Spinal cord injury (SCI) is a serious neurological trauma that is challenging to treat. After SCI, many neurons in the injured area die due to necrosis or apoptosis, and astrocytes, oligodendrocytes, microglia and other non-neuronal cells become dysfunctional, hindering the repair of the injured spinal cord. Corrective surgery and biological, physical and pharmacological therapies are commonly used treatment modalities for SCI; however, no current therapeutic strategies can achieve complete recovery. Somatic cell reprogramming is a promising technology that has gradually become a feasible therapeutic approach for repairing the injured spinal cord. This revolutionary technology can reprogram fibroblasts, astrocytes, NG2 cells and neural progenitor cells into neurons or oligodendrocytes for spinal cord repair. In this review, we provide an overview of the transcription factors, genes, microRNAs (miRNAs), small molecules and combinations of these factors that can mediate somatic cell reprogramming to repair the injured spinal cord. Although many challenges and questions related to this technique remain, we believe that the beneficial effect of somatic cell reprogramming provides new ideas for achieving functional recovery after SCI and a direction for the development of treatments for SCI. Spinal cord injury (SCI), a type of central nervous system (CNS) injury, can affect motor and sensory functions in the innervated area in mild cases and lead to paraplegia in worst-case scenarios. The incidence of traumatic spinal injury is 10.5 cases per 100,000 individuals worldwide . SCI sigin vitro expansion, and the potential loss of multipotency during in vitro expansion , subacute phase (48 h to 14 days), intermediate phase (14 days to 3 months), and chronic phase (> 3 months) . Acute SCell death is a major mechanism of secondary injury . InitialThere are three major challenges in the treatment of SCI. First, reactive glial cells respond rapidly, and because axons take time to regrow, scars formed by reactive glial cells can obstruct the growth of severed axons. Second, many injured neurons are lost due to neuronal death or apoptosis, and residual neural stem cells are insufficient to replenish these lost neurons. Third, reactive glia have both positive and negative effects, as they stimulate the release of neurotrophic factors, as well as cytokines that inhibit axonal regeneration . VariousResearchers have used strategies involving identifying the type and site of specific injuries, removal of bone fragments and foreign bodies, and physical stabilization and decompression of the spine to treat SCI . AdditioSome studies have demonstrated that moderate inhibition of glial scar formation can promote functional recovery after SCI . For exaStem cell-based therapies, including embryonic stem cell, stromal stem cell, neural stem cell and iPSC therapies, are promising approaches for spinal cord repair . For insin vitro or in vivo  into target cells such as neurons by biotechnological means  in vivo . There ain vitro . Some sc results .Conduits, scaffolds, fibers, sheets, hydrogels and particles can be used as biomaterial therapies for SCI . The useCombinatorial treatments have been developed based on the complex pathophysiological changes after SCI. These approaches involve the delivery of a combination of biomaterials and cells or soluble molecules to the site of injury . The comin vivo using viral vectors with specific promoters , and Y-27632] can induce the conversion of rat dermal fibroblasts into neurons function .in vitro. The fibroblast-derived glutamatergic neuron-like cells had neuron-specific transcriptional profiles, displayed action potentials and could form functional synapses. Moreover, after transplantation into the brains of postnatal mice, fibroblast-derived glutamatergic neuron-like cells integrated into local neuronal circuits , POU class 3 homeobox 2 (Pou3f2) and myelin transcription factor 1 like (Myt1l), is sufficient to reprogram mouse embryonic fibroblasts and postnatal tail-tip fibroblasts into neurons, including some glutamatergic neurons and GABAergic neurons. These fibroblast-derived neurons generate action potentials and form functional synapses  (synapses . In addiNeurod1) .in vitro. During this reprogramming process, fibroblast-specific genes are silenced, whereas neuron-specific genes are activated (Combinations of brain-enriched neurogenic microRNAs (miRNAs), such as miR-124 and miR-9/9*, significantly mediate the direct transformation of adult fibroblasts into functional neurons and can increase the efficiency of this transformation. During the direct conversion of mature fibroblasts into neurons, this combination can contribute to neurogenesis and inhibit fibroblast progression by altering the chromatin structure of cells  or maintctivated .Motor neurons are specialized neurons located in the anterior horn of the spinal cord that innervate the skeletal muscle and control its movement. Degeneration or loss of motor neurons is a typical feature of SCI .in vitro. Similarly, human-derived fibroblasts can be converted into motor neurons by these seven factors and Neurod1. When treated with these 7 factors, mouse fibroblast-derived motor neurons skip the neural progenitor phase. The resulting cells not only exhibit the gene expression profiles of motoneurons but can also form functional synapses with muscles and generate repetitive action potentials. In vivo, these reprogrammed motor neurons can efficiently integrate into the spinal cord when transplanted into the ventral cavity of the neural tube in chick embryos , motor neuron and pancreas homeobox 1 (Hb9), ISL LIM homeobox 1 (Isl1) and transcription factor neurogenin 2 (Ngn2) can directly transform mouse fibroblasts into motor neurons with high efficiency  embryos .in vitro , was found to effectively downregulate the expression of fibroblast-specific genes and upregulate the expression of neuron-specific genes, thereby converting mouse and human fibroblasts into motor neurons and bypassing the neural progenitor stage  in vivo .Important progress has been made in the development of transcription factor- or small molecule-mediated fibroblast reprogramming strategies for repairing the injured spinal cord. However, it remains unclear whether combining transcription factors and small molecules could be more effective for fibroblast reprogramming. The combination of the transcription factors Ngn2, SRY-box transcription factor 11 (Sox11), Isl1, and Lhx3 and the small molecules forskolin and dorsomorphin has been found to directly transform adult skin fibroblasts into motor neurons. The transformed cells were shown to have the electrophysiological characteristics of mature spinal motor neurons, form neuromuscular junctions with skeletal muscle and control muscle activity. These researchers also used the transcription factors Isl1 and Lhx3, indicating that these factors may be key for reprogramming fibroblasts into motor neurons .SCI causes demyelination of myelinated nerve fibers, creating an obstacle to spinal cord repair, for which myelin regeneration is critical. Oligodendrocytes are mainly involved in the production and maintenance of myelin sheaths in the CNS . Myelinain vitro. These oligodendrocyte progenitor cells exhibit an oligodendrocyte-like bipolar morphology and gene expression profile and could be cultured to the fifth generation. Furthermore, following transplantation into hypomyelinated mice, these cells can survive and wrap around host axons to further produce dense myelin sheaths (Inducing the expression of factors such as oligodendrocyte transcription factor 1 (Olig1), oligodendrocyte transcription factor 2 (Olig2), NK2 homeobox 2 (Nkx2.2), NK6 homeobox 2 (Nkx6.2), SRY box transcription factor 10 (Sox10), ST18 C2H2C-type zinc finger transcription factor (ST18), myelin regulatory factor (Gm98), myelin transcription factor 1 (Myt1) or the combination of the transcription factors Nkx6.2, Sox10, and Olig2 can transform mouse embryos and lung fibroblasts into oligodendrocyte progenitor cells  sheaths .in vitro under specific conditions. Oct4-induced oligodendrocyte progenitor cells propagate in vitro with more than 31-fold higher efficiency. Transplantation of these cells into mice effectively promotes functional recovery after SCI and reduces tumorigenic risk by reducing host genome modification , SRY-box transcription factor 2 (Sox2), Kruppel-like factor 4 (Klf4), Myc-like transcriptional regulator Myc-like (c-Myc), and transcription factor 3 (Tcf3) with the small molecule PDGF-AA has been shown to reprogram mouse fibroblasts into oligodendrocyte progenitor cells function .in vitro, the results have established a solid foundation for using fibroblast reprogramming strategies in vivo. With further advancements, this technique could be used to overcome more challenges in spinal cord repair. In the abovementioned in vivo transplanted studies, neurons, motor neurons, and oligodendrocyte progenitor cells obtained from fibroblasts contributed to spinal cord repair and promoted functional recovery, indicating that transplantation of fibroblast-derived cells is a potential and promising therapy for SCI , a microtubule-associated protein, is abundantly expressed in neuronal cells . The ovein situ . When coin situ . VPA, a in situ . Studies were shown to transform primitive astrocytes into neural stem-like cells. In a contusion SCI mouse model, the combination of these two transcription factors effectively increased the porosity of glial scar tissue at the injury site, promoting myelin regeneration in axons after injury and improving the recovery of motor function  can reprogram astrocytes into neurons through the progenitor cell stage  in vivo . In vitrfunction .in situ in the dorsal spinal cords of adult mice. Reprogrammed neurons can integrate into local neural circuits and can respond to different afferent inputs from the dorsal root ganglia. Ngn2 has also been found to reprogram astrocytes into neurons at the site of injury in SCI models  is a ribonucleic acid-binding protein involved in neurogenesis. To date, several laboratories have demonstrated that PTB silencing can effectively reprogram brain-derived astrocytes into functional neurons in vitro . Moreovein vitro .in situ. It was concluded that the replenished neurons observed in vivo originated from endogenous neurons and were not reprogrammed brain astrocytes. Similarly, some researchers believe that astrocyte reprogramming is a long and gradual developmental process in vivo and that the conversion rate might be related to virus concentration and type. The origin of the replenished neurons cannot be determined through currently available biotechnological tools. However, it is clear that these neurons can promote functional recovery in disease models. Therefore, we recently explored the role of PTB silencing in spinal cord repair.However, an interesting challenge was recently noted in this field . It has in vitro. In a mouse model of compression SCI, PTB knockdown moderately reduced the density of the glial scar without destroying its overall structure while increasing the number of motoneuron-like cells around the injured area, effectively reducing cell apoptosis around the injured area and ultimately promoting the recovery of motor function in SCI mice  receptor inhibitor PD168393 has been reported to cause NG2 cells to acquire a neuronal phenotype. PD16839 was shown to reprogram NG2 cells directly into neurons in a contusion SCI mouse model, significantly increasing the number of neurons at the injury site and effectively improving neurobehavioral performance after injury .High ectopic expression of Sox2 can lead to the reprogramming of NG2 cells into mature spinal cord neurons that can form synaptic connections with endogenous neurons in the spinal cord in SCI mouse models. These induced spinal cord neurons undergo neuronal conversion around the lesion site and form connections to achieve spontaneous functional recovery. Moreover, they effectively reduce the formation of glial scars after SCI and promote functional recovery in mice .The above studies show the substantial potential of NG2 cell reprogramming in spinal cord repair. It has been demonstrated previously that inhibition of NG2 cells can promote the repair of SCI . TherefoNumerous studies have revealed that neural progenitor cells transplanted into various animal models can be induced to differentiate into target cells using specific approaches and that these cells promote functional recovery . Althougin situ. The transcription factor Ascl1 combined with growth factors was shown to convert spinal cord endogenous neural progenitor cells into oligodendrocytes in situ  can transform spinal endogenous neural progenitor cells into mainly GABAergic neurons  in situ . Howeverin vivo. Thus, the transformation of endogenous neural progenitor cells into neurons could be a novel and effective treatment strategy for spinal cord repair if these cells meet the requirements of specific neuronal subtypes and oligodendrocytes after injury (Currently, SCI treatment is limited by the restricted differentiation of endogenous neural progenitors r injury .in situ. Astrocyte reprogramming makes use of endogenous activated astrocytes that are adjacent to the lost neurons to regenerate functional cells in the injured area after SCI (in situ. However, there are fewer residual NG2 cells and neural progenitors than astrocytes around the injured site after SCI; thus, NG2 cell and neural progenitor reprogramming-mediated spinal cord repair is relatively difficult (In previous studies, fibroblast-derived neurons or oligodendrocyte progenitor cells were transplanted into the spinal cord for spinal cord repair . The usefter SCI . In addiifficult . Reactivifficult . The gravia viral infection, in which viral vectors integrate into the host cell genome (in vivo, cell type specificity is difficult to achieve, and toxicity is a challenge (Although recent progress has been made in the application of somatic cell reprogramming technology for spinal cord repair in preclinical studies, there are still some challenges in translating this strategy to clinical settings for SCI treatment. First, safety remains the most important issue related to somatic cell reprogramming for SCI treatment. Some transcription factors that induce somatic reprogramming are also highly expressed in some tumors. For instance, many studies have revealed that Sox2 is overexpressed in squamous cell carcinomas in many tissues, including the paranasal sinuses, hypopharynx, larynx, and lung . Second,l genome . Despitel genome . Third, hallenge . Fourth,hallenge .In vivo reprogramming is a very promising approach for treating SCI in clinical settings because it utilizes endogenous cells. The development of AAV-mediated gene therapy involving cell-type-restricted promoters makes it possible to target resident cells in the spinal cord, which is the advantage of in situ cell reprogramming. AAV-mediated therapies have been successfully translated to the clinic in some cases; for example, an AAV9 vector has been used to induce the expression of SMN1 in motor neurons for treating spinal muscular atrophy (in vivo reprogramming in clinical settings (Although skin fibroblasts from patients can be used for fibroblast reprogramming strategies, which is a promising strategy for autologous transplantation, research is mostly limited to cellular studies and animal experiments. Therefore, the clinical application of fibroblast-derived cells for therapy may involve many challenges. How to determine the optimal number of transplanted cells, balance efficacy and safety, and improve the survival rate of transplanted cells and their functional integration with host circuits requires further exploration. Extensive studies are required in the future to improve the efficacy of fibroblast-derived cell transplantation for the clinical treatment of SCI.  atrophy . NG2 cel atrophy ; thus, tsettings .in situ. The opposing view is that in vivo replenished neurons are derived from endogenous neurons rather than reprogrammed brain astrocytes. Although the origin of replenished neurons in vivo following PTB silencing or Neurod1 overexpression has not yet been conclusively determined, these neurons promote functional recovery in disease-model mice. Therefore, from the perspective of promoting functional recovery, somatic cell reprogramming technology still has substantial potential for promoting spinal cord repair.Recently, a different view related to astrocyte reprogramming has emerged . In addiin vivo.The efficacy of somatic cell reprogramming treatment strategies in human clinical trials could be limited due to the lack of control groups, and improvements in function observed in the trials could be related to decompression surgery at the time of cell transplantation or natural recovery after SCI rather than therapeutic effects . Future The development of somatic cell reprogramming approaches for spinal cord repair has progressed rapidly in recent years. However, due to the complexity of this process, the specific mechanisms require further investigation . BypassiGC designed the review. RY wrote and drafted the manuscript. All authors contributed to the revision of the manuscript and approved the final version.


Pneumonia is one of the most common pathologies seen in the inpatient setting. The rapid response to treat febrile patients with infiltrates on chest x-ray has reduced hospital length of stay and hospital costs. However, the automatic reaction to treat all infiltrates and opacities seen on a chest x-ray as pneumonia can be costly. This report presents the case of a patient suspected initially of having pneumonia, who was unresponsive to broad-spectrum antibiotics. A 58-year-old woman presented with dyspnea on exertion and a nonproductive cough. Her chest x-ray showed dense right-sided coalescent opacities encompassing the entirety of the right lung. Flexible bronchoscopy biopsy specimens revealed the cause to be cryptogenic organizing pneumonia. This case highlights the diverse set of pulmonary pathologies that can mimic pneumonia and should be suspected in cases of antibiotic-resistant suspected pneumonia patients. Cryptogenic organizing pneumonia (COP), known formerly as bronchiolitis obliterans organizing pneumonia, is a form of idiopathic diffuse interstitial lung disease. This rare form of pneumonia has no known direct cause but is associated with many caustic inhaled agents and pathogens. This report presents the case of a patient initially suspected of having pneumonia who was unresponsive to broad-spectrum antibiotics and ultimately diagnosed with COP.A 58-year-old woman with a history of chronic obstructive pulmonary disease presented to the emergency department with primary concerns of dyspnea on exertion and constant nonproductive cough, progressively worsening over the last two weeks. Associated symptoms included subjective fever, chills, decreased appetite, and dizziness. She had a body temperature of 100°F (37.8°C), heart rate of 108 beats per minute (bpm), respiratory rate of 28 breaths per minute, oxygen saturation of 87% on room air, and peripheral blood pressure measurement of 135/92 mmHg. Her complete blood cell count revealed leukocytosis at 18,000/μL. Her laboratory results showed she was hyperchloremic (112 mEq/L) with low bicarbonate levels  indicated dense patchy consolidations in the entirety of the right lung with sparse involvement of the left lung peripherally. The CT also indicated a small pleural effusion in the right pleural space. By day three of admission, the patient showed minimal signs of clinical improvement on broad-spectrum antibiotics. Her sputum cultures and stains were negative, and blood cultures were not growing any bacteria after 48 hours, leading to the decision to perform a flexible bronchoscopy with bronchoalveolar lavage (BAL) for further diagnostic workup. BAL revealed mixed cellularity with neutrophils, lymphocytes, and eosinophils. Lymphocytes were the predominant cell, encompassing over 40% of counted cells. A lung biopsy was performed in the right superior lobe at a point where the bronchiole was partially obstructed by an unknown growth. A histopathological examination of this sample demonstrated granulation tissue buds extending into the bronchiole tissue, mild mononuclear cell interstitial inflammation, and foamy macrophages in the lung immediately surrounding the granulation tissue. These findings are consistent with COP; however, a surgical lung biopsy would be required for a definitive diagnosis. After a lengthy discussion with the treatment team and the patient, the patient decided to undergo treatment for COP rather than proceed with the surgical biopsy, given her radiographic evidence and clinical status. She was started on high-dose prednisone at 60 mg once daily and 500 mg of azithromycin daily. Four days after starting this treatment plan, the patient experienced overall improvement. Her oxygen saturation was 95%, her respiratory rate was 18 breaths per minute, her heart rate was 90 bpm, and she was functionally able to ambulate the hospital halls without experiencing more than mild dyspnea.COP is a rare disease; a major teaching hospital in Canada measured the cumulative prevalence at 6.7 cases per 100,000 hospital admissions ,3.Chest x-rays and high-resolution CT scans are first-line diagnostic workups for COP, often showing patchy diffuse consolidations mostly involving bilateral lower zones and bilateral patchy peripherally located consolidations or ground-glass opacities . The diaThere have been no controlled trials comparing medications or duration of treatment in COP. Treatment regimens are based on current consensus guidelines , centereThis case report highlights the clinical and radiographic features of COP, an uncommon lung pathology. It offers an additional differential diagnosis for patients with suspected pneumonia unresponsive to antimicrobial therapy. This case report also highlights the limited research focused on the treatment of COP. The current treatment of COP is based on consensus guidelines. This case report illustrates the useful nature of macrolide antibiotics in COP. A controlled clinical trial based on macrolide therapy in COP, especially compared to glucocorticoid therapy alone, could yield crucial clinical knowledge in the treatment of COP.


Developments in deep learning have great potential for efficiently generating large-scale datasets to enable researchers to perform population-sized investigations, but the time and effort associated with producing robust hexahedral meshes has been a limiting factor in expanding finite element studies to encompass a population. Here we developed a fully automated pipeline capable of taking magnetic resonance knee images and producing a working finite element simulation. We trained an encoder-decoder convolutional neural network to perform semantic image segmentation on the Imorphics dataset provided through the Osteoarthritis Initiative. The Imorphics dataset contained 176 image sequences with varying levels of cartilage degradation. Starting from an open-source swept-extrusion meshing algorithm, we further developed this algorithm until it could produce high quality meshes for every sequence and we applied a template-mapping procedure to automatically place soft-tissue attachment points. The meshing algorithm produced simulation-ready meshes for all 176 sequences, regardless of the use of provided  or predicted  segmentation labels. The average time to mesh all bones and cartilage tissues was less than 2 min per knee on an AMD Ryzen 5600X processor, using a parallel pool of three workers for bone meshing, followed by a pool of four workers meshing the four cartilage tissues. Of the 176 sequences with provided segmentation labels, 86% of the resulting meshes completed a simulated flexion-extension activity. We used a reserved testing dataset of 28 sequences unseen during network training to produce simulations derived from predicted labels. We compared tibiofemoral contact mechanics between manual and automated reconstructions for the 24 pairs of successful finite element simulations from this set, resulting in mean root-mean-squared differences under 20% of their respective min-max norms. In combination with further advancements in deep learning, this framework represents a feasible pipeline to produce population sized finite element studies of the natural knee from subject-specific models.Osteoarthritis of the knee is increasingly prevalent as our population ages, representing an increasing financial burden, and severely impacting quality of life. The invasiveness of  Osteoarthritis (OA) of the knee is increasingly prevalent as our population ages, affecting an estimated 654.1 million individuals aged 40 and over in 2020 worldwide, including 15.8% of the North American population . Patientin vivo biomechanical data relating to the knee, with some researchers relying on externally attached pressure transducers, motion capture, electromyography  how closely do finite element meshes derived from deep learning segmentation labels match their manually segmented counterparts; and 3) how sensitive are the final simulation results to the predicted tissue labels?Developing a working FE simulation of a single knee typically begins with medical images, which then undergo segmentation, reconstruction, meshing, and mesh registration. Traditionally, the primary bottlenecks preventing clinical adoption are segmentation and meshing, which may take several days work per knee . Recent manual data set  excluding the added blending algorithm, again with blending, and the reserved test dataset utilizing predicted segmentation labels.To answer these questions, we have implemented a completely automated imaging-to-simulation pipeline . We usedpercent nodal coverage  for a validation dataset used to detect overfitting, and reserved an additional 14 subjects  for a final test set, unseen during training. We trained the model until the mean Dice similarity coefficient (DSC) of the validation set reached 89%  or three-voxel (bone) uniform kernel to remove segmentation artifacts before we reconstructed the surface using marching cubes . After velements . To presFor the tibia, femur, and patella bones, we created uniform triangular rigid body surface meshes using Voronoi clustering , with a Python libraries, encapsulating novel logic into functions, and developing an object-oriented application point interface with unified helper methods allowing for simplified plotting and cell quality calculations during any step following creation of the ill-conditioned mesh. Making these changes allowed us to improve vectorization, locate and fix typographical errors resulting from repeated logic, and will facilitate future algorithm adaptation for other joints. We added patellar cartilage meshing by adapting the femoral cartilage algorithm. The initial tibial cartilage meshing algorithm based on raytracing an interior grid with radial sectors was prone to failure. Discarding back faces during a planar projection and basing placement of the interior grid on a scaled bounding box improved robustness. Meshing can still fail if a cartilage hole lies on the edge of the interior grid, so we added a fallback method using a rectilinear grid of rays bounded by the unscaled bounding box.Excluding a cartilage mesh blending step , with each configuration treated separately to eliminate negative volumes or extreme skewed elements that resulted in an oscillating optimization solution. For example, we implemented logic confirming degenerate nodes were at the same topological indices when detecting step degenerates, which previously only checked if neighboring elements shared a single edge.A primary failure mode of the original package was looping infinitely during the final mesh optimization, which we traced back to the misclassification of degenerate elements. We included additional controls to more accurately classify the configuration of six-node elements  segmentation labels proved much faster than starting from scratch. Future researchers should not underestimate the time savings made possible by even a simple predictive model, and semi-supervised methods make it possible to train such models with limited data (In combination with further advancements in deep learning, this framework represents a major advance in the study of natural knee biomechanics, and presents a feasible way to produce ted data .alpha-build framework such that it may be adapted to any laminar structure approximated by a planar or cylindrical surface. Few modifications are necessary for other “hinge” joints, and the hip joint would only require the addition of a spherical coordinate raytracing function. The pipeline presented here has potential to improve our statistical shape and function models of the knee joint by better capturing population-based variation through inclusion of large-volume patient datasets. Integrating this pipeline with longitudinal patient datasets like the Osteoarthritis Initiative allows us to develop libraries of patient-specific models to quantitatively investigate relationships between anatomy, joint loading and longitudinal joint degeneration.We’ve designed our


We aimed to explore voxel-mirrored homotopic connectivity (VMHC) abnormalities between the two brain hemispheres in left temporal lobe epilepsy (lTLE) patients and to determine whether these alterations could be leveraged to guide lTLE diagnosis.Fifty-eight lTLE patients and sixty healthy controls (HCs) matched in age, sex, and education level were recruited to receive resting state functional magnetic resonance imaging (rs-fMRI) scan. Then VHMC analyses of bilateral brain regions were conducted based on the results of these rs-fMRI scans. The resultant imaging data were further analyzed using support vector machine (SVM) methods.Compared to HCs, patients with lTLE exhibited decreased VMHC values in the bilateral middle temporal gyrus (MTG) and middle cingulum gyrus (MCG), while no brain regions in these patients exhibited increased VMHC values. SVM analyses revealed the diagnostic accuracy of reduced bilateral MTG VMHC values to be 75.42% (89/118) when differentiating between lTLE patients and HCs, with respective sensitivity and specificity values of 74.14% (43/58) and 76.67% (46/60).Patients with lTLE exhibit abnormal VMHC values corresponding to the impairment of functional coordination between homotopic regions of the brain. These altered MTG VMHC values may also offer value as a robust neuroimaging biomarker that can guide lTLE patient diagnosis. Epilepsy is a common neurological disorder that causes affected patients to experience altered brain activity and recurrent seizures . An estiThe development of novel neuroimaging platforms holds great promise as a means of diagnosing lTLE and other neurological diseases. For example, resting state functional magnetic resonance imaging (rs-fMRI) is a non-invasive blood oxygen level-dependent neuroimaging strategy that can be used to directly visualize and assess functional connections among regions of the brain in a quantitative manner, allowing for the interrogation of neural network connections between the hemispheres of the brain . SeveralArtificial intelligence-based strategies have been used with increasing frequency in the context of diagnostic neuroimaging, with computer-aided SVM approaches being a subject of growing interest in this field that can aid in automating the diagnostic processing and identifying lesions. Owing to their high-resolution, rapidity, and non-invasive nature, neuroimaging techniques are commonly used to guide the diagnosis and evaluation of epilepsy patients. For example, abnormal degree centrality as a potential imaging biomarker for right temporal lobe epilepsy ; decreasSupport vector machine (SVM) techniques enable the automated recognition of patterns within particular datasets , making Here, a combination of VMHC values and an SVM approach was utilized to assess resting-state functional connectivity between the two hemispheres of the brain and to examine how this relationship is linked to lTLE patient clinical characteristics. The overall goal of this approach was to establish the ability of altered VMHC values to facilitate the neuroimaging-based diagnosis of lTLE patients.In total, 58 lTLE patients that had been diagnosed as per the criteria established by the International League Against Epilepsy (2017) were recruited for the present study from Tianyou Hospital affiliated with Wuhan University of Science and Technology. In parallel, 60 age-, sex-, and education level-matched healthy control (HC) participants were recruited. All lTLE patients met a minimum of two of the following criteria : a histoAn Ingenia 3.0 T scanner  equipped with a standard head coil was used to perform rs-fMRI scanning for all study participants. Scanning was conducted while participants remained still while lying down with their heads fixed in place with a belt. Foam padding and earplugs were used to mitigate scanner-related noise and head movements. Participants were directed to remain awake and not think about anything specific. rs-fMRI scans were performed with the following settings: repetition time = 2,000 ms, echo time = 25 ms, 36 axial slices, slice thickness = 3 mm, gap = 1 mm, 90° flip angle, field of view = 220 mm × 220 mm. The duration of rs-fMRI scanning for each participant was 8 min, with 240 volumes being obtained per participant.x, y, or z axes or >2° of maximal rotation. Data were then subjected to spatial registration in the standard Montreal Neurological Institute (MNI) space followed by resampling at 3 mm × 3 mm × 3 mm. The resultant images were then smoothed using a Gaussian kernel, linearly detrended, and subjected to bandpass filtering (0.01–0.08 Hz). Covariates such as head movement parameters, average whole-brain signals, white-matter signal, and signal derived from a defined ventricular region of interest were removed. Global signal was retained throughout rs-fMRI connectivity data processing.The MATLAB Data Processing Assistant for rs-fMRI (DPARSF) application was used to pre-process rs-fMRI data . The ini1 was used to conduct VMHC analyses. Prior to these analyses, images were standardized to a symmetrical spatial template as follows: an average image for all participants was generated by averaging all normalized gray matter images; the established mean image was averaged with its bilateral mirror version to produce a symmetrical template mask to facilitate VMHC statistical analyses; and individual gray matter images were registered to this template, followed by non-linear transformation to yield functional images. Images were then smoothed using a 6 mm full-width at half-maximum isotropic Gaussian kernel. The time-series data for each voxel in the cerebral hemisphere were then extracted for each participant group following pretreatment and registration to the standard Montreal (MNI) space, after which Pearson correlation coefficients were calculated between individual voxels in symmetrical positions on either side of the brain to generate VMHC values. The resultant data were then converted via Fisher Z-transformation into a Z-value graph to facilitate subsequent statistical comparisons between groups. VMHC statistical analyses were performed using cerebral hemispheres in the symmetric template generated above. A previous study has described the details of VMHC acquisition .SPSS 22.0 was used to analyze all data. Results were reported as x ± s. Demographic and clinical data were compared between lTLE patients and HCs using independent sample Mean VMHC values from identified abnormal brain regions were extracted, and Pearson’s correlation analyses were employed to assess the relationship between these values and clinical parameters of interest.c = −1 for HCs). In order to evaluate the classification performance of unobserved data, the sample set of SVM was divided into training set and test set. We perform classification and feature selection by constructing random SVM cluster based on subjects’ brain fMRI data. The grid search method and default functional kernels of Gaussian radial basis were applied to optimize the parameters with the “leave-one-subject-out” method to acquire the optimal sensitivity and specificity. VMHC values extracted from the bilateral middle cingulum gyrus (MCG) and middle temporal gyrus (MTG) were assessed for their ability to differentiate between lTLE patients and HC individuals using this approach based the method.The MATLAB LIBSVM package was used to implement an SVM analysis. The LIBSVM classifier was trained using providing examples of the form, where x represents the VMHC values of these abnormal clusters, and c is the class label  when differentiating between lTLE patients and HC individuals, with respective sensitivity and specificity values of 74.14% (43/58) and 76.67% (46/60) .Lastly, mean VMHC values were obtained for the bilateral MCG and MTG regions, with Pearson’s correlation analyses then being used to examine the relationship between these values and clinical parameters including age at seizure onset and disease duration. However, no significant correlations between VMHC values and these variables were detected in this patient cohort.Here, rs-fMRI data were used to compare differences in interhemispheric VMHC values between lTLE patients and HC individuals. Relative to these controls, lTLE patients exhibited reduced VMHC values in the bilateral MTG and bilateral MCG. This is the first report to our knowledge to have employed an SVM approach to gauge the diagnostic utility of VMHC abnormalities in the bilateral MTG and MCG as an lTLE-related neuroimaging biomarker. This strategy ultimately revealed that reduced bilateral MTG VMHC values may offer significant value as a sensitive and specific biomarker capable of distinguishing between lTLE patients and HCs.via the trans-MTG approach (Prior work has shown that lTLE patients exhibit reduced VMHC values in the MTG, bilateral medial superior frontal gyrus, bilateral inferior parietal lobule, and supplementary motor area . Zhao etapproach . The MTGapproach . In contapproach , while tapproach , and theapproach . Reductiapproach , with reThe cingulate gyrus functions as an important mediator of learning and retention in addition to connecting the medial temporal lobe and the PCC , 48. TheHere, reduced bilateral MTG and MCG VMHC values were evident in lTLE patients. The key regions of the DMN include the MTG and the PCC/precuneus , which cThe advent of increasingly advanced artificial intelligence strategies has been leveraged to guide neuroimaging-based computer-guided diagnostic efforts for patients with a range of neurological and pathological diseases. Novel MRI scanning and reconstructive strategies have been successfully leveraged to aid in diagnosing various diseases. Gao et al. , for exaThere are certain limitations to this analysis. For one, patients were treated for an extended period with AEDs, potentially altering rs-fMRI signals and associated study results. Indeed, as some AEDs have been shown to alter nervous system activation, it is not possible to exclude that AED treatment may have impacted the inter-group differences observed herein, underscoring the need for further research regarding the link between AED use and VMHC changes. Second, this was a cross-sectional study. Future longitudinal analyses are warranted to explore dynamic VMHC changes in particular regions of the brain. Lastly, this study was based on resting-state analyses, and further experiments combining both resting- and task-state fMRI have the potential to provide further insight regarding the magnitude of VMHC alterations in different regions of the brain under task conditions.In summary, altered VHMC values in the bilateral MCG and MTG may correspond to altered resting-state activity in these areas in lTLE patients. Changes in VMHC values in the MTG may also offer great potential as a neuroimaging biomarker that can guide lTLE diagnosis.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by the Ethics Committee of the Tianyou Hospital Affiliated to Wuhan University of Science and Technology. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.JW, RG, LC, and HR: conceptualization, project planning and methodology, and manuscript review and editing. JLW, SZ, and JL: data analysis and manuscript first draft. All authors contributed to the article and approved the submitted version.


Several studies have suggested that greater adiposity in older adults is associated with a lower risk of Alzheimer’s disease (AD) related cognitive decline, some investigators have postulated that this association may be due to the protective effects of the adipose tissue-derived hormone leptin. In this study we sought to demonstrate that higher body mass indices (BMIs) are associated with greater baseline FDG PET measurements of the regional cerebral metabolic rate for glucose (rCMRgl), a marker of local neuronal activity, slower rCMRgl declines in research participants with amnestic mild cognitive impairment (aMCI). We then sought to clarify the extent to which those relationships are attributable to cerebrospinal fluid (CSF) or plasma leptin concentrations.We used baseline PET images from 716 73 ± 8 years-old aMCI participants from the AD Neuroimaging Initiative (ADNI) of whom 453 had follow up images . For the leptin analyses, we used baseline CSF samples from 81 of the participants and plasma samples from 212 of the participants.As predicted, higher baseline BMI was associated with greater baseline CMRgl measurements and slower declines within brain regions preferentially affected by AD. In contrast and independently of BMI, CSF, and plasma leptin concentrations were mainly related to less baseline CMRgl within mesocorticolimbic brain regions implicated in energy homeostasis.While higher BMIs are associated with greater baseline CMRgl and slower declines in persons with aMCI, these associations appear not to be primarily attributable to leptin concentrations. With agHowever, to date, controversy exists on how overweight and obesity affect the risk for AD and its clinical course. A number of studies reported a higher risk for future AD in middle aged overweight/obese subjects. In contrast, elevated body weight has been found to have protective properties in elderly subjects leading to the description of the “obesity paradox” in AD . ImportaWhile potential biological mechanisms of the AD obesity paradox remain elusive, adipokines—and most prominently leptin–have been extensively discussed in the context of body weight and AD. Being secreted by adipocytes, leptin concentrations rise proportionally with fat mass and its putative functions—next to a major role in energy homeostasis—include potential neuroprotective properties .via identical transport mechanisms. Cerebral glucose metabolism on the other hand depends on local neuronal function and activity, which is why FDG uptake has been extensively used as non-invasive method for the estimation of the regional cerebral metabolic rate of glucose utilization (rCMRgl) in the study of AD and potential risk factors  and a subsample (N = 453) with available follow-up FDG imaging data. Under consideration of the previously proposed neuroprotective properties of the adipokine leptin we additionally explored the brain metabolic correlates of both plasma and CSF leptin concentrations in further subsamples.We therefore aimed to investigate the relationship of BMI with rCMRgl and its longitudinal declines in a large clinical population with a diagnosis of amnestic mild cognitive impairment (aMCI), hypothesizing that a higher baseline BMI would be related to greater rCMRgl and less longitudinal decline within AD typical brain regions. We performed voxel based analyses of FDG-PET imaging data in a sample of 2 ADNI is a large scale ongoing multicentric longitudinal study with the goal to identify biological and neuroimaging biomarkers of MCI and Alzheimer’s disease. Cross-sectional FDG PET data were downloaded for N = 716 aMCI subjects with baseline anthropometric data . Of these subjects, N = 453 had additional follow-up scans (≥6 months). Within the cross-sectional sample, data on plasma and CSF leptin concentrations  were available for N = 202 (plasma leptin) and N = 81 (CSF leptin) subjects. Baseline BMI was calculated as: (weight in kg)*(height in m)–2. Additional detailed information on recruitment, inclusion/exclusion criteria and sampling methods we refer to the ADNI website.3All data were downloaded from the LONI ADNI data repository.via global mean correction, consistent with previous BMI related and ADNI based publications . Voxel-wise analyses were conducted using multiple regression models to examine associations of baseline BMI with rCMRgl in the entire sample of aMCI subjects. Here, different models were applied to investigate the impact of different variables. First simple models were carried out adjusting for baseline age and gender only. Further models included additional adjustments for carriers of the ε4 allele (binary yes/no) or global cognition as measured by the ADAS-cog 11 as a continuous variable. Longitudinal analyses were performed analogously with the correction for follow-up time. Multiple regression analyses of plasma and CSF leptin concentrations with rCMRgl also included different models: A simple model with age and gender as covariates of no interest and a full model with additional adjustments for ε4 carriers and BMI, in order to account for the positive association between BMI and leptin, thus allowing to investigate leptin-specific effects. For all analyses we used a standard whole brain gray matter mask to reduce the risk of artifacts. Tables with corresponding detailed results are provided as Post-hoc analyses regarding differential associations of BMI and leptin concentrations in ε4 carriers vs. non-carriers were investigated by comparing slope strengths of the respective variable of interest  using SPM’s ANOVA. Corresponding detailed results (figures and tables) are provided as Additional 4 which provides robust permutation based non-parametric statistics and does not require to prespecify any arbitrary thresholds. Results were considered significant at p < 0.05 FWETFCE whole brain corrected after 5,000 permutations (E = 0.6). For ANOVA based interaction analyses results are illustrated and reported at a more exploratory threshold of p < 0.1 FWETFCE. MRIcron software5 was used for illustration generations.For all analyses we made use of the Threshold Free Cluster Enhancement (TFCE) toolboxFor non-imaging analyses we used SAS statistical software (SAS 9.3 and Enterprise Guide 5.1).p < 0.02). Cross-sectionally, BMI was not significantly related to cognitive performance . Longitudinally however, a higher baseline BMI was associated with less cognitive decline .Population characteristics are illustrated in p < 0.05 TFCE FWE whole brain corrected) of BMI with rCMRgl within parietooccipital brain region, most significantly within the bilateral precuneus. Additional adjustment for cognitive function  did not significantly change these results. Adjustment for ε4 carriers yielded a similar yet less significant pattern of bilateral associations within the parietal lobe (left > right). Worse cognitive function on the other hand–as measured by the ADAS-cog 11—was associated with lower rCMRgl within largely overlapping brain regions  did not significantly change our main results (data not shown).Additional p < 0.05 TFCE FWE whole brain corrected) of baseline BMI with longitudinal rCMRgl declines  within the bilateral posterior cingulate, the bilateral lateral and medial temporal lobe and the parietal lobes . Adjustment for ε4 carriers yielded a similar yet less extent pattern of inverse associations. Simple models additionally yielded positive associations of BMI with rCMRgl declines  within the left precentral gyrus. However, when adjusted for cognitive decline  none of these associations remained significant, whereas cognitive decline was associated with widespread and highly significant rCMRgl declines within similar AD-typical brain regions (overlap illustrated in p > 0.1 TFCE FWE whole brain corrected).Detailed results are illustrated in post-hoc adjustments for plasma glucose differences (N = 446) did not significantly change our main results (data not shown).Additional p < 0.001; CSF: rho = 0.67: p < 0.001; partial correlations adjusted for age and gender). Uncorrected for BMI, plasma leptin concentrations yielded a distinct pattern of both positive and negative associations with positive associations being located within the cerebellum and the parietooccipital cortex, whereas, extensive negative associations were found within the frontal cortex–most significantly within the medial prefrontal cortex (mPFC)—and the right ventral striatum. After additional correction for BMI, only negative associations remained significant within the bilateral medial and lateral PFC. A similar, yet more pronounced pattern was observed for CSF concentrations (unadjusted for BMI) with positive associations within the cerebellum and parietooccipital cortical regions and extensive negative associations within the medial and lateral prefrontal cortex, the bilateral insula and the bilateral dorsal and ventral striatum. After additional adjustment for BMI, CSF leptin concentrations were still positively associated with occipital and cerebellar regions  and negatively associated with medial cortical regions including the medial prefrontal gyrus together with more dorsal aspects of the cingulate gyrus and the right dorsal and ventral striatum expanding toward the right anterior and posterior insular cortex and the hypothalamus. In contrast, BMI was not significantly associated with rCMRgl when controlled for plasma and CSF leptin concentrations respectively. Of note, when BMI was analyzed individually in both subsamples , no significant associations were found for BMI in the CSF subsample (N = 81). In the plasma subsample (N = 202), positive (with cerebellar rCMRgl) and negative  associations were seen for BMI that closely resembled our associations with leptin, but were much less extent. With respect to positive associations observed in the entire sample (N = 716) of aMCI participants, overlap within the left parietal cortex was only seen at more liberal thresholds .For detailed cross-sectional results please see p < 0.05 FWETFCE) associations were found for both plasma and CSF plasma concentrations.For longitudinal declines of rCMRgl no significant (Significant ε4*leptin interaction terms (for detailed results see post-hoc adjustments for plasma glucose differences (N = 201 and N = 81 respectively) did not significantly change our main results (data not shown).Additional N = 716 aMCI patients . These associations were largely limited to heteromodal parietal association areas  that are typically affected by AD and showed a near-complete overlap with rCMRgl correlates of cognitive function. In a subsample of N = 453 subjects with follow-up data a comparable yet more extent pattern of inverse associations of baseline BMI with rCMRgl declines  was observed. Again, these associations were confined to AD-typical brain regions and showed strong overlap with the correlates of longitudinal cognitive decline. However, while cross-sectional results were independent of cognitive function, our longitudinal analyses of BMI did not remain significant when controlling for cognitive decline. For plasma and CSF concentrations of the adipocyte derived hormone leptin, we show a bidirectional pattern of positive associations with cross-sectional rCMRgl, restricted to parietal, occipital, temporal (in parts) and cerebellar regions and negative associations within prefrontal/limbic and subcortical structures. However, after adjustment for BMI, leptin concentrations were almost exclusively negatively associated with mesocorticolimbic brain regions implicated in the regulation of energy homeostasis and longitudinal analyses did not yield significant associations on the whole-brain level. Additional post-hoc analyses only showed subtle differences between carriers and non-carriers of the APOE ε4 risk allele for associations of BMI and leptin concentrations with brain glucose metabolism.Here we investigate the relationship of BMI with rCMRgl (as estimated by PET FDG uptake) and its longitudinal declines in a large clinical population diagnosed with aMCI. Additionally we explored the relationship between plasma and CSF concentrations of the adipokine leptin with cerebral glucose metabolism. Briefly summarized, a higher baseline BMI was associated with higher rCMRgl in a sample of Epidemiological data provide support for our cross-sectional and longitudinal observations. Higher BMI In older subjects has been repeatedly found to be associated with a decreased risk for dementia and AD, while on the other hand several studies found middle aged overweight or obese subjects to have an increased risk for future AD . NeverthN = 963) cross-sectional study of patients diagnosed with AD or MCI and cognitively healthy subjects  studies have found increased mesial temporal atrophy in AD patients with low body weight  while obsubjects . Neverthsubjects . Hence, subjects . Given tsubjects , our ressubjects . Howeversubjects .On the other hand, brain metabolic reductions may be influenced by a partial volume effect due to regional brain atrophy, which has not been corrected for in this study. Since BMI and adiposity have been repeatedly shown to be associated with brain structural alterations in healthy and diseased populations, this may have affected our results. Nevertheless, previous studies found AD-related hypometabolic patterns not to be significantly affected by atrophy e.g.,  and the via the arcuate nucleus of the hypothalamus  without additional implementation of an input function , since the respective prerequisite data are not provided by ADNI. Additional limitations of this study include the use of BMI as an estimate of adiposity. Overweight and obesity are characterized by increases in both fat mass (FM) and fat-free mass . Although BMI is the most frequently used surrogate for adiposity, no inferences can be drawn regarding body composition. Interestingly, post-hoc analyses did not indicate a significant age group<BMI interaction term  on the level of cross-sectional and longitudinal, results of this study may not be generalizable to younger populations.On the other hand, we found extensive negative associations of both plasma and CSF leptin with cross-sectional rCMRgl of prefrontal and subcortical structures including the dorsal and ventral striatum, the insular cortex and parts of the hypothalamus. Additional adjustment for BMI attenuated these associations, however, the pattern of involved frontal and subcortical regions remained unchanged, particularly for CSF measures of leptin. Interestingly, these brain regions are strongly implicated in the neurobiology of homeostatic functions . ConsideIn this study we found that higher BMI is cross-sectionally associated with higher rCMRgl in subjects with aMCI. Analogously, analyses of longitudinal rCMRgl changes showed less decline in aMCI subjects with a higher baseline BMI. Both cross-sectional and longitudinal associations were confined to brain regions that typically exhibit regional hypometabolism in AD and showed strong overlap with rCMRgl correlates of cognitive performance. These data support a potential beneficial effect of a higher body weight on the level of brain glucose utilization, however, mechanisms remain unclear. Although the adipocyte-derived hormone leptin is thought to exert neuroprotective effects in the context of AD, additional cross-sectional analyses showed mostly negative associations of plasma and CSF leptin concentrations, predominantly located within mesocorticolimbic brain regions implicated in the regulation of energy homeostasis and eating behavior. These observations most likely mirror leptins primary physiological functions, hence, the potential beneficial effects of a higher body mass index seem not to be primarily attributable to leptin concentrations.https://adni.loni.usc.edu/data-samples/access-data/.Publicly available datasets were analyzed in this study. This data can be found here: https://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf?). The patients/participants provided their written informed consent to participate in this study.The ADNI study was approved by the Institutional Review Boards of all of the participating institutions (for a full list of institutions see CW: study design, data analysis, interpretation of data, and manuscript preparation. KC: data analysis, interpretation of data, and critical revision of the manuscript. YC, VD, and YS: data preparation and processing and critical revision of the manuscript. ER: interpretation of data and critical revision of the manuscript. All authors contributed to the article and approved the submitted version.


There is a paucity of information regarding the uptake of the COVID-19 vaccine among community-dwelling persons living with dementia and their family caregivers. We examined factors influencing COVID-19 vaccine acceptance and hesitancy among community-dwelling persons living with dementia and their family caregivers during the early months of the vaccine rollout . Data came from three waves of telephone interviews (Mtime = 38.33 minutes) with 26 family caregivers living in rural Appalachian Virginia . We conducted a four-stage trajectory-based thematic content analysis and used the health belief model to interpret the data. Whereas all family caregivers and their relative living with dementia were eligible for the vaccine at Wave 3, only 10 dyads received it, while 10 dyads did not. In two families, the caregivers received the vaccine but not the person living with dementia; in four families, the caregiver had not received the vaccine, but their relative did. COVID vaccination acceptance was influenced by perceived direct and indirect health risks, cues from trusted allies, and ability to overcome vaccination barriers. Homebound people living with dementia faced unique barriers including transportation to vaccine sites and providers’ inability to deliver the vaccine to the home. Caregivers who refused or delayed vaccinations for themselves or their relatives discussed confusion about eligibility, low perceived risk of COVID, vaccine fear, and personal choice beliefs. Findings inform direct care delivery for interdependent family members who live in remote locations facing a public health crisis.


Implants are essential therapeutic tools for treating bone fractures and joint replacements. Despite the in-depth study of osseointegration for more than fifty years, poor osseointegration caused by aseptic loosening remains one of the leading causes of late implant failures. Osseointegration is a highly sophisticated and spatiotemporal process in vivo involving the immune response, angiogenesis, and osteogenesis. It has been unraveled that the nervous system plays a pivotal role in skeletal health via manipulating neurotrophins, neuropeptides, and nerve cells. Herein, the research related to nervous system-driven osseointegration was systematically analyzed and reviewed, aiming to demonstrate the prominent role of neuromodulation in osseointegration. Additionally, it is indicated that the implant design considering the role of neuromodulation might be a promising way to prevent aseptic loosening. Bone implants are widely used in orthopedics and dentistry to reduce pain and rehabilitate bone function . HoweverNerve tissue, the main component of the nervous system, is composed of neurons (nerve cells) and glia. The neuron has the function of receiving stimulation and conducting excitation. It is also the basic functional unit of nerve activity. Glia play a supporting, protective, and nutritional role in nerve tissue. After being stimulated, neurons can produce excitation and conduct excitation along nerve fibers, and thus affect the innervated tissues. Studies have shown that neurotrophins, neuropeptides, and nerve cells affect skin wound-healing , pregnanOnce implanted, the bone tissue’s nerve system is injured. A scarce amount of research has investigated the function of the nerve fibers in bones due to their scarcity in numbers compared to other tissues. It is also challenging to locate nerves in the bone due to technical limitations. However, it has been recognized that the nervous system plays a pivotal role in bone development and fracture healing . MoreoveThe research of osseointegration began in the 1950s when bioengineer Per-Ingvar Brandmark found that the titanium component could only be retrieved if the surrounding bone was destroyed after implanting titanium components into rabbit femurs . Since tThe implantation of the implant invariably results in a vascular rupture in the surrounding area. As a result, the implant’s surface contacts the patient’s blood. A blood clot immediately forms on the implant’s surface several hours after imploding . The bloThe most evident contribution of blood clot formation is to limit bleeding, after which the blood clots act as a temporary matrix for wound healing , which cDuring the first 24 h, the inflammatory process response peaks after the blood clot formation and lasts 7 days following the injury . A favorAdditionally, macrophages develop specialized and polarized functional characteristics in the setting of a particular immune response. Traditional activated macrophages  and alternatively activated macrophages  are two types of polarized macrophages . IFN-γ cThe formation of new blood vessels is known as angiogenesis . This prOsteogenesis and angiogenesis are closely related since blood vessels transport nutrients and oxygen to organs during bone regeneration. In response to hypoxia, osteoblasts activate the hypoxia-inducible factor-α (HIF-α) pathway. HIF-α promotes angiogenesis and osteogenesis by increasing the VEGF levels in osteoblasts. The mice which were genetically modified by the deletion of the von Hippel–Lindau gene expressed large amounts of VEGF and developed extremely dense and well vascularized long bones . In tissMesenchymal cells, pre-osteoblasts, and osteoblasts link to the implant’s surface covered by the calcified fibrillar layer on the first day after implantation to generate collagen fibrils of osteoid tissue. A braided bone and later a reparative trabecular bone grow at the gap between the implant and the host bone after a few days of implantation, with bone trabeculae delimiting vast marrow areas rich in blood vessels and mesenchymal cells . The ostBone formation, modeling, and remodeling comprise the three processes during osseointegration. Osteoblasts and bone-resorbing osteoclasts collaborate closely during these processes, forming a “bone multicellular unit” . OsteoblAccording to data from clinical and experimental investigations, the neurological system, including neurotrophins, neuropeptides, and nerve cells, appears to have a role in diverse bone functions. A paucity or complete loss of peripheral innervation might result in a fracture without the bone healing . The calNerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) are neurotrophins (NTs). They share a high level of similarity and trigger biological reactions that are very comparable. Neurotrophins are generated by non-neuronal cells such as leukocytes and fibroblasts and act on non-neuronal cells in various ways. The growing amount of evidence implies that NTs play an important role in bone formation . NeurotrFurthermore, all neurotrophins target p75, a tumor necrosis factor receptor family member . TrkA waThe receptor’s dimers and the kinase are activated when a neurotrophins bind to Trk receptors. Each Trk receptor has ten conserved tyrosines in its cytoplasmic domain, three of which are found in the kinase domain’s autoregulatory loop. The phosphorylation of these amino acids further activates the kinase. The other residues’ phosphorylation aids signaling by establishing docking sites for adaptor proteins that connect these receptors to intracellular signaling pathways such as the Ras/ERK protein kinase pathway, the PI3 K/Akt kinase pathway, and the PLC-γ1 pathway ,49.P75 binds to the whole neurotrophin family. It belongs to the TNF receptor/Fas/CD40 superfamily of receptors and is a transmembrane glycoprotein. The p75 receptor can alter neurotrophin activities by interacting with various Trk receptors . The higRita Levi-Montalcini found NGF in the 1940s, which was isolated in high quantities by the 1960s . The higNGF is required for bones to respond to mechanical stress. The surfaces of mammalian bones are extensively innervated by sensory neurons that emerge from the dorsal root. Mechanical impulses cause osteoblasts on the bones’ surface to produce more NGF, which stimulates TrkA sensory neurons, causing the release of osteogenic cues that govern osteocytic Wnt/-catenin signaling and promote bone formation. The osteocyte is the main bone cell in charge of translating mechanical stimuli into signals that affects bone turnover. These cells have extensive dendritic links to bone cells throughout the skeleton and the capacity to produce both anabolic and catabolic signaling molecules, suggesting that they might serve as mechanosensors .The ability of topically given NGF to enhance bone formation was tested using a rat model of mandibular distraction osteogenesis. It was discovered that NGF may enhance innervation and bone regeneration and induce osteoblastic cell differentiation . As showTreatment with anti-NGF antibodies significantly reduces the pain behavior associated with bone cancer. Using a prostate-specific bone cancer model in a mouse femur, NGF-sequestering antibodies were administered. It was observed that the administration of a blocking antibody to NGF significantly reduced both early- and late-stage bone cancer pain-related behaviors to a level equivalent or greater to that observed following an acute administration of 10 mg/kg or 30 mg/kg of morphine sulfate .NT-3, a neurotrophin, plays a pivotal role in spinal neurons’ survival and the regeneration of axons, embryonic blood vessels, limb bone development, vascular endothelial cell migration, and other processes . NT-3 anTrkB is a single high-affinity receptor that NT-4/5 binds to and activates. The granulocytes produced mRNA for the NT-4/5 gene . TrkB poBrain-derived neurotrophic factor (BDNF) was identified in the 1980s and is found in trace amounts in the central nervous system . BDNF haMoreover, BDNF plays a key role in the activation of osteoclasts. Research on multiple myeloma (MM) discovered that human osteoclast precursors expressed BDNF receptor TrkB and a Trk inhibitor, K252a, significantly decreased BDNF-stimulated osteoclast production, suggesting that BDNF utilized TrkB for its influence on osteoclasts. BDNF increased the expression of the RANKL in bone marrow stromal cells, promoting osteoclasts’ development . PolymorGlial cell line-derived neurotrophic factor (GDNF) was initially identified as a glioma cell line-secreted factor that might help fetal ventral midbrain neurons survive in vitro . RET, GFPlatelet-derived growth factors (PDGFs) are important mitogens for numerous mesenchymal cell sorts, such as fibroblasts and smooth muscle cells, as well as certain neuroectodermal cell populations, such as oligodendrocytes. PDGF has many variants, each communicating with two unique dimerized receptors (A and B) that have varied affinities . AccordiDuring osseous repair, PDGF is among the most essential biological agents. PDGF’s capacity to serve as a chemoattractant and mitogen for mesenchymal cells causes angiogenesis and recruits osteoprogenitor cells to contribute to its powerful stimulatory actions . PDGF isThe fibroblast growth factor (FGF) gene family now has nine members, all of which are expressed in mammals. Acidic and basic FGF, commonly known as FGF-1 (aFGF) and FGF-2 (bFGF), are the most prevalent in normal adult tissues. To transduce signals in target cells, FGFs bind to numerous FGFRs. A mouse fracture model investigated the influence of an aFGF injection on normal wound repair. The aFGF infusions boosted cartilage size while decreasing type II procollagen and proteoglycan-essential protein mRNA expression . FGF-2 hNeuropeptides are small proteinaceous molecules generated by nerves, which are produced at nerve terminals upon neuron activation, and then bind to neural sensors to operate on neuronal substrates . The datCalcitonin gene-related peptide (CGRP) is a peptide that belongs to the calcitonin family. The whole nervous system, the cardiovascular and respiratory systems, and the thyroid gland all contain CGRP. Bone marrow and periosteal tissues were similarly shown to have an equal distribution of CGRP . Humans CGRP has been found to aid in transmitting pain and sensitization . In oste+ neurons are related to initiating bone growth, accelerated bone formation, and cartilage and muscle specialization in limb bud development . . 142]. SOsteoblast growth and differentiation are aided by Schwann cells. Co-culturing osteoblasts with Schwann cells can increase their proliferation and differentiation. Another research study reported that in an in vitro indirect coculture setting, Schwann cells preserve their regular potential to generate neurotrophins, boosting osteoblast proliferation and differentiation . Semapho−/− mice have a low bone mass. Even though bone-specific Sema3A-deficient mice had a reduced expression of Sema3A, their bone masses were normal. On the other hand, mice lacking Sema3A in their neurons fell short in terms of bone mass, similar to Sema3a−/− mice, indicating that neuron-derived Sema3A accounts for the observed abnormalities in bone ..192].To increase bone formation during tissue engineering, BDNF may promote neurogenesis and osteogenesis in hBMSCs . PeripheThe heat created during an implant osteotomy may cause osteonecrosis and delayed bone healing, thereby compromising initial bone-anchoring osseointegration and fixation equipment. Core–shell polymeric biodegradable microspheres containing PDGF can avoid heat-induced bone damage. In one study, PDGF increased cell viability and decreased osteonecrosis, while PDGF-simvastatin administration in a sequential manner increased osteogenesis and encouraged bone maturation . MagnesiMoreover, BMSCs transfected with bFGF will significantly enhance vascular tissue repair and increase osseous formation and remodeling . The effCGRP may promote osseointegration in the early to middle stages since it modulates peri-implant angiogenesis and osseointegration dysfunctions caused by diabetes . The IANThe sensitivity for loads is relatively modest in the situation of the implant. Grafting Schwann cells into the implant site has been shown to increase the sensory reactions of dental implants to a rate equivalent to natural teeth. After a peripheral nerve injury, Schwann cells form a cellular ring to accept regenerated sprouts from the axonal stump. Secondly, it may produce several neurotrophic factors and receptors, including NGF, BDNF, NT-3, and GDNF, which are necessary for axonal regeneration after nerve injury . SchwannIt has been documented that sensory nerves play a role in osteogenesis. When sensory nerve tracts are implanted into tissue-engineered bone, vascularization and neurotization are greatly improved, resulting in a greater osteogenesis impact than tissue-engineered bone alone C–E 204]204].2 glass particles with and without BDNF, and the degree of regeneration was measured after 5 weeks. Compared to WT mice that did not receive the BDNF-functionalized cement/MBG composite, the bone formation in the WT mice who received the BDNF-functionalized cement/MBG composite was considerably increased 205]. Thencreased .Above all, while some researchers have yielded promising outcomes, the mechanism of surface modification on osseointegration and innervation remains a mystery. The surface modification of materials should be pursued further for the advanced study of the nervous system, and its mechanism should be unraveled.A vast amount of research and evidence has demonstrated that neurotrophins, neuropeptides, and nerve cells participate in bone formation, bone regeneration, and other bone-related activities. The nervous system has an impact on osseointegration at various stages. For example, the inflammatory response is mediated by several neurotrophins and neuropeptides. They have a variety of effects, including increasing immune cell proliferation and influencing antibody synthesis, among others. Some neurotrophins and neuropeptides work together to promote neovascularization and angiogenesis. After implantation, they can also facilitate osseous development and remodeling during osseointegration. Accordingly, few researchers have launched pioneering studies into the surface-modification of the implant material to manipulate the nervous system and promote osseointegration. As a result, this review underlines the relevance of the nervous system in osseointegration and calls for a possible approach to improve osseointegration from a novel viewpoint.


With this interventional CMR (iCMR) technique, theelectrophysiological procedure is performed while the patient is inside the CMRscanner. Advantages of iCMR include real-time imaging of the heart, real-timetracking and navigation of the catheters 2A 65-year-old male with symptomatic persistent typical atrialflutter was referred for rhythm management to our centre. Previous ECGsconfirmed a typical counterclockwise atrial flutter. His past medical historyincludes hypertension, gout, sleep apnoea, and epilepsy. In the past few years,more than three electrical cardioversions with early recurrences of atrialflutter were performed. Amiodaron to maintain sinus rhythm wasinitiated.At the time of presentation in the outpatient clinic, the ECGshowed sinus rhythm with a rate of fifty beats per minute. Physical examinationwas unremarkable. Echocardiography showed a good left ventricular functionwithout valvular dysfunction and moderate left atrial dilatation (39 ml/m2).Laboratory analysis was unremarkable. The patient had no contraindications formagnetic resonance imaging; and after the patient provided informed consent, hewas scheduled for an iCMR procedure.In our institution, iCMR procedures are performed using aconventional 1.5 T MRI scanner  that can be transformed into an interventional CMRsuite.Pre-ablation imaging commenced with a baseline ECG-triggeredrespiratory-navigated 3D whole-heart balanced steady-state free precession(bSSFP) sequence to acquire the full anatomy of the heart and surroundingstructures. The heart was segmented to create a 3D shell which was thenintegrated into the navigation system  as a roadmap for the iCMR procedure and active catheter tracking.In contrast to passive catheter tracking that relies on catheter visualizationdue to susceptibility artefacts, active tracking uses micro coils within thecatheter tip to determine its location. The CTI was visualized in three imagingplanes. In addition to the right anterior oblique (RAO) and the left anterioroblique (LAO) view, we also used a transversal view to visualize the isthmusfrom superior. The RAO view shows the isthmus in its full length while the LAOview reveals the medial or lateral position of the CTI line regarding theintra-atrial septum and the ostium of the coronary sinus (CS).see video online). One catheter was placed in the CS,followed by the ablation catheter. Although these catheters are 9F, theirmaneuverability and stability are comparable with irrigated ablation cathetersusing in fluoroscopic-guided ablation procedures. Prior to ablation, a ‘designline’ was created to identify the optimal route through the isthmus towards theinferior caval vein, followed by the definitive ablation line.Following baseline imaging, MRI compatible catheters  wereintroduced in the femoral vein. These unique catheters regard two bipoleirrigated-tip ablation catheters with two MR receive coils in the distal end foractive MR tracking, displaying its real-time location inside the 3D shell(o and mean duration(SD) 44 (17) sec of ablation lesions)were required to complete the CTI line and create a bidirectional block. This bidirectional block was confirmed by a color-codedmap representing the time delay between the pacing signal of the CS catheter andthe activation time of the areas around the tricuspid annulus . During a 30-minute waiting period, additionalECG-triggered breath-hold black-blood T2-weighted MR imaging was performed tovisualize edema in the ablation region (The optimal target ablation line is different for each patient,based on the route that gives the best catheter stability while taking intoconsideration the presence of a prominent sub-eustachian pouch or Eustachianridge, and the length and thickness of the isthmus. In this patient, iCMRprovided unique information about these anatomic variations that may challengethe CTI ablation. The MRI images showed that a lateral isthmus was interferencewith the hepatic vein, which would challenge catheter stability. A more septalisthmus position was rather thick with potentially increasing difficulties tocreate transmural ablation lesions. Finally, a medial position of the CTI waschosen . Cine MRn region . These i3In this case we illustrate that iCMR allows the visualization ofpatient specific anatomy of the CTI to guide catheter ablation from thetricuspid annulus to the inferior caval vein. The CMR-derived anatomicalinformation was used to decide on a relatively long medial ablation line in arather thin-walled region of the CTI, which also allowed a better catheterstability than a more lateral position. Further studies are required to evaluatewhether real-time visualization of the complete ablation line anatomy, real-timetracking of the ablation catheters, and electrical confirmation of abidirectional block increase procedural success rate.The authors declare that they have no known competing financialinterests or personal relationships that could have appeared to influence the workreported in this paper.


Elevated levels of oxidative stress are usually observed following injuries, leading to impaired tissue repair due to oxidation-related chronic inflammation. Several attempts have been made to manage this unfavorable situation, and the use of biomaterials with antioxidant activity is showing great promise in tissue engineering and regenerative medicine approaches. Bioactive glasses (BGs) are a versatile group of inorganic substances that exhibit an outstanding regenerative capacity for both hard and soft damaged tissues. The chemical composition of BGs provides a great opportunity for imparting specific biological activities to them. On this point, BGs may easily become antioxidant substances through simple physicochemical modifications. For example, particular antioxidant elements (mostly cerium (Ce)) can be added to the basic composition of the glasses. On the other hand, grafting natural antioxidant substances  on the BG surface is feasible for making antioxidant substitutes with promising results in vitro. Mesoporous BGs (MBGs) were demonstrated to have unique merits compared with melt-derived BGs since they make it possible to load antioxidants and deliver them to the desired locations. However, there are actually limited in vivo experimental studies on the capability of modified BGs for scavenging free radicals ). Therefore, more research is required to determine the actual potential of BGs in decreasing oxidative stress and subsequently improving tissue repair and regeneration. The present work aims to highlight the potential of different types of BGs in modulating oxidative stress and subsequently improving tissue healing. A normal tissue healing process includes four overlapping stages of (I) hemostasis, (II) inflammation, (III) proliferation, and (IV) remodeling, which play central roles in the repair process . NumerouPrior studies have presented particular types of nanosized particles as antioxidant substances; ceria (nanoceria), carbon materials ), manganese (Mn), and selenium (Se) are among the most well-studied free radical scavengers ,8. NumerExperimental studies have clarified that applying the above-mentioned antioxidants in combination with other biocompatible materials may result in the generation of tissue replacements with a more potent regenerative capacity . Among tTo the best of our knowledge, this is the first review report specifically discussing the usability and applicability of BGs for modulating oxidative stress and, subsequently, improving wound healing. To this aim, we first introduce free radicals and antioxidants and then deal with the significance of modulating oxidative stress in the tissue healing process. Finally, different types and formulations of BGs will be described as suitable materials for scavenging free radicals and improving tissue repair and regeneration.•), anion radical superoxide (O2–•), hydrogen peroxide (H2O2), peroxyl radical (ROO•), and nitric oxide (NO•) that are mainly generated by mitochondria . Th. Th2-inc2–54CaO–6P2O5 mol%). The films containing the lowest concentration of PPh (1.5 w/w) exhibited good cytocompatibility, significantly increased alkaline phosphatase (ALP) activity, and induced the expression of bone extracellular matrix proteins  in human normal osteoblasts in vitro; in contrast, they reduced the production of intracellular ROS in macrophages. Furthermore, the composites loaded with PPh showed antibiofilm properties against Gram-positive and Gram-negative bacteria. The results indicate that the developed constructs represent potential multifunctional biomaterials with a wide range of tunable physicochemical and biological properties that are beneficial for tissue engineering. In another study, ferulic acid, which is known to be an antioxidant phenolic phytochemical, was utilized for developing chitosan–BG–ferulic acid (CS-BG-FA) composite coatings by using the alternating current electrophoretic deposition (AC-EPD) technique [The use of BG-polymer composites may provide additional advantages for tissue engineering and drug delivery applications. For example, polymers may act as a cross-linking bridge to enhance the interfacial interaction between glasses and loaded drug, which can significantly increase the drug-loading capacity while avoiding initial burst release . In ordeechnique . The preAs earlier mentioned, MBGs are an extraordinary class of BGs that hold great promise in drug delivery and tissue engineering strategies ,99. Up t2–15CaO–5P2O5 and 80SiO2–20CaO (mol.%) MBGs samples doped with 5.3 mol.% of CeO2 showed good catalase activity while still exhibiting proper bioactivity properties [2–15% CaO glass in which Ce  partially replaced CaO [3+ and Ce4+  was detected at the MBG surface. The glasses showed a high antioxidant effect  without causing any adverse impacts on bioactivity and cytocompatibility. In order to promote the therapeutic effects of MBG nanoparticles (MBGNs), their endowment with additional antioxidant properties has become of great interest to control the oxidative stress associated with bone remodeling defects. As a result, the pro-osteogenic and anti-inflammatory activities of antioxidant mesoporous spherical Ce-doped MBGNs (100–300 nm) have been verified by Zheng et al. using a two-step strategy [2–30CaO, mol%), and then a post-impregnation approach was developed for the modification of MBGNs with Ce. With a concentration of Ce4+ (relative molar percentage of 74%) higher than that of Ce3+, the obtained Ce-doped MBGNs at 1 mg/mL showed no cytotoxicity against fibroblasts. Moreover, a reduction in the expression of genes responsible for oxidative stress in macrophages (J774a.1) was observed after incorporating Ce into MBGNs. Ce-doped MBGNs also suppressed pro-osteoclastogenic responses due to their pro-osteogenic activities, which make them promising candidates as advanced biomedical devices for targeting infected bone defects and inflammatory bone diseases  [Most antioxidant MBGs have been prepared by incorporating Ce into their chemical composition . Since toperties . In 2021aced CaO . These ustrategy . First, porosis) ,107.In addition, to incorporate antioxidant elements, MBGs can be loaded with antioxidant natural or synthetic macromolecules for modulating oxidative stress and accelerating tissue healing. On this matter, gallic acid, polyphenols (POLY), and anthocyanins were successfully loaded into Ce-doped MBGs to enhance their antioxidant activity . The res4+/Ce3+, in the scaffolds. In some studies, Ce-doped MBGs were embedded into polymeric matrices to make composites with antioxidant activity and high tissue regeneration capacity. For instance, Ce3+/Ce4+-containing MBGs were previously added to alginate beads for bone tissue engineering applications [2 mol% could counteract the oxidative stress without a negative impact on the proliferation of pre-osteoblastic cells MC3T3-C1 cells. However, cell differentiation was decreased as a function of Ce-content in the samples.Ce-containing MBG-derived 3D scaffolds were also successfully developed with drug delivery ability for possible use in tissue engineering applications . These sications ; the res2–15CaO–5P2O5 mol.%) to obtain a triply functional biomaterial combining an apatite-forming ability (which is key in the context of bone regeneration) and ion/drug release. The release profiles of curcumin from these glasses were able to exert pharmacological activities, thus showing great promise in overcoming the typical limitations of curcumin ; however, the antioxidant properties in vitro/in vivo were not specifically investigated in that study. Shruti et al.  also incControlling oxidation could be the key that opens the doors of a new type of targeted biomedicine with huge impact and opportunities for improving therapy. This is a partially unexplored land requiring, firstly, a better knowledge of the biomolecular mechanisms behind oxidation and related physiological/pathological effects, as well as the relationship between oxidation and immunomodulatory pathways. Implantable BGs can play a major role in this scenario as they are able to indeed exert antioxidant effects on cells and tissues through two main modalities, i.e., the release of antioxidant ions or antioxidant biomolecules. In this regard, great promise has been shown by MBGs as they can act as carriers for the uptake and delivery of both therapeutic agents, alone or simultaneously. In fact, metallic elements such as cerium can be incorporated into the glass network during the synthesis process and then released upon contact with biological fluids according to controllable kinetics. On the other hand, cerium was reported to delay the apatite-forming ability of BGs, and hence the bioactivity, due to the formation of competitive and insoluble cerium phosphate phases. In order to manufacture BGs with higher bioactivity, a suitable morphology should be selected. In this regard, MBGs with high specific surface area due to nanotexturing and nanosize allow the bioactivity-related concerns of Ce-containing glasses to be overcome. Furthermore, a range of organic molecules, even characterized by challenging properties such as insolubility in water, could be loaded into the nanosized pores of MBGs, from which they can then exert the desired therapeutic action. This is the case of curcumin, which can be potentially used for the treatment of various oxidation-related diseases ranging from skin wounds to cancer. How to govern the concurrent release of ions and biomolecules in terms of synergistic/antagonistic interactions is one of the great challenges for BG researchers and biomaterials scientists in general.Moreover, the surface reactivity of BGs can be effectively exploited for grafting procedures and functionalization strategies, involving both the outer surface of glass products and the walls of internal nanopores (as in the case of MBGs), thus further expanding the versatility of such biomaterials.