products has been relatively slow.This special issue plans to focus on the challenges faced in evolving AI into more clinically meaningful for diagnostic imaging. The research in translational imaging AI requires a clear definition of clinical problems suitable to AI, improvement to the traditional convolution neural network (CNN), management of the image volume and quality in clinical settings, and the testing and integration of AI tools into clinical workflow. This special issue, Machine Learning for Computer-Aided Diagnosis in Biomedical Imaging, was organized with the paper on state-of-the-art concepts and practices in diagnostic imaging in radiology, pathology, and others, as summarized below. These papers address the common radiological or pathological areas of unmet needs, where a fully developed reliable AI tool would help to augment current practice or workflow. A review paper on automated segmentation of pelvic cancer discussed the critically important issues to bridge the gap between computer vision and patient care and pointed to the need for better input data quality, more common dataset for development, and testing of segmentation algorithms . The papTwo papers offer timely discussions on the use of AI for patient care. The use of AI to detect hospital-acquired thrombocytopenia in ICU post-operation . In the A new three-step process for brain tumor classification consists of initial annotation of the region of interest, feature extraction using DenseNet-41, and classification using the novel CornerNet for Brain MRI analysis, with good performance when applied to two different datasets . In addiThe use of deep learning with 3D optical coherence tomography images is an example of how these tools are becoming ubiquitous in all medical imaging. The paper evaluated four pre-trained CNN methods and concluded that EfficientNetB4 showed the best performance in identifying pathologic myopia from the 3D optical imaging system .The total kidney volume is a biomarker to quantify disease progress of the autosomal dominant polycystic kidney disease. The biomarker analysis was carried out by integrating attention mechanisms, cosine loss function, and sharpness aware minimization to U-Net, which helped address the problems associated with the small number of MR images in the dataset .In closing, while we noted significant and persistent progress in computer-aided diagnosis in diagnostic imaging, challenges do remain. We need more data sets with higher image quality. We need significant improvements in the science and technology of the convolutional neural network. We need to consider how we should integrate many AI tools into a clinical flow. There are significant barriers to the implementation of AI tools in real-world scenarios, not least the requirement for informatics support and development, which are often lacking in hospital systems. There also remains a need for a clear definition of what clinical problem AI should address. AI will eventually become an integral part of the digital transformation of diagnostic imaging that calls for the intimate and sustained collaboration of scientists, clinicians, engineers, and managers.


Plasmodium spp. It is transmitted to humans by the bite of an infected female Anopheles mosquito. It is the most common disease in resource-poor settings, with 241 million malaria cases reported in 2020 according to the World Health Organization. Optical microscopy examination of blood smears is the gold standard technique for malaria diagnosis; however, it is a time-consuming method and a well-trained microscopist is needed to perform the microbiological diagnosis. New techniques based on digital imaging analysis by deep learning and artificial intelligence methods are a challenging alternative tool for the diagnosis of infectious diseases. In particular, systems based on Convolutional Neural Networks for image detection of the malaria parasites emulate the microscopy visualization of an expert. Microscope automation provides a fast and low-cost diagnosis, requiring less supervision. Smartphones are a suitable option for microscopic diagnosis, allowing image capture and software identification of parasites. In addition, image analysis techniques could be a fast and optimal solution for the diagnosis of malaria, tuberculosis, or Neglected Tropical Diseases in endemic areas with low resources. The implementation of automated diagnosis by using smartphone applications and new digital imaging technologies in low-income areas is a challenge to achieve. Moreover, automating the movement of the microscope slide and image autofocusing of the samples by hardware implementation would systemize the procedure. These new diagnostic tools would join the global effort to fight against pandemic malaria and other infectious and poverty-related diseases.Malaria is an infectious disease caused by parasites of the genus  Plasmodium parasites and transmitted to humans by the bite of an infected female mosquito of the Anopheles genus. Over 241 million malaria cases were estimated in 2020, an increase from the 227 million of 2019 according to the World Health Organization (WHO)  or microscopy, anti-malarial drugs are administered. The treatment used should be determined by Plasmodium species, parasitaemia density, drug-resistant pattern where the infection was acquired, signs of severe malaria, and patient tolerance of oral medication , are being developed for the automated diagnosis of blood slides. Distinguishing between erythrocytes infected or uninfected with malaria parasites is possible with deep learning detection-based models. Image analysis techniques allow the detection of malaria parasites in digital images by pre-trained deep learning models with large image datasets. This process would emulate the optical microscope visualization of thick and thin blood smear samples and automate the procedure. Smartphone applications could integrate image analysis technology based on AI and would be an affordable option for resource-poor environments in endemic areas.The implementation of early detection systems for malaria epidemics is a high priority in Sub-Saharan African regions . New advPlasmodium life cycle is crucial to perform a correct diagnosis by microscopic examination of blood smears. The life cycle must be considered when experts perform manual labelling of digital images. Immature P. falciparum trophozoites (ring stage), White Blood Cells (WBCs), and erythrocytes are commonly labelled in malaria thick and thin blood smear digital images , the lower production of merozoites per erythrocytic cycle, the predilection of parasites to develop inside old erythrocytes and the earlier development of immunity due to the combination of the previous factors  test is a qualitative screening method for rapidly detecting the presence of malaria parasites in centrifuged capillary and venous blood  or universal antigen target for all malaria parasites, such as Plasmodium lactate dehydrogenase (p-LDH) or aldolase  are a suitable option and complement for detecting aldolase . HRP2 ishrocytes . Gene de by RDTs . A prozo by RDTs . False-p by RDTs . RDTs ar by RDTs .Plasmodium DNA, and has high sensitivity, specificity and relatively low complexity  diagnosis is a suitable alternative to conventional techniques. It is based on the amplification of mplexity . It is mmplexity . In addinfection  or low pnfection , which anfection . Nowadaynfection . This monfection . As an enfection .Bacillus stearothermophilus DNA polymerase  is a molecular technique based on the amplification of nucleic acids employing lymerase . It has lymerase . A fluorarasites . It is narasites .Serology is based on the detection of antibodies against blood-stage malaria parasites. It is not commonly used for a rapid malaria diagnosis, although it is mainly used to perform seroprevalence studies of the disease. As an example, Immunofluorescence Antibody Testing (IFA) uses specific antigens for the quantification of IgG and IgM antibodies in serum samples  diagnosis. The possibility to integrate predictive models and image acquisition in a single device confers a wide range of applications in the field of image analysis for diagnostics.Microscopy automation to move blood smear samples and capture focused images automatically is a challenging approach. Automation would solve the limitations related to the non-fully autonomous diagnosis procedure performed. Image processing methods allow automation of the diagnosis, although a person is still needed to move the X-Y axis and issue focus of the microscope. A few studies have implemented automatic hardware devices to solve this problem and optimise the automation of malaria diagnosis . MicroscP. falciparum is estimated to affect young children under 5 years old in Sub-Saharan Africa, in areas with resource-poor settings  and the Probitas Foundation.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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Physician Assistant (PA) have been deployed to increase the capacity of a team, supporting continuity and medical cover. The goal of this study was to assess the implementation of PAs on continuity of surgical rounds, on the collaboration of nurses and physicians and on support of administrative work.This cross-sectional survey was performed on nurses and physicians who work full-time at a surgical ward in a Swiss reference center. PAs were introduced in our institution in 2019. Participants answered a self-developed questionnaire 6 and 12 months after the implementation of PAs. Administrative work, teamwork, improvement of workflow, and training of physicians has been assessed. Participants answered questions on a 5-point Likert scale and were stratified according to profession .n = 53) reported a positive effect on the regular conduct of rounds . A significant improvement of nurse-doctor collaboration has been reported . Nurses  reported the that PAs are integrated in the physicians team rather than the nurses team  and a significant beneficial effect on the surgical clinic . Improved overall management of surgical cases was reported by the physicians  .Participants (The implementation of PA has improved the collaboration of physicians and nurses substantially. Continuity of rounds has improved and the administrative workload for residents decreased substantially. Overall, the implementation of PA was reported to be beneficial for the surgical clinic. Physicians assistants (PAs), or Clinical nurse specialists (CNS) in Switzerland are a novel medical profession and are inspired by experiences from countries including the United States, Canada, or Australia –3.The positive effect of PAs on routine clinical work has been reported in numerous studies . The rolAlthough many critical issues such as the exact scope of practice or patient acceptance of PAs have been resolved, the PA profession remains young and continues to evolve . Over tiThe reporting of this cross-sectional survey study follows the Consensus-Based Checklist for Reporting of Survey Studies (CROSS) . A self-Nurses and physicians were fully informed about the survey and agreed to participate. With the return of the questionnaire, all participants approved further usage of anonymized data for (scientific) analyses and subsequent publication. An ethical approval was therefore waived.n = 8), teamwork and training (n = 10). Questions on daily surgical and administrative work included: subjective improvement of the amount of administrative work, continuity in ward rounds, improved discharge management, relief in routine “ward-workload”; The believe whether PAs are a decent addition to the surgical clinic or not; and if implementation of PAs result in improved efficiency during rounds.The self-developed questionnaire consists of 18 questions and assesses the following points: continuity in daily surgical and administrative work , interdisciplinary acceptance, improvement of training.The PAs were implemented in 2019 and 6 (early survey) and 12 (late survey) months after the implementation nurses, and physicians working at the surgical ward, were asked to fill out the self-administered questionnaire. The data were manually transferred to a digital working sheet. To minimize human error in data entry, each data point was controlled by a second transcriber. A prior training or study preparation was not warranted.The Swiss surgical reference institution employs 14 to 15 residents per year. The center employed 2 PAs, both with a nursing background.All included participants worked at least 3 years full-time equivalent at the surgical ward. The PAs are enrolled in a structured Certificate of Advanced Studies (CAS) training program.Continuous variables are presented as mean and standard deviation (SD), categorical variables as count and percentage. Group comparisons (6 weeks and 12 weeks) was performed with paired t-test on continuous variables and chi-squared test for categorical variables. Data of nurses and physicians are presented separately. The Likert scale was transformed into a continuous scale to improve comparability and readability. All statistical analyses were performed with R .n = 52) reported an improvement of the organization of ward . Further, the consistency of rounds has improved over 6 months . A high interdisciplinary acceptance of the PAs was reported  as well as a great team integration . The collaboration of nurses and physicians improved substantially after the implementation of PAs . The administrative work, and the work at the ward were more or less affected by PAs . The highest improvement following PAs implementation were reported to be support of physicians   reported PAs to be a part of the physicians team rather than the nurses team . The statistical significant beneficial effect of the implementation of PAs on the surgical clinic was further reported by the nursing staff . The implementation of PAs had did not affect the administrative work of the nurses , however, the nurses reported a significantly beneficial support of PAs for the residents   reported the PAs to be a great support during regular rounds . Physicians further reported Pas to be a great support for the residents . The interdisciplinary acceptance  and the team integration to the medical team were very high . Over time the collaboration of nurses and physicians improved significantly following the implementation of PAs . Further, the implementation of PAs improved discharge management  (Fig. Participating physicians (There were no significant different reports comparing attending and residents.The implementation of PAs improved the collaboration of nurses and physicians substantiallyPAs improve the continuity and the organization of routine surgical rounds, as well as discharge managementThe positive effect of routine PA-involvement on clinical wards was reported by both nurses and physiciansThe implementation of PAs in Swiss surgical clinics is a novel approach that aims to improve interdisciplinary work and routine workflow. The present study aimed to assess the effect of implementation of PAs in a European reference center on nurses and physicians after 6 and 12 months following the implementation. The main results included:Task-shifting of physicians work from physicians to nurses aimed to tackle growing doctor shortage and reduce physicians workload, as well as human resource costs . Task-shThe role of PAs is expanding globally. Despite only working during daytime hours on weekdays, PAs are involved in more than half of all patient encounters, and lead most of the multidisciplinary meetings . The intOverall, this study suggests that the implementation of PAs has a positive effect on the surgical clinical. This includes the aforementioned improved collaboration, and the improved management of daily ward work. PAs have been shown to indirectly benefit the medical health care system by optimizing patient management . The comOne limitation of the present study is the lack of the use of standardized questionnaires. However, the goal was to assess the effect of the implementation of PAs at our Swiss surgical reference center, and therefore the questionnaire was designed specifically for the local issues at hand. As no validated questionnaires have been developed before, a novel questionnaire was developed. Second, one might argue that local training of PAs is required prior to analyzing the effect. We therefore performed the survey 6 and 12 months after the implementation and found comparable results, suggesting that the PAs are integrated very early into the medical team.The present data show the beneficial effect of the introduction of PAs on the surgical team. This beneficial effect becomes more profound over time and includes improved nurse-doctor collaboration, improved patient management, consistency of medical rounds and better discharge management. In a time of ongoing standardization of health care, PAs will play an increasing role in surgical care. Both subjective analysis and objective studies on the impact of this trend are mandated to optimize the benefit of this development.


Iatrogenic perforation is a complication that can occur during endodontic treatment. If left untreated, it adversely affects the prognosis of the tooth. The use of optimal magnification and appropriate repair material help in achieving favourable outcome. The current case report illustrates the management of concomitant strip and apical perforation in the mesial canals of lower first molar of 13 years old paediatric patient. The management of perforations was done with MTA under 25x magnification of a dental operating microscope. The periapical radiograph and clinical investigations revealed complete bone formation at the furcal area adjacent to the repaired strip perforation and ossification of the apical lesion indicating a favourable healing outcome at 18 months of follow up. Root canal perforation is a passage of communication formed between the root canal system (RCS) and the surrounding periodontium.14The current case report describes the management of concomitant strip perforation and apical perforation in the mesial canals of the lower first molar in a 13 years old child with 18- months follow-up.A 13-years-old male patient was referred by the general dental practitioner (GDP) to the university endodontic clinics. Patient presented with a complain of severe pain while eating in the lower right quadrant. The pain started two weeks ago after some complication occurred during endodontic treatment of tooth no 46 that was initiated by GDP. The assessment of treatment notes and intraoral periapical radiographic (IOPAR) records confirmed the presence of concomitant strip perforation and apical perforation with transportation in the mesial canals of tooth 46  and 1b. The inferior alveolar nerve block was administered by injecting 1.8ml of 2% mepivacaine hydrochloride with 18 micrograms of adrenaline  as local anaesthetic and rubber dam isolation of tooth 46 was performed. Subsequently, the temporary filling was removed for accessing the canal orifices. The mesial canals were renegotiated under magnification of a dental operating microscope . The pre-curved stainless-steel hand K-files  were used to follow the original path of canals and achieve the working length of the canals. The working length was confirmed by taking an IOPAR radiograph . The preThe tooth was found to be asymptomatic to percussion and palpation at 18 months follow up. The post-operative radiographs showed fully healed bone at the furcation area adjacent to the perforation site with the normal width of periodontal ligament space, and initial ossification of the apical lesion adjacent to the mesial root, representing a good healing outcome .The incidence of iatrogenic root perforations during root canal treatment ranges from 2% to 12%.Careful examination and early detection and diagnosis are pivotal for proper management and repair of iatrogenic perforations.The success of perforation treatment is high if the canals are properly cleaned and the perforations are repaired by a suitable material such as mineral trioxide aggregate (MTA).The early repair of the iatrogenic perforation defects with MTA under high magnification is a viable treatment modality for improving the prognosis of repair. In the current case, complete bone formation at the furcal area adjacent to the repaired strip perforation and ossification of the apical lesion was noted at 18 months follow up indicating a favourable healing outcome.MHA: Perioperative care, Patient consent, Patient treatment.TAA: Write up, Literature search, Follow up.MQJ: Write up, Proof reading, and is responsible for integrity of research.


The Covid-19 pandemic has led to huge disruptions and multi-domain healthcare crisis, with additional impact on children and young people (CYP) affected by Attention Deficit and Hyperactivity Disorder (ADHD).We conducted an online survey and obtained responses from 62 Paediatricians who provide ADHD services for CYP about their experience of Service disruption and adaptations during the first Covid-19 lockdown in the United Kingdom between March and June 2020. The responses were both quantitative and qualitative.The Paediatricians reported huge service disruptions such that almost half ceased the assessment of new patients with ADHD, and only 5% were able to offer physical monitoring for most patients. However, all respondents had adopted telemedicine, which allowed them to maintain high levels of non-physical service provision for existing patients. The Paediatricians used risk stratification strategies to determine which patients were more likely to benefit from the limited available face to face appointments for physical monitoring. The Paediatricians demonstrated clinical pragmatism to meet the needs of their patients such as starting medication without physical exam especially if the patient's behaviour was so challenging that it was presenting a crisis at home, and setting aside monthly limits for stimulant medications. Some respondents reported helpful cross-service collaborations to support CYP with ADHD and their families.The Covid-19 pandemic has had adverse effect on many CYP with ADHD and caused huge disruption to the ADHD services that support them. As the pandemic continues to cause disruptions to ADHD services, the service adaptations emerging from the literature including some of those identified in this study could be useful to support more stable and sustainable ADHD services, both during and after the pandemic. This is to ensure that affected persons continue to access adequate ADHD-related care; which could reduce their risk of Covid-19 infection. Unfortunately, ADHD services were not spared by the massive disruption engendered by the pandemic and related lockdowns Recognising the potential protective role of ADHD treatment in reducing the risk of Covid-19 infection transmission th wave of Covid 19 infection and were re-introducing restrictions due to the rapid spread of the Omicron variant. Thus, there continues to be a need to reflect on the strategies to support ADHD services for providing sustainable care for CYP with ADHD while the pandemic continues. Some of the adjustments and lessons learnt will remain useful after the pandemic and help to inform future service adaptions due to as yet unknown challenges such as a new pandemic. The current study explored the Covid-19 pandemic experiences of United Kingdom (UK)-based Paediatricians who assess and treat CYP with ADHD. We sought the Paediatricians' views on Service disruptions and the adjustments they made during the first Covid-19 lockdown in the UK between March and June 2020. The findings of the study add to the increasing pool of studies helping to shape practice in the management of ADHD during the continuing Covid-19 pandemic and beyond.Two years into the pandemic, service disruptions continue to be caused by Covid-19. At the time of writing this paper, many countries were in their 42.An online custom-designed questionnaire was developed by two Consultant Neuro-developmental Paediatricians with further input from a Consultant Child and Adolescent Psychiatrist. The questionnaire included structured and open-ended questions related to practice during the first Covid-19 pandemic lockdown in United Kingdom between March and June 2020. The structured questions were: experience of redeployment to other clinical areas to support Covid-19 patients; proportion of new and follow-up patients seen for face to face and or remote consultations; proportion of follow-up patients having their height, weight and Blood Pressure monitored according to UK guidelines; experience of starting, titrating or changing medications with or without recent physical measurements; awareness of specific pandemic-related guidelines for ADHD management; forms of telemedicine or digital technology being used for patient consultation; other modifications or flexibilities introduced to usual clinical practice; use of non-pharmacologic support strategies, and involvement of other staff in supporting ADHD management. Each closed question was followed by an open-ended question which invited participants to provide free-text qualitative comments to contextualise their responses to the closed question. The survey was approved by the Executive committee of the George-Still Forum (GSF), which is a UK-wide ADHD Clinical Network whose membership consists of mainly Neurodevelopmental Paediatricians. Links to the survey were emailed to all the delegates who attended the GSF annual scientific meeting in 2019 and provided consent to be contacted. The survey ran between June and July 2020. Responses to structured questions are presented in the results as proportions. We applied reflexive thematic content analysis 3.A total of 62 responses were received out of 115 delegates who attended the last GSF annual scientific conference in 2019 who were sent the survey link by email. This represents 54% response rate. Most of the respondents (62%) were not redeployed from their main clinical roles to support Covid-19 patients. Consistent with the prevailing pandemic-induced change in service delivery, all respondents had adopted remote service provision, of which the most common was by telephone (98%). Report of service disruption was most pronounced for new ADHD referrals as almost half of respondents (47%) ceased service provision for this cohort and only 28% were able to maintain services for most of their new referrals. Conversely, service provision remained high for existing patients requiring non-physical ADHD follow-up appointments. For the latter cohort, 65% of respondents were still offering services to most patients, and only 16% interrupted their service provision.The respondents' qualitative comments provided further insights into these altered service arrangements. For example, some respondents pointed out that they ceased new ADHD assessments because the simultaneous closure of schools meant that the collateral information required for completion of new ADHD assessments was not available. Others noted that where the collateral information was already available, they were able to proceed with new ADHD assessment through remote sessions. Similarly, some respondents felt able to remotely initiate medications for patients newly diagnosed with ADHD if the patient had already had normal physical exam prior to the lockdown.th centile, those on the upper ceiling of the normal range of medications , patients who had had home measurements that were outside normal limits, or those with other presentations considered to require urgent face to face clinical review.The physical monitoring required for ADHD management was severely interrupted such that only 5% of respondents reported being able to obtain measurements for most of their patients. Where physical monitoring occurred, most still occurred in specialist centres (25%), while others took place at home (13%), or in primary care (10%). Qualitative comments indicated that clinicians used risk stratification strategy to determine the patients most likely to benefit from the limited available face to face appointments for physical monitoring. In this context, respondents prioritised face-to-face monitoring for: patients with pre-existing concern about their physical well-being such as weight already below 9The disruption of face-to-face clinical contact and difficulty with obtaining physical measurements led some respondents to adopt more cautionary approaches to ADHD clinical work. Qualitative comments highlighted two such cautions: not to initiate new medications especially when baseline physical investigation was not possible, and avoiding changes to the dose of existing medication unless the patient was well known and had a trend from past physical measurements that was in the normal range.Some of the participants were aware of the European ADHD Guidelines Group Covid-19 recommendation The respondents reported how the alterations in clinical service provision during the pandemic led to promotion of self-reliance among families. The respondents indicated that at the beginning of the pandemic, many families were not able to check weight, height, blood pressure and height at home but the proportion increased during the lockdown. In some cases, specialist services sourced the equipment for families while clinicians provided written or live guidance on their appropriate use. Many families preferred home measurements due to worry about exposure to Covid-19 if they came to the clinic. Some respondents rationalised which measurements families needed to focus on. For example, some advised less focus on height because, in their experience, once yearly height measurements can be adequate.Similarly, some respondents reported some helpful cross-service collaborations to support CYP with ADHD during the first Covid-19 pandemic lockdown in the UK. Respondents mentioned the support of Specialist Nurses who provided more than a quarter (26%) of the required face to face appointments. Some services set up specific nurse-led clinics for physical monitoring for patients who needed to be seen in person. Collaboration with clinicians in Child and Adolescent Mental health services (CAMHS) was also reported to have provided 19% of the required face to face appointments. Some schools supported CYP with ADHD by offering physical monitoring for the few more vulnerable children who were allowed to be in school during the lockdown.4.The Covid-19 pandemic caused significant challenges for CYP with ADHD and their families, and for the services that support them. This survey of Paediatricians providing ADHD assessment and treatment during the first Covid-19 lockdown in the UK between March and June 2020 noted huge service disruptions such that almost half of the respondents ceased the assessment of new patients with ADHD, and only 5% were able to offer physical monitoring for most patients. However, all respondents had adopted telemedicine, which allowed them to maintain high levels of non-physical service provision for existing patients. The Paediatricians used risk stratification strategies to determine which patients were more likely to benefit from the limited available face to face appointments for physical monitoring. The Paediatricians demonstrated clinical pragmatism to meet the needs of their patients such as starting medication without physical exam especially if the patient's behaviour was so challenging that it was presenting a crisis at home, and setting aside monthly limits for stimulant medications. Some respondents reported helpful cross-service collaborations to support CYP with ADHD and their families.These findings are consistent with other studies from different parts of the world such as summarised in a recent review Some CYP with ADHD have experienced increased ADHD symptoms and related difficulties during the ongoing Covid-19 pandemic Telemedicine has been crucial in maintaining ADHD Service provision while limiting face-to-face contact to reduce the risk of Covid-19 transmission. There is increasing evidence that tele-medicine is effective in the diagnosis and treatment of ADHD https://www.bhf.org.uk/informationsupport/support/manage-your-blood-pressure-at-home). One advantage of home Blood Pressure monitoring is reduced potential for “white coat syndrome”. For example, one study showed that CYP with ADHD seen face to face during the first Covid-19 lockdown in the UK tended to have higher Blood Pressure compared with their re-pandemic readings but improved after the lockdown without further intervention One of the challenges for telemedicine-based ADHD treatment is the need for physical examination. The current study and others show that some parents were able to check weight, height, Blood Pressure, and Pulse at home. Some ADHD services are providing the equipment for families that do not already have them. Some clinicians in the current study were able to provide live guidance for parents to use the equipment. Also there are easy to access online instructions on how to check Blood Pressure , patients who had had home measurements that were outside normal limits, or those with other presentations considered to require urgent face to face clinical review.While acknowledging the important contribution of telemedicine, the nature of ADHD service provision is such that some face to face meetings would still be required. In this case, the current study suggests some triaging strategies to identify and prioritise the CYP who would most benefit from a face to face appointment. These include: patients with pre-existing concern about their physical well-being such as weight already below 9The strengths of this study include the use of both quantitative and qualitative comments to explore the experiences of the Paediatricians who are supporting CYP with ADHD. Another strength is the UK wide membership of GSF, which provides some support for the external validity in relation to neurodevelopmental paediatricians' practice during the period of the survey. Some implications for practice include rapid adoption of telemedicine, pragmatic application of clinical guidelines, maintaining some face to face treatment based on clinically triaged needs, and cross-service collaborations. The study's limitations include the relative small sample size, the absence of comparative pre-pandemic data on ADHD-related telemedicine, lack of data on non-ADHD paediatric practices, lack of location-specific data, and the cross-sectional and self-report nature of the survey.5.The Covid-19 pandemic has had adverse effect on many CYP with ADHD and caused huge disruption to the ADHD services that support them. The pandemic continues to be a challenge through the emergence of new variants such as Omicron that was causing the re-introduction of restrictions at the time of writing this paper. Thus, it is possible that disruptions to ADHD services are likely for some time. This shows the need to continue to learn from helpful service adaptions that can be maximised to provide more stable and sustainable ADHD services during this pandemic. Also, ADHD services need to consider continuing positive pandemic-engendered ADHD service changes that are now emerging from the literature where such changes can help to improve effective and efficient care delivery even after the current pandemic. These positive changes that are now emerging from the literature could also serve as blue prints in the event of a future pandemic.


To assess the incidence and causes of persistent thigh pain and peri-implant fractures after union in patients of intertrochanteric fractures treated with short cephalo-medullary nails.A retrospective observational study conducted at a Level 1 Trauma centre. A total of 122 patients of intertrochanteric fractures who were operated using short cephalo-medullary nails (170mm and 200mm lengths) between January 2018 to June 2019 were included in the study. Main outcomes measured were the incidence of thigh pain and peri-implant fractures.Out of the 122 patients with a mean follow-up of 14.1 month, 12 patients had persistent thigh pain. Six patients had the helical blade protruding from the lateral cortex, two of them had distal tip of nail abutting on the anterior cortex and four cases had prominent proximal segment of nail which may explain the cause of their pain. Five of these patients had a combination of these findings. Two patients had pain for which no other obvious cause was found. There were no cases of peri-implant fractures in our study.Thigh pain associated with the use of short cephalon-medullary nails is often unrelated to nail length and can be prevented by using proper surgical technique. There seems to be no association between the use of short nails and peri-implant fractures. Management has evolved from conservative management to early surgical intervention wherever feasible, to allow early mobilisation. Most of the older literature suggests the use of long proximal femoral nails for intertrochanteric fractures in elderly osteoporotic patients, the rationale being splintage of entire femur using a long nail reduces the chances of peri-implant fractures and also negates the chances of thigh pain due to impingement of nail tip against the anterior femoral cortex3. However, using long nails for all such cases is fraught with its own problems and risks. Use of short nails have numerous advantages like shorter operative and anaesthesia time, less blood loss, less reaming (reduced chances of emboli) and reduced chances of distal perforation, all of which have been proven in numerous studies7. In spite of all these advantages there is a theoretically increased risk of peri-implant failures and thigh pain with the short nails. Clinical results of short nails are comparable to their longer counterparts even with theoretical biomechanical handicap. Many surgeons have also begun to use distally unlocked short nails in intertrochanteric fractures with good clinical outcomes9.Fractures around hip are debilitating injuries. They are associated with high mortality rates, reported to be around 10% in some studies as well as morbidity associated with immobilisation in elderly patientsThere are far too few studies focussing on the aspect of thigh pain and re-fractures after surgery because of which there is huge void in our knowledge about the incidence, aetiology, and ways to prevent these complications associated with short nails. Also, there are many conflicting views about the aetiology of pain in these patients which cannot be attributable to the nail size alone.In this study we have tried to find the answer to the question that whether there is any significant increase in the incidence of thigh pain and peri-implant fractures in patients of intertrochanteric fractures operated using short cephalomedullary nails. We have also tried to ponder about the probable causes of pain when present and whether it can be attributed to the size of the nail used.10 managed operatively using short cephalomedullary nail with clinical and radiographic signs of union with a minimum follow-up of 12 months were included in the study. We excluded patients of polytrauma, pathological fractures, revision surgery, non-union and implant failure.After institutional review board approval, a retrospective study was conducted on patients of intertrochanteric fractures operated at our institute with short cephalomedullary nails (170mm and 200mm) between January 2018 and June 2019. The aim of the study was to assess the incidence and causes of thigh pain and peri-implant fractures in these patients. All patients over 60 years of age with closed isolated intertrochanteric fractures After adequate effect of anaesthesia, patient was positioned on the traction table and closed reduction attempted. After successful closed reduction, internal fixation was done using standard technique of cephalo-medullary nailing with short nail with helical blade  . Post-op11 and was compared it to its pre-trauma status. Descriptive statistics were elaborated in form of mean/standard deviations for continuous variables and frequency/percentage for categorical variable. Group comparisons for continuously distributed data were made using independent 't' test. Chi-squared test was used for group comparisons of categorical data. In cases where the expected frequency in contingency table was less than 5 for >25% cells, Fischer's exact test was used instead. Statistical significance was kept at p value <0.05.Medical records were studied for obtaining the demographic data, surgical details, radiographs, and information regarding the implant. Outpatient records were studied to retrieve data regarding follow-up. SPSS v23 [IBM corp.] was used for data analysis. At each follow-up visits the patients were enquired regarding thigh pain. Intensity of thigh pain when present was quantified using visual analogue scale (VAS). If they complained of thigh pain, we further enquired about the site of pain, onset of pain (since post-operative period or after some time lapse), nature of pain and its relationship to ambulation (whether pain is relieved on rest or not). Mobility status of the patients were quantified using the modified Harris hip score (mHHS)A total of 122 patients of intertrochanteric fractures satisfying our inclusion criteria was found in our records. There were 79 males and 43 females. The mean (SD) age of patients included in the study was 70.18 (6.94) years. The basic demographic data of our patients is showed in The mean (SD) of Age (Years) in the group with thigh pain was 70.67 (4.66) with an age range of 64 - 78 years. The mean (SD) of Age (Years) in the group without thigh pain was 70.13 (7.16) with the age range of 60 - 89. There was no significant difference between the groups in terms of Age (Years) . Mean time for radiographic union was 20.2 weeks.Fisher's exact test was used to explore the association between 'Thigh Pain' and 'Gender' as more than 20% of the total number of cells had an expected count of less than five. There was no significant difference between the various groups in terms of distribution of Gender .11 of 82.5. The pain was localised to proximal thigh in all the patients and not associated with groin pain or tingling or paraesthesia ruling out any other causes like meralgia paraesthetica, co-existing hip arthritis, blade cut through which was confirmed by evaluation of their radiographs.Twelve patients (9.8%) complained of thigh pain at follow-up. Out of the twelve patients eight of them independently mobile while four patients needed cane/stick. None of the patients had peri-implant fractures, even though five patients had history of fall at home after surgery. The mean pain score using visual analogue scale was 3.25 with individual scores ranging between 2-4. The pain was mild to moderate in intensity and did not affect their mobility or ability to perform activities of daily living with an average modified Harris hip scoreSix patients had prominent proximal blade due to improper length of the helical blade. Five of them had point of maximum tenderness over the proximal blade insertion site while others had diffuse pain over proximal thigh. However, only two of them had long blade as the only radiographic finding while the rest had some other associated findings.2 = 0.063, p = 1.000).Two cases had too posterior an entry point which led to nail abutment at the anterior cortex while three cases had excessive bowing of femur that led to similar finding. Four cases had a prominent proximal nail segment, out of which in only one patient was it the only associated finding. Five of the twelve patients had one of the above causes as isolated finding. The other five had a combination of findings as summarised in Thigh pain and peri-implant fractures has been reported as drawbacks of using short nails. Advantages offered by short nails are alluring but at the same time apprehension of these pitfalls often creates a dilemma in the mind of treating surgeon regarding ideal choice of implants. Hence, we conducted this study to assess the actual magnitude of these impediments while using short CMN.In our study, we observed that the short versions of the cephalo-medullary nail (170mm and 200mm) was associated with thigh pain in 12 patients (9.8%). We did not encounter any cases of peri-implant fractures even though five patients reported low energy trauma  after surgery. We further examined and analysed the radiographs of each patient who complained of thigh pain at follow-up. We found that majority of the cases had a finding  which can explain the reason for thigh pain apart from the nail length. The most common findings were improper length of helical blade with lateral overhang of the blade, causing irritation of the vastus lateralis and tensor fascia lata muscles . This waet al12 on proximal thigh pain after femoral nailing with Grosse-Kempf nail for diaphyseal fractures observed that heterotrophic ossification was a major cause of persistent thigh pain. However, we did not encounter any case of heterotrophic ossification in our study. The study also sheds light on other probable causes, but the underlying point being that thigh pain is also associated with long nail and short nail length may not be a risk factor as has been the common notion.There is a lacuna in our current understanding on the subject of thigh pain and peri-implant fractures after proximal femoral nailing due to lack of objective data and quality evidence. A study by Dodenhoff et al13 highlighted the problem of mismatch of nail and femur geometry. In their study they encountered problems related to the mismatch of the proximal end of the nail in 11 cases. Nine of these patients presented with thigh pain due to the redundant proximal end of the nail. In another study by Rosen et al14, they commented that lateral hip pain from proximal locking device insertion and prominence continues to be one of the most frequent complaints following this surgical procedure. Another factor for thigh pain is the length of the nail chosen. There is no Level I or II evidence that favour one nail length over other . In a randomised controlled trial conducted by Parker and Cawley15 they concluded that there was a trend toward greater residual pain for those treated with the shorter nail, although this was not statistically significant and cautioned about the excessive use of these short versions of the nail. Though there is no biomechanical study that has determined the ideal length of nail for cephalo-medullary nailing, there has been a trend of decreasing size of the implants from 220-250mm nails to the shorter versions (170-200mm nails). Nails as short as 160mm have been used in some situations with good clinical results16. In this study we did not find any significant difference in the incidence of peri-implant fractures or thigh pain between 170mm and 200mm nails.A study by Jin-Song Pu et al17, they concluded that though peri-implant fractures were rare incidences, chances of its occurrence were 3.7 times higher with PFN compared to DHS. Numerous studies have attempted to evaluate these factors but have their own set of flaws, like use of previous generations of nails (gamma nails were used in most of the studies), longer length of nails (240-250mm nails were more commonly used in the past) and nail-femur geometry mismatch. In a study by Robinson et al18, they found that the risk of femoral peri-implant fracture after hip surgery was 40 times more than general population. However, these previous generations of short nails used, had many flaws. They were rigid, stainless-steel implants with large locking bolts at the distal tip of the nail in the diaphyseal region. Also, there was frequent mismatch of the nail and femoral geometry that frequently created stress risers. In addition, these original relatively large diameter short nails were associated with intra-operative insertional fractures. The problems have largely been addressed in the newer generations of nail which have taper stem, oblique distal bolts and more anatomical bend leading to lesser incidence of peri-implant fractures.In a study by Muller Another important and upcoming problem is the exponential increase in total knee arthroplasties. With the increased in longevity, more and more patients suffering from knee osteoarthritis are opting for arthroplasty. Use of stem in femoral component would not be possible in presence of long nail and hence we need to consider short nails in these patient populations. This makes it even more important to understand in detail, the pros and cons associated with the use of short nails in geriatric population.The lifestyle and mobility of elderly population in Asian countries differs significantly from the western populations. Most of the elderly population, even before the trauma are confined mostly to low demand home-bound activities like stair climbing, morning walks and kneeling for prayers. In contrast, the elderly in western countries lead a more demanding lifestyle including independent driving, routine exercises and in some cases participation in active sports. This may explain the lower incidence of peri-implant fractures and thigh pain in our study compared to other studies involving western populations. However, this demographic and lifestyle differences may change when the current generations born after 1990s ages as their lifestyle and mobility expectations are quite similar to the western populations. It would be interesting to see if the short nails survive this test of time.The limitations of the study, firstly, relatively small sample size, which may affect the quality of final outcome. Another limitation is the short duration of follow-up (mean follow-up of 14.1 months). Though we believe that more than 12 months of follow-up is sufficient for peri-trochanteric fractures for union and clinical outcomes, the incidence of peri-implant fractures and thigh pain need longer periods of follow-up. We plan to continue the study on our patients and document the long-term results with regard to the parameters considered in this study.Thigh pain associated with the use of short cephalomedullary nails is often unrelated to nail length and can be prevented by using proper surgical technique. There is no association between the use of short nails and peri-implant fractures. Modern short nail designs are much safer with respect to peri-implant fractures as evident by no cases in our study. However, further better designed clinical studies with larger sample size and longer follow-up are required to make the evidence unequivocal.


Model-informed drug development (MIDD) is unarguably the cornerstone of pharmacological research in the 21st century . It refeThis multifaceted tool has revolutionised the scope of recent drug discovery and development efforts. Over the last decade, the application of MIDD methodologies has become a popular approach for drug development and applied pharmacotherapy projects in industry, academia and, more notably, in global regulatory agencies  . At leasThis research topic aims to bring together scientists from academia, industry, and regulatory authorities to discuss the most recent advancements in MIDD and their multidimensional role in drug discovery and development. This editorial seeks to discuss current research trends in the field of MIDD and translational pharmacology and share our perspective on the importance of MIDD in modern drug discovery and development.There is a long-standing history of applying MIDD to inform regulatory decisions at the FDA . In the The rampant increase in MIDD-related publications over the last few years is a testament to the piqued interest in the scientific community. MIDD techniques enable the integration of data from clinical trials and non-clinical investigations in a drug development programme. Modelling techniques that are frequently employed include population pharmacokinetics (popPK) modelling, PBPK modelling and exposure-response modelling . CurrentKang et al. successfully demonstrated the utility of a K-PD model in describing the anticancer effect of BoNT/A1 in a syngeneic mouse model transplanted with melanoma cells (B16-F10). The developed K-PD model adequately captured the dynamics of tumour growth, and simulation studies were conducted to determine the optimal dose under various dosing scenarios.Pharmacometrics is the core of MIDD and is the science of developing mathematical models to quantitatively describe relationship exposure and response . In the Yow et al.). These models include PopPK models, QSP, system-based models, and mechanism-based PK/PD models . Particularly in the case of special populations, therapeutic drug monitoring (TDM) is often used to ensure that the exposure of the drug is optimal by comparing plasma concentration levels against a therapeutic range . Currently, QSP modelling to inform key decisions in drug development is still evolving, and only a handful of successful examples are available in the literature (Unlike the traditional pharmacometric models, which rely largely on available preclinical or clinical PK data and model structures that are selected based on statistical methods and biological plausibility grounds, QSP is a quantitative approach that incorporates mechanistic information of a biological system and drug mechanism to predict and define disease pathophysiology and therapeutic interventions . QSP modterature . As QSP Yu et al. developed and demonstrated the utility of a supervised machine learning model to categorise and examine the magnetic resonance imaging features of brain tumours. Implementation of AI/MI in drug discovery and development will assist with the interpretation of clinical data and can standardise results across labs, thereby reducing biases and human errors (Lastly, the use of AI and ML has been increasing in the pharmaceutical industry to overcome the high failure rate in drug development . As suchn errors . The futn errors .MIDD has developed into an effective method to aid modern drug discovery and development. It plays a critical role in regulatory decision making and is gaining more acceptance in the community. Incorporating and leveraging newer techniques, such as MI/AI, are on the rise and will undoubtedly reshape drug development in the long term.