The influence of maternal autoimmunity mediators on child development and brain function has been the subject of several studies. Clinically, most have focused on the association between maternal autoimmunity and the diagnosis of autism in children. On the other hand, data are rarer concerning the rest of the mental disorders and mainly, they are obtained from small cohorts.The aim of this study is to discuss the association between the presence of autoimmune pathology in the mother and the development of mental disorders in the childwe conducted our study through a descriptive study of six clinical cases.80 % the patients treated were male57% had a characterized depressive disorder34% had ADHD9 % had ASDMaternal autoimmune diseases were associated with increased mental disorders in children. These results suggest a possible shared genetic vulnerability between the two conditions or a potential role of maternal immune activation in the expression of neurodevelopmental disorders in children.None Declared


Gastric metastasis of lung cancer is rare, and the cases of disappearance of gastric metastasis and liver metastasis caused by oxitinib treatment have not been reported.A 47-year-old male patient with no history of diabetes, hypertension or smoking presented with chest discomfort after eating. At the time of consultation, the diagnosis of adenocarcinoma of the right lower lobe of the lung with liver and gastric metastasis was considered by pathological examination of biopsy of the fundus of the stomach near the cardia, pathological examination of CT-guided lung aspiration and pathological examination of liver occupancy aspiration, combined with immunohistochemical results. He was found to have exon 19 deletion in next generation sequencing. We performed osimertinib on him (EGFR–TKI) systemic therapy, followed by local radiation therapy to the right lower lung primary lesion.After systemic treatment with osimertinib and local radiotherapy of the primary site, the metastases disappeared and the primary site showed post-radiotherapy changes, and the evaluated efficacy was complete remission.This is the first report to our knowledge of a patient who presented with gastric and hepatic metastases from lung cancer and achieved complete remission with osimertinib and local radiotherapy, with good quality of life, which also provides a basis for future clinical work and is of great significance. The diagnosis and treatment of advanced non-small cell lung cancer (NSCLC) have changed dramatically since the discovery of several oncogenic driver mutations  and the advancement of research into corresponding targeted therapies , bone (25%), adrenal glands (22%), kidney (10–15%) and pericardium (20%)  was admitted to the hospital with apparent cause of chest discomfort after eating and feeling of obstruction to eating. Computed tomography (CT) scans of the chest, abdomen and pelvis were performed after admission, showing a lesion in the lower lobe of the right lung with a high likelihood of lung cancer, an abnormally enhancing foci in the parietal lobe of the liver with metastases not excluded, and a hypodense foci in the lower segment of the right anterior lobe of the liver Fig. a–f. In o). Based on a review of the literature, it is considered that although the mechanism of gastric metastasis from lung cancer has not been clearly elucidated, the possibility of hematogenous dissemination through the rich vasculature of the stomach is high considering the anatomical structure of the stomach, but this conjecture has also not been clearly confirmed  when patients with EGFR-mutated advanced NSCLC were treated with an EGFR tyrosine kinase inhibitor (TKI) monotherapy compared to standard chemotherapy (Pezzuto et al. Our review of the literature found that systemic treatment followed by local treatment was beneficial in delaying drug resistance in patients (Al-Halabi et al. This is the first report to our knowledge of a patient who presented with gastric and hepatic metastases from lung cancer and achieved complete remission with osimertinib and local radiotherapy, with good quality of life, which also provides a basis for future clinical work and is of great significance. In conclusion, for patients with stage IV lung cancer with oligometastases, the addition of local therapy after systemic therapy may help delay drug resistance and facilitate survival.


In order to efficiently investigate the effect of the mesoscale heterogeneity of a concrete core and the randomness of circular coarse aggregate distribution on the stress wave propagation procedure and the response of PZT sensors in traditional coupling mesoscale finite element models (CMFEMs), firstly, a mesoscale homogenization approach is introduced to establish coupling homogenization finite element models (CHFEMs) with circular coarse aggregates. CHFEMs of rectangular concrete-filled steel tube (RCFST) members include a surface-mounted piezoelectric lead zirconate titanate (PZT) actuator, PZT sensors at different measurement distances, a concrete core with mesoscale homogeneity. Secondly, the computation efficiency and accuracy of the proposed CHFEMs and the size effect of representative area elements (RAEs) on the stress wave field simulation results are investigated. The stress wave field simulation results indicate that the size of an RAE limitedly affects the stress wave fields. Thirdly, the responses of PZT sensors at different measurement distances of the CHFEMs under both sinusoidal and modulated signals are studied and compared with those of the corresponding CMFEMs. Finally, the effect of the mesoscale heterogeneity of a concrete core and the randomness of circular coarse aggregate distribution on the responses of PZT sensors in the time domain of the CHFEMs with and without debond defects is further investigated. The results show that the mesoscale heterogeneity of a concrete core and randomness of circular coarse aggregate distribution only have a certain influence on the response of PZT sensors that are close to the PZT actuator. Instead, the interface debond defects dominantly affect the response of each PZT sensor regardless of the measurement distance. This finding supports the feasibility of stress wave-based debond detection for RCFSTs where the concrete core is a heterogeneous material. As typical structural components carrying increasing vertical or axial load, large-scale concrete-filled steel tube (CFST) members have been extensively applied as columns in high-rise buildings or arches and piers in long-span bridges. The non-uniformly distributed temperature in the curing procedure of the concrete core of CFST members after pouring concrete and the unavoidable long-term shrinking and creeping of concrete core may cause interface debond defects between the concrete core and steel tube, weakening the desired confinement effect of the steel tube on the concrete core and negatively affecting the ductility and load-carrying capacity of the CFST members. Therefore, the development of reliable interface debond defect detection methodologies for the CFST members is of great emergency. Most of the traditional non-destructive testing (NDT) techniques, which have been successfully applied in defect detection for reinforced concrete (RC) or steel structures, including infrared thermal imaging ,2, electRecently, defect detection for concrete materials, composites, RC and steel structures based on stress wave measurement using piezoelectric lead zirconate titanate (PZT) actuators and sensors have attracted much attention ,11,12,13One of the most potential defects in CFST members is the interface debond defect between the concrete core and steel tube. In order to accurately detect interface debond defects in CFST members, Xu et al. ,22 develHowever, one of the main concerning shortages in the above-mentioned numerical analysis on stress wave travel in CFST members is that the concrete core was considered as a homogeneous material with uniform material parameters. Considering the fact that concrete is a typical heterogeneous material, composed of mortar, coarse and fine aggregates and an interfacial transition zone (ITZ) between aggregates and the mortar, etc., it has been a common concern if the mesoscale heterogeneity and randomness of aggregate distribution in the concrete core dominantly affect stress wave travel within CFSTs and PZT sensor responses at different measurement distances when compared with interface debond defects in CFSTs . With thThe mesoscale homogenization method is computationally efficient for the behavior simulation of mesoscale concrete materials and structures, where the mesoscale concrete is modeled with a number of representative area elements (RAEs) two-dimensionally (in 2D) or representative volume elements (RVEs) three-dimensionally (in 3D). The concrete material of each RVE or RAE is homogenized with uniform mechanical properties ,33,34. WIn the study by Wang et al. , the effIn this paper, multi-physics coupling mesoscale finite element models (CMFEMs) composed of a surface-mounted PZT actuator, a surface-mounted or embedded PZT sensor, and a 2D mesoscale RCFST specimen with randomly distributed circular aggregates are firstly established. After that, the corresponding coupling homogenization finite element models (CHFEMs) with different RAE dimensions are established to study the effect of RAE dimensions on both stress wave fields and the response of PZT sensors at different measurement distances. For simplicity, the stress wave fields in mesoscale finite element models (MFEMs) and the corresponding homogenization finite element models (HFEMs) with and without debond defects are determined considering different RAE dimensions. The effects of RAE dimensions on the simulation results of stress wave fields are analyzed comprehensively. Therefore, the PZT sensor responses with different measurement distances in CMFEMs and the corresponding CHFEMs with and without debond defects under various excitation signals are also determined considering different RAE dimensions. The results show that the mesoscale heterogeneity of a concrete core and the randomness of circular aggregate distribution only have a certain influence on the response of PZT sensors that are close to the surface-mounted PZT actuator. Compared with the mesoscale heterogeneity of a concrete core in the form of the random distribution of circular aggregates, the interface debond defect dominantly affects the stress wave fields and the response of PZT sensors at various measurement distances.In recent years, the effect of the morphology of coarse aggregates on the properties of concrete materials and structures has been an active topic . In thisThe piezoelectric equation for the employed PZT patches can be found in the previous studies ,37,38,39In addition, the equation of motion for the coupled RCFST–PZT model is described in the form of vectors and generalized matrices ,35:(2)M0In this study, the plane dimensions of the concrete core of the 2D RCFST member are 400 mm by 400 mm and the thickness of the concrete core is 10 mm. The concrete core is surrounded by a plane steel tube with a thickness of 5 mm. The employed PZT patches acting as either sensors or actuators are of a length of 10 mm and a thickness of 0.3 mm. The polarization direction of each PZT patch is its thickness direction. In order to investigate the influence of different measurement distances between the PZT actuator and the PZT sensors, a number of mesoscale RCFST–PZT coupling models with different PZT sensor locations are established with the RAM approach ,35.The size and quantity of circular aggregates in a specific RCFST member are specified according to an ideal gradient curve shown as follows .(3)P with the Walraven method.i-th and j-th circular aggregates and In a Cartesian coordinate system, the coordinates of the center of a circle are randomly generated within the RCFST member using the Monte Carlo method. In order to avoid circular aggregate overlap and contact, the distance between any two circular aggregates must be greater than a certain value. The overlap of two circular aggregates is judged based on the distance between their centers according to Equation (5). The aggregate with a large radius should be put in first because the effective delivery area after the successful delivery of an aggregate is gradually reduced.Here, three CMFEMs with different randomly distributed circular coarse aggregates mimicking the mesoscale heterogeneity and randomness of a concrete core, i.e., CMFEM 1, 2 and 3, are established as shown in As a further investigation of the previous study by Wang et al. , CHFEMs In order to study the computational accuracy of the CHFEMs, CHFEMs with different RAE dimensions are established for each CMFEM. The material properties including density, Poisson’s ratio and elastic modulus of each RAE with different dimensions can be determined according to the method proposed by Wang et al. , where eFor the debond defect detection of RCFST members using stress wave fields and PZT sensor response measurements, high-frequency signals are commonly used as inputs on a PZT actuator mounted on the surface of the steel tube of an RCFST. The high-frequency excitation signal leads to a short stress wave wavelength, where fine meshing and short integration time steps are required. Here, the typical 2D RAE dimensions of 20 mm by 20 mm, 25 mm by 25 mm and 40 mm by 40 mm for each CMFEM model are considered to distinguish the size effect of RAEs on the stress wave fields and PZT sensors measurement simulation results. Since the advantage of the computational efficiency of CHFEM has been demonstrated in the recent research by Wang et al. , a compaFor the mesoscale simulation of the stress wave field within different mesoscale RCFSTs, it is convenient to exclude the direct and inverse piezoelectric effects of PZT actuators and sensors and the coupling effect between them and the RCFST member. In this study, the stress wave propagation procedure within different mesoscale finite element models (MFEMs) of RCFSTs and the corresponding homogenization finite element models (HFEMs) employing different RAE sizes under the excitation of a pulse force are investigated for comparison.The applied pulse force signal for stress wave fields and modulated sinusoidal excitation signal for the PZT sensor measurement simulation is the same as that in . The modThe measurement results of different PZT sensors under both sinusoidal and modulated signals are simulated using both the CMFEMs and the corresponding CHFEMs, where the circular coarse aggregates are randomly distributed and the concrete core is heterogeneous at the mesoscale.In the study by Wang et al. , the infWithout a loss of generality, the stress wave fields of the healthy MFEM 1 without interface debond defects and the corresponding HFEMs with different RAE dimensions at different time instants are investigated and compared at first. The three side dimensions of 20 mm, 25 mm and 40 mm for square RAEs are considered.In In addition to a comparison of the element numbers, DOFs and the computation time for stress wave propagation simulation between the healthy MFEM 1 and its corresponding HFEMs with different RAE dimensions are shown in In order to further investigate the effect of different RAE dimensions on the stress wave field simulation results and to compare it with that of the interface debond defect, the stress wave fields of the MFEM 1 with a debond defect and the corresponding HFEMs with different RAE dimensions at different time instants are simulated. As shown in The stress wave fields of the MFEM 1 with an interface debond defect and its corresponding HFEMs with different RAE dimensions are shown and compared in When comparing the stress wave fields of the healthy RCFSTs at each identical time instant shown in In practice, for the debond detection of RCFST members, it is difficult to get the stress wave fields at different time instants. PZT sensors are usually used to measure the stress wave at certain locations and the measurements are used to detect the debond defect. Therefore, a further numerical study on the response of PZT sensors in CMFEMs and the CHFEMs at different measurement distances is carried out to distinguish the influences of the mesoscale heterogeneity of concrete on PZT sensor measurement and those of debond defects in the following chapter.The effects of both themesoscale heterogeneity of concrete cores in the form of randomly distributed circular coarse aggregates and debond defects on the output of PZT sensors at different measurement distances from the PZT actuator are investigated. Multi-physics field simulation on the measurement of PZT sensors of three CMFEMs and the corresponding CHFEMs with different RAE dimensions under both sinusoidal excitation and modulated excitation is performed. The frequency of the sinusoidal input signal is 20 kHz and the frequency of the modulated excitation signal described in Equation (3) is 20 kHz. Both input signals are of an amplitude of 10 V. The distances between the PZT sensor and actuator are assigned to be 80 mm, 160 mm, 240 mm, 320 mm and 410 mm. The distance of 410 mm means that the PZT sensor is installed on the opposite side surface of the RCFST, representing the surface-mounted PZT actuator and sensor installation strategy. Considering the similarity of the stress wave fields of the HFEMs with different RAE dimensions shown in In order to investigate the effect of interface debond defect on PZT sensor measurements, a numerical simulation on the PZT response of the three CMFEMs with identical debond defects, CMFEM 1D, CMFEM 2D and CMFEM 3D, is also carried out. Comparing the PZT sensor response at identical measurement distance of CMFEMs with and without a debond defect as shown in In this section, the time-domain responses of PZT sensors at different measurement distances from the PZT actuator of the three CMFEMs with and without an interface debond defect under the modulated sinusoidal excitation signal are investigated and the results are shown in The similarity of the PZT sensor measurements at an identical CMFEM measurement distance to different mesoscale structures can be found in In the previous study by the authors of , the infTo further compare the influence of the debond on the measurement of PZT sensors at different measurement distances, the responses of PZT sensors of the CHFEMs with an interface debond defect using different RAE dimensions are shown in A further investigation on the influence of RAE dimensions of CHFEMs on PZT sensor responses under the modulated sinusoidal excitation signal is performed. From all the above-mentioned simulation results of both CMFEMs and CHFEMs, it is concluded that debond defects are the dominant factor affecting the PZT sensor’s response at identical measurement distances. A close look at the influence of the heterogeneity of concrete cores and randomness of coarse aggregate distribution in RCFSTs on the responses of PZT sensors at different measurement distances is taken in a quantitative manner in the following chapter.Further analysis of the maximum amplitude of the time-domain response of the PZT sensors under a sinusoidal input signal and of the wavelet packet energy of the response of PZT sensors under a modulated input signal is carried out.As shown in Here, the effect of different measurement distances on the response of PZT sensors is further elucidated under sinusoidal signals. The average amplitude and variance in PZT sensors at identical measurement distances in the three CMFEMs and three CHFEMs shown in Here, the influence of the mesoscale hetereogeneity of a concrete core and the randomness of coarse aggregate distribution and of the debond defect on the responses of the PZT sensors of three CMFEMs and the three CHFEMs corresponding to CMFEM 1 under the modulated sinusoidal signal is further distinguished.A wavelet packet analysis of each sensor response is carried out to determine the wavelet packet energy of the output signals collected by each PZT sensor , and theAs shown in Multi-physics and multi-scale CMFEMs composed of a PZT sensor, a PZT actuator and a 2D RCFST cross-section are constructed, and the corresponding CHFEMs with different RAE dimensions are established. The feasibility of using CHFEMs for stress wave field and PZT sensor response simulation and their computational efficiency are illustrated. Then, the difference in the influences of the mesoscale heterogeneity of a concrete core in the form of the randomness of coarse aggregate distribution in a RCFST and of the debond defect on the responses of PZT sensors at different measurement distances are elucidated. Based on the analysis of the numerical simulation results, the following conclusions can be made.(1) The feasibility and the computational efficiency of the proposed mesoscale homogenization approach for RCFST stress wave fields and PZT sensor response simulation are numerically confirmed. The stress wave fields of the CMFEMs and their corresponding CHFEMs with different RAE dimensions are similar, and the influence of an interface debond defect on the stress wave field is dominant. The concrete core with mesoscale homogeneity in the form of random coarse aggregate distribution in RCFSTs has no obvious influence on the stress wave fields of RCFST specimens.(2) By comparing the PZT sensor measurement simulation results of healthy CMFEMs and those of the corresponding CHFEMs, the heterogeneity in the form of random concrete core distribution only affects the responses of PZT sensors close to the PZT actuator. The influence of mesoscale heterogeneity on PZT sensor measurement becomes weaker when the measurement distance increases. RAE dimensions have no obvious influence on the PZT responses of CHFEMs. This finding also works for CMFEMs and CHFEMs of RCFST members with interface debond defects.(3) From the simulation results of the CMFEMs and the CHFEMs, it is clear that the interface debond defects of RCFSTs have a more obvious effect on the response of each PZT sensor when compared with those of a heterogenous and random distribution a concrete core at the mesoscale in RCFSTs. (4) The findings from this study imply that the interface debond defect detection method using stress wave measurement from a PZT sensor is reasonable in practice even though the concrete core in RCFST specimens is a heterogenous and random material. The mesoscale heterogeneity and randomness of concrete cores affect PZT sensor responses locally, and the interface debond defect is the dominant factor affecting the PZT sensor measurement no matter what the measurement distance is.


While social media is increasingly used by dermatologists to educate the public , any socTikTok and Instagram were selected for their size and dearth of published literature, compared to the known presence of misinformation on platforms like Twitter and Facebook . On TikTNondermatologists made up the majority  of telangiectasia-related content on TikTok . Of 123 Many patients use social media platforms for dermatologic information . Our finThis study provides a sample of content creators in telangiectatic-related content. This study reinforces the importance of social media presence of board-certified dermatologists to comment on and combat inaccuracies by creating educational content and reacting to erroneous information. Further research is necessary to evaluate the scope of misinformation and its deleterious effects.


Pandemic caused by the virus COVID-19 had a significant impact on mental health of the population, not only by increasing the levels of stress and anxiety, but by affecting the most vulnerable ones, aggravating the symptoms of mental illnesses in people suffering from one of the mental health conditions [1], including the people suffering from schizophrenia. Pandemic made the increased need of that particular patient population for various psychotherapeutic and sociotherapeutic interventions even more evident. Art therapy is a form of psychotherapy that in itself integrates expressive characteristics of art with explorative characteristic of psychotherapy using the visual language of arts as the main media of communication and expression. Art therapy has been used from its beginnings with people suffering from one of the psychotic disorders [2] and it is enlisted today in NICE guidelines as one of the psychological therapies of schizophrenia [3].To understand and to activate the potential of artistic expression in patients suffering from psychotic disorders during the pandemic of virus COVID-19.During the period of lockdown in pandemic of virus COVID-19, a young male patient suffering from schizophrenia was admitted to the Acute ward of the University psychiatric hospital Sveti Ivan in Zagreb. As the patient was keen on visually expressing himself, five individual psychodynamically oriented art therapy sessions were carried out on a weekly basis with professionally trained art therapist during the period of patient’s hospitalization. The patient was offered various art materials allowing him to visually express himself in a free manner and the artistic artefact created during the process served as a catalyst for later therapeutic work.splitting, hidden aggressive potentials and, in the end, the nature of father-son relationship connecting the image of coronavirus causing fear and discomfort with the image of the oppressive father.During the therapeutic process, single image was being gradually made and developed session by session. As new layers of color and form were added to the painting, each session revealed new layers of meaning and symbolism to both patient and therapist. First sessions pertained to the anxiety caused by the experience of pandemic, but as the process moved forward, deeper subject matters were brought to the surface, such as the nature of the therapeutic relationship, patient’s Circumstances caused by the pandemic of virus COVID-19 aggravated the patient’s symptoms and his internal conflicts. The art therapeutic process, with its possibility of projections and its multilayered interpretations, enabled the patient to express the true conflict and disturbing content hiding underneath the anxiety related to the pandemic of coronavirus which the patient was primarily complaining about.None Declared


Case Reports in Neuropharmacology 2022 represents the diverse range of research and clinical applications in this vast field. From the use of new medications for post-surgical pain management to the recognition of rare drug-induced side effects, the present Research Topic highlights the breadth and complexity of neuropharmacology research and practice. These case reports emphasize the importance of personalized approaches to medical treatment, careful monitoring of potential drug interactions and side effects, and continued research to improve patient outcomes in this field.The Research Topic of The four articles of this Research Topic share a common neuropharmacology background as well as an emphasis on patient outcomes. One of the highlights of this Research Topic is the variety of specific Research Topic covered, while at the same time each article highlights the importance of personalized approaches to medical treatment and the need for careful monitoring of potential side effects and drug interactions.Liu et al. report on the use of dinalbuphine sebacate (DS), a mixed kappa opioid agonist/mu opioid antagonist, as part of a multimodal analgesia (MMA) protocol for morbidly obese patients undergoing laparoscopic sleeve gastrectomy. These patients are at an increased risk of opioid-related side effects, such as post-operative nausea and vomiting and respiratory depression. Obstructive sleep apnea, which is prevalent among patients with morbid obesity, further put these patients at risk for respiratory depression  in a non-obese patient following thoracoscopic wedge resection of pulmonary nodules. This report adds valuable information to the literature on PUS, specifically regarding its occurrence in non-obese patients and the potential role of propofol anesthesia in its development. PUS has been previously associated with urinary uric acid (UA) disorders, reported in morbidly obese patients undergoing gastric bypass surgery and/or propofol anesthesia in individuals with preexisting UA metabolic disorders  isoforms. The article discusses the impact of different medications on CAMK2 activity and associated calcium signaling and suggests personalized treatment regimens based on CAMK2 catalytic activity. The hypothetical treatment framework proposed by the authors is an important step towards clarifying the questions that will guide further research. This is an essential consideration, as dysregulation of calcium signaling can have profound consequences for neuronal development, function, and survival (survival . The repDuan et al. discuss a rare case of severe skin rash and lymphadenopathy associated with the use of lamotrigine and valproic acid in a patient with bipolar disorder type I. The case highlights the potential for severe skin reactions and lymphadenopathy associated with the use of these medications and emphasizes the need for caution during titration and early withdrawal of both when signs of hypersensitivity appear. While the dermatologic toxicity of lamotrigine is known, this report is a reminder of the importance of careful consideration of the unknown variables that can complicate the course of apparently well charted adverse effects risk trajectories.Together, these articles underscore the importance of personalized approaches to medical treatment, particularly in patient populations with specific vulnerabilities or susceptibilities to certain side effects. They also highlight the need for careful monitoring of potential drug interactions and side effects to ensure the best possible patient outcomes. By understanding the neuropharmacology underlying different medical conditions and treatments, we can continue to develop effective and personalized approaches to medical care.


To the Editor,We read with great interest the article by Atalay et al. in which they illustrate the frequent presence of hummingbird signs in their patient group with idiopathic normal pressure hydrocephalus (iNPH) . The resThe authors found the presence of the hummingbird sign in 92.3% of their iNPH subjects. Remarkably, a perfect agreement for the hummingbird signs was met between three observers , increasTaken together, we think that the high prevalence of the hummingbird sign in the study of Atalay et al. may be associated with possible underlying comorbid PSP pathology in some of those patients which could not be excluded via the patient selection method. To clarify this issue, future prospective studies including a large group of patients with a definitive iNPH diagnosis are warranted. The results of these studies may provide crucial contributions regarding the diagnostic process of iNPH. Besides, these study results may enlighten the pathophysiological role of the brainstem in iNPH symptomatology, and also its role in the clinical manifestations of neurodegenerative diseases such as PSP.


The journal retracts the 2021 article cited above.Following publication, concerns were raised regarding the contributions of the authors of the article. Our investigation, conducted in accordance with Frontiers policies, confirmed a serious breach of our authorship policies and of publication ethics; the article is therefore retracted.This retraction was approved by the Chief Editors of Frontiers in Chemistry and the Chief Executive Editor of Frontiers. The authors do not agree to this retraction.


Interest in calcium phosphate cements as materials for the restoration and treatment of bone tissue defects is still high. Despite commercialization and use in the clinic, the calcium phosphate cements have great potential for development. Existing approaches to the production of calcium phosphate cements as drugs are analyzed. A description of the pathogenesis of the main diseases of bone tissue  and effective common treatment strategies are presented in the review. An analysis of the modern understanding of the complex action of the cement matrix and the additives and drugs distributed in it in relation to the successful treatment of bone defects is given. The mechanisms of biological action of functional substances determine the effectiveness of use in certain clinical cases. An important direction of using calcium phosphate cements as a carrier of functional substances is the volumetric incorporation of anti-inflammatory, antitumor, antiresorptive and osteogenic functional substances. The main functionalization requirement for carrier materials is prolonged elution. Various release factors related to the matrix, functional substances and elution conditions are considered in the work. It is shown that cements are a complex system. Changing one of the many initial parameters in a wide range changes the final characteristics of the matrix and, accordingly, the kinetics. The main approaches to the effective functionalization of calcium phosphate cements are considered in the review. Bone tissue is a part of the human musculoskeletal system, which participates in the transfer of force from one part of the body to another under controlled tension, and protects and fixes internal organs. In addition to performing a mechanical function, bone tissue performs a biological function, as it participates in metabolism ,2,3,4. BBone tissue’s ability to regenerate effectively, maintain mineralization and repair itself after damage depends on its ability to dynamically remodel. However, the regenerative process is limited by the ability to self-repair: osteogenic insufficiency occurs if the critical size of the defect is exceeded, and the defect is filled with fibrous connective tissue.There are many different clinical circumstances under which a significant part of bone or a whole bone is lost. Bone defects can be caused by various reasons. They can be associated with various pathogenic conditions and clinical outcomes, including injuries (fractures), infections (osteomyelitis), tumors, osteoporosis, and many other bone diseases .According to statistics, 20 million orthopedic surgeries in the world per year are performed, 70% of which require the use of bone implant material for filling and repairing bone defects .Various osteoplastic materials can be used to fill in bone defects caused by various diseases, or for the purpose of their prevention. They are able to deliver functional substances locally, fill in defects and serve as a material for bone tissue reconstruction.2+ ions during resorption can affect the differentiation of osteogenic cells and the level of inflammatory cytokines.Calcium phosphate cements are similar in composition to the mineral component of bone tissue. They have a high specific surface area and are used in medicine as osteoplastic materials. Blocks and granules made of pre-hardened cement are a promising type of skeleton for the restoration of bone defects. They have an increased rate of resorption compared to matrices obtained by high-temperature processing. Functional substances can be volumetrically incorporated into them at the stage of mixing the components. The kinetics of the release of functional substances may vary. The release of CaThe functionalization of calcium phosphate cements is of great clinical interest for the treatment or prevention of various diseases of bone tissue. Prolonged elution is the main requirement for carrier materials of pharmaceutical substances. Another important requirement is the absence of a mutual negative influence of the functional substance and the matrix on each other’s properties. The release of functional substances from calcium phosphate cements depends on many parameters of the matrix, specific interactions between the functional substance and the matrix, as well as environmental factors.A significant advantage of calcium phosphate cements is the wide range of changes in the properties of matrices that can affect the release of functional substances and the process of bone tissue restoration.2+ ions and phosphatases, and form amorphous calcium phosphate on the surface, followed by the formation of hydroxyapatite crystals from it. Hydroxyapatite is the most important inorganic phase in bone (molecular formula Ca10(PO4)6(OH)2; it contains impurity ions such as CO32−, Cl−, F−, Na+, Mg2+, K+, Zn2+, Fe2+, Cu2+, Sr2+ and Pb2+ ..244].The release curves of functional substances from calcium phosphate matrices most often show bimodal release. In this case, a typical initial release occurs within the first 24 h, followed by a sustained slow release . This coMulti-stage release profiles potentially offer much greater advantages over monotonic drug elution kinetics. The rapid initial release is able to effectively stop the pathological process, while its longer second release phase will gradually support the healing process .The rate of release of functional substances depends on the morphology of the cement stone particles, as it leads to a different degree of adsorption of the substance on the inner surface. Desorption of functional substances from the surface of calcium phosphates with needle morphology of crystals is higher compared to desorption with lamellar morphology .The surface charge of molecules of functional substances increases adsorption with the surface of calcium phosphate cement due to electrostatic attraction. Positively charged functional substances bind to the surface of calcium phosphate, since there are many negatively charged phosphate and hydroxide ions on the surface. Negatively charged functional substances bind to the surface of calcium phosphate with a large amount of calcium ions , such asHowever, the presence of cephalexin has been reported to inhibit the growth of hydroxyapatite crystals. This is due to the ability of carboxylic acid molecules to be adsorbed on the surfaces of the initial components and nascent crystals, and to inhibit the growth of the target phase .The values of the surface zeta potential are negative for calcium phosphates, but they differ depending on the arrangement of atoms on two types of crystal planes along the (a) axis and along the (c) axis . Plane , high-performance liquid chromatography (HPLC) and fluorescent polarization immunoassay (FPIA). The electrochemical impedance spectroscopy (EIS) of Pasqual Group positions is a method for determining the amount of a drug without aliquot selection, as required by traditional methods .A brief review of the scientific literature over the past 5 years on calcium phosphate cements as carriers of functional substances for the treatment of bone tissue is presented in Bone tissue repair is often limited by large defects and associated complications . Effective treatment strategies are aimed at the resection of the affected area of bone tissue, followed by treatment. Due to the limited availability of the affected bone for systemic therapy and for the prevention of postoperative complications, a local therapy method is used with the delivery of functional substances during surgery, or using minimally invasive procedures. Local prolonged drug delivery systems in effective therapeutic doses to the site of bone disease can contribute to the effective treatment of various bone diseases with the least side effects.2+ ion is an important homing signal; it brings together various cell types necessary to initiate bone remodeling. Ca2+ ions affect protein growth factors, and additionally stimulate the expression of osteogenic marker genes.Calcium phosphate cements have a chemical composition similar to the inorganic component of bone tissue. They are biocompatible, resorbable, injectable and self-hardening. They can take the form of a bone defect and fit tightly to the bone bed. The CaAt present, the most common approach to using calcium phosphate cements as scaffolds is the bulk incorporation of anti-inflammatory, antitumor, antiresorptive, and osteogenic functional substances.The functionalization of calcium phosphate cements for a specific task requires an understanding of cement systems. Cements are complex systems. Changing one of the many parameters of the system changes the final characteristics of the matrix in a wide range, including the kinetics of elution of functional substances.In this paper, the diseases of bone tissue are described, in the treatment of which calcium phosphate cements can be used as carriers of functional substances. Knowledge of the pathogenesis of diseases and the methods of treatment used—in particular, drug therapy—can help develop the concepts of directed functionalization for various clinical cases. We tried to isolate and describe in detail the factors that affect the release of functional substances from calcium phosphate cements, as related to the parameters of the cement system and the nature and affinity of functional substances for restoring bone tissue with the matrix.Over the past two years, interesting reviews have been published by various scientific groups, which indicate an undying interest in calcium phosphate cements. A more detailed description of the properties of injectable calcium phosphate cements and the possibilities of their regulation can be found in the Vezenkova review, where cements are considered from the point of view of obtaining an osteoinductive product . The mecThe functionalization of calcium phosphate cement is one of the most important directions for solving the problems of the treatment and restoration of bone tissue.The use of calcium phosphate cements as carriers of anticancer drugs and bisphosphonates is addressed in the reviews of Zogakis et al.  and NtepBased on an understanding of the importance of calcium phosphate cements in the process of bone tissue restoration, and the possibility of functionalization by incorporating various drugs and growth factors directly into the volume of the cement matrix, or via encapsulation in polymer carriers, we assume that future research will aim at solving the problems of interaction between the carrier and functional substances, stabilizing (controlling) the release of functional substances from the matrix, and creating ideal frameworks  aimed at faster restoration of the integrity of bone tissue.


Pneumonia is the most frequent lower respiratory tract disease and a major cause of morbidity and mortality globally . SeveralThe most common classification of pneumonia is based on the location where pneumonia occur. Community-acquired pneumonia occur at the community and hospital-acquired pneumonia occur at the hospital. Pneumonia among residents of nursing homes or long-term care facilities is categorized as nursing-home-acquired pneumonia. This concept is based on the idea that the causative bacterium of pneumonia is determined to some extent by the location where pneumonia occur and serves as a guideline for the use of antibiotics ,3,4. GuiAspiration pneumonia is the most dominant form of pneumonia in older adults . Many stSerial studies concerning the relationship between forced vital capacity (FVC) on spirometry and death due to pneumonia in older people have been published by the same laboratory in Japan. In the first study, the authors analyzed the data of a large cohort and found that low FVC was associated with a high all-cause mortality rate of community-dwelling older people . In the Taken together, the above four reports indicate a strong relationship between impairment of skeletal muscle and pneumonia or pneumonia-related death of older adults. Mendes and colleagues showed that healthcare-associated pneumonia is the main causes of hospital admission and death among patients with pneumonia, the majority of which were empirically treated, in Portugal . The higThe remaining four papers in this issue highlight the importance of comprehensive functional assessment and interdisciplinary team care, which is beyond the use of antibiotics, in older patients with aspiration pneumonia. Yoshimatsu et al. reported no evidence of the benefit of anaerobic coverage in the antibiotic treatment of aspiration pneumonia . They alSince this special issue reveals the importance of skeletal muscle and an interdisciplinary team approach, it will help clinicians make decisions and treatment choices. We appreciate the valuable contributions of all authors. We are also grateful to the reviewers for their professional and constructive comments and to the JCM team for their continuous support with this special issue.


The goal of hemodynamic resuscitation is to optimize the microcirculation of organs to meet their oxygen and metabolic needs. Clinicians are currently blind to what is happening in the microcirculation of organs, which prevents them from achieving an additional degree of individualization of the hemodynamic resuscitation at tissue level. Indeed, clinicians never know whether optimization of the microcirculation and tissue oxygenation is actually achieved after macrovascular hemodynamic optimization. The challenge for the future is to have noninvasive, easy-to-use equipment that allows reliable assessment and immediate quantitative analysis of the microcirculation at the bedside. There are different methods for assessing the microcirculation at the bedside; all have strengths and challenges. The use of automated analysis and the future possibility of introducing artificial intelligence into analysis software could eliminate observer bias and provide guidance on microvascular-targeted treatment options. In addition, to gain caregiver confidence and support for the need to monitor the microcirculation, it is necessary to demonstrate that incorporating microcirculation analysis into the reasoning guiding hemodynamic resuscitation prevents organ dysfunction and improves the outcome of critically ill patients. The core of hemodynamic resuscitation has traditionally focused on blood pressure and cardiac output; however, these measurements imperfectly reflect tissue perfusion. The recent emphasis on clinical signs of tissue perfusion such as capillary refill time and skin mottling is an important step toward a perfusion driven resuscitation. However, these types of skin perfusion assessment techniques are severely limited as these indices assess a relatively large volume of tissue and alterations in other microcirculatory beds may remain hidden using these techniques.In patients in shock of various origins, an important number of studies have consistently demonstrated that persistent microcirculatory alterations are associated with organ dysfunction and mortality. More than 600 papers have highlighted the clinical relevance bedside monitoring of the microcirculation. This level of interest led to the publication in 2018 of guidelines for the assessment of sublingual microcirculation by the European Society of Intensive Care Society Task Force [The future challenge is to transform microcirculation monitoring from an important research tool into an essential bedside monitoring technique used by clinicians to individualize hemodynamic resuscitation based on microvascular parameters. The purpose of this paper is to provide an update on the current state of microcirculatory monitoring in critically ill patients, and to present an approach for guiding therapy. We present a viewpoint on its potential role in the future of hemodynamic monitoring and on how it could influence the hemodynamic management of critically ill patients.The two main determinants of the primary function of the microcirculation for oxygen transport are convection  and diffusion  to the cells). Parameters related to the convective  and diffusive  capacity of the microcirculation are used to quantify the functional state of the microcirculation. Most hemodynamic strategies used in ICU focus on promoting blood flow and arterial oxygen transport (convection). However, achieving adequate diffusing capacity is also essential for optimal oxygen transport to the tissues, a variable that can only be measured by direct observation of the microcirculation. For example, the diffusive capacity of the microcirculation may be compromised during fluid therapy if increased RBC flow cannot compensate for dilution of RBC mass and if tissue edema induces increased diffusion distances between RBC and tissue cells, making it more difficult for oxygen to reach the latter. Understanding these two main components of oxygen transport to cells is essential to best guide hemodynamic strategies.The analysis of the microcirculation allows clinicians to appreciate the behavior of the different constituents of the blood and their interactions with the endothelium and the glycocalyx. For example, its observation by hand-held vital microscopes (HVM) not only allows detailed quantification of the behavior of red blood cells directly responsible for oxygen transport to tissues, but also allows observation and quantification of the behavior of leukocytes . VisualiThe goal of hemodynamic resuscitation is to meet the oxygen and metabolic needs of the various organs, which can only occur through optimization of the microcirculation Fig. . We hopeThis is essential because clinical studies in different states of shock both in adult and pediatric patients have consistently shown that the persistence of microcirculatory alterations with lost of coherence between macrocirculation and microcirculation is predictive of organ failure and unfavorable outcomes in a more sensitive and specific manner than systemic hemodynamic and biological parameters –16. PrevAn other illustrative example of the potential interest in microcirculation assessment is the evaluation of the response to fluids. While a lot of emphasis has historically focused on the SV response to fluid infusion, the microcirculation represents a perhaps more element of the response in terms of tissue perfusion –22. A stIt is therefore necessary to integrate the analysis of the microcirculation in the reasoning guiding hemodynamic resuscitation to prevent organ dysfunction and improve the outcome of critically ill patients. Hemodynamic individualization based solely on macrocirculatory parameters is an incomplete view of hemodynamic optimization and the microcirculation must also be taken into account.There are a number of different methods to assess the microcirculation at the patient's bedside; all have strengths and future challenges Table . It is i2 delivery and local metabolism. Different adaptations of optics can allow measurements of hemoglobin levels and O2 saturation in microvascular vessels. In addition, it is also feasible to assess local redox state of the mitochondria through the analysis of ultraviolet absorbance [The recent introduction and validation of automated microcirculatory analysis software allowing point-of-care application of sublingual microcirculation-guided therapy is a significant step toward the introduction of routine use of HVM technology at the bedside , 24. It sorbance . In futuA further expansion of microcirculatory monitoring will occur when microcirculatory information is obtained from the microcirculation of organs themselves, as opposed to using the sublingual area as a proxy. Indeed, prior studies have assessed skin, conjunctiva, nail fold, rectal, stoma and vaginal microcirculations in various clinical conditions, although sublingual microcirculation is by far the most studied and clinically relevant microcirculatory bed to date. Even though several experimental studies have shown a coherence between sublingual and other organ surfaces, such as the intestines and kidney microcirculation , 27, it An interesting technique for monitoring organ microcirculation at the patient’s bed is contrast-enhanced ultrasound (CEUS) which uses gas microbubbles surrounded by a stabilizing envelope (phospholipid or protein envelope) Table . Differe2, CRT and peripheral perfusion index (PPI) [Several techniques for the evaluation of peripheral perfusion are proposed Table . Alteratex (PPI) . These p2 extraction and microvascular reactivity. A slower recovery of StO2 during the reperfusion phase is an independent predictor of mortality in patients with sepsis [Near-infrared spectroscopy (NIRS) Table  has beenh sepsis .Magnetic resonance imaging (MRI) Table  allows fThe monitoring of brain microcirculation is a challenge due to its inaccessibility. However, the retina is considered a window to the brain  and retiIn order to establish microcirculation analysis as a standard of care, it is necessary to demonstrate that the integration of microcirculation analysis has an impact on the prevention and treatment of organ dysfunction Fig. . It is aVery few studies have used microcirculation-targeted resuscitation. The ANDROMEDA-SHOCK trial , 50 suggWe can speculate on how the future diagnostic platform of the critically ill patient could be realized as technology develops, and more and more insight is gained into the pathogenesis and cellular origin of disease. Ultimately such a holistic diagnostic platform aimed at understanding the mechanism of disease and guiding therapy would have to encompass the total hierarchy of the cardiovascular system from the macrocirculation to the microcirculation including both cellular and subcellular components Fig. . The varParallel to such hardware developments will be the development of an innovative mathematical resource that continuously develops physiological models of the virtual patient and has the ability to identify changes in the phenotype of organ and cellular systems. It is expected that AI will play a central role in the translation of the evaluation of the clinical condition of the virtual patient and to predict response to clinical interventions. This is achievable, for example, for the case of the microcirculation, by integrating AI methodologies with algorithmic analysis of microcirculatory images able to differentially diagnose specific alterations in the phenotype of the microcirculation known to be corrected by specific therapeutic interventions . AI willThe classical therapeutical interventions have variable effects. Fluids may improve microcirculation in the early stages of shock, but this improvement may not occur in the later stages . The optVasoactive agents also have variable effects on microcirculation, improving microcirculation in some patients but failing in others. It should always be kept in mind that the effect of vasopressors is dependent on blood volume, the functionality of vasopressor receptors and the intensity of microvascular alterations.The development of new therapeutics is warranted to restore microcirculation when it is compromised.l-arginine [4) (cofactor of nitric oxide synthases) [Manipulation of nitric oxide (NO) pathways was one of the first routes explored given its crucial role in controlling microvascular perfusion . In expearginine  and tetrnthases) . But stunthases) , 60.Alternatively, manipulating the arachidonic pathway is an attractive future direction and trials evaluating the impact of vasodilatory prostaglandins are underway. Legrand et al. , 55 are As during inflammatory and infectious states, cellular interactions within the microcirculation evolve toward a proadhesive and procoagulant phenotype, attempts to minimize cell aggregation should be tested. Multiple interventions were tested in experimental conditions, but few reached the clinical arena. Among these, ascorbate and several anticoagulants were particularly promising. Prior preclinical studies have repeatedly demonstrated that ascorbate improves microvascular perfusion and decrease white blood cells and platelets adhesion in experimental models of sepsis –59. In sBecause of its antioxidant properties, albumin is also an interesting therapeutic option to limit glycocalyx alterations and preserve endothelial function in intensive care patients . HoweverFuture hemodynamic strategies in ICU patients should integrate macrocirculatory and microcirculatory optimization in an attempt to give clinicians the most complete picture of their patient's physiology and thus provide a clear path to treatment Fig. . In the Hemodynamic management requires individualization of macrovascular and microvascular parameters. Clinicians are currently blind to what is happening in the microcirculation of organs, which prevents them from individualizing resuscitation by targeting the microcirculation. Limiting hemodynamic resuscitation to an optimization of the systemic hemodynamics without knowledge of the microcirculation exposes to persisting alterations in tissue perfusion or excessive therapeutic interventions. The challenge for the future is to have noninvasive, easy-to-use equipment that allows for reliable assessment and immediate quantitative analysis of the microcirculation at the patient's bedside. The use of automatic analysis and the future possibility of introducing artificial intelligence into the analysis software  could make it possible to eliminate observer bias and provide orientation of therapeutic options coupled with an analysis of the microvascular responses to the applied interventions. In addition, to gain caregiver confidence and support for the need to monitor the microcirculation, it is necessary to demonstrate that incorporating microcirculation analysis into the reasoning guiding hemodynamic resuscitation prevents organ dysfunction and improves the outcome of resuscitation patients.


Numerous clinical and epidemiological studies show that the rate of comorbidity of anxiety disorders is high in bipolar patients compared to the general population. This is associated with a poorer prognosis, poorer functioning and higher suicidal risk. Anxiety comorbidity should therefore be carefully investigated.Our main objectives are to explore the therapeutic complexity of anxiety disorders in patients with bipolar disorder To investigate the existence of psycho-pathological links and vulnerabilities between bipolar disorder and anxiety disorders.through a clinical vignette and a review of the existing literature on the comorbidity of anxiety disorders and bipolar disorders, and the resulting therapeutic issuesAnxiety comorbidity is quite common in the bipolar population. In the American National Comorbidity Survey (NCS), lifetime comorbidity is close to 90%. Two recent French clinical studies show the existence of at least one anxiety disorder in approximately 25% of bipolar subjects (24% and 27.2%), which will have an impact on the course of the bipolar disorder, with a particular increase in the risk of suicide, hence the importance of adequate treatment. This treatment faces two obstacles: the risk of manic episodes under antidepressants and the risk of dependence on benzodiazepines. Emphasis is also placed on non-drug approaches, including cognitive-behavioural and psycho-educational therapies.Anxiety comorbidity is not without consequence on the evolution of bipolar disorder. Its particularly high prevalence means that it cannot be neglected or ignored in current practice.None Declared


This review article discusses the epigenetic regulation of quiescent stem cells. Quiescent stem cells are a rare population of stem cells that remain in a state of cell cycle arrest until activated to proliferate and differentiate. The molecular signature of quiescent stem cells is characterized by unique epigenetic modifications, including histone modifications and deoxyribonucleic acid (DNA) methylation. These modifications play critical roles in regulating stem cell behavior, including maintenance of quiescence, proliferation, and differentiation. The article specifically focuses on the role of histone modifications and DNA methylation in quiescent stem cells, and how these modifications can be dynamically regulated by environmental cues. The future perspectives of quiescent stem cell research are also discussed, including their potential for tissue repair and regeneration, their role in aging and age-related diseases, and their implications for cancer research. Overall, this review provides a comprehensive overview of the epigenetic regulation of quiescent stem cells and highlights the potential of this research for the development of new therapies in regenerative medicine, aging research, and cancer biology. Stem cells are cells that have the ability to self-renew and differentiate into different cell types. They are critical for the maintenance and repair of various tissues in the body. One unique characteristic of stem cells is their ability to enter a state of quiescence, or a dormant state, in which they stop actively dividing and remain in a state of inactivity until activated to differentiate.Quiescence is an important state for stem cells, which allows them to maintain their stem cell properties and respond to changing physiological demands. Further research into the regulation of quiescence in stem cells will be essential for the development of new therapies for a range of diseases and conditions .Quiescent stem cells are a unique and important population of cells that play a critical role in tissue maintenance and regeneration. These cells have been found to have a distinct molecular signature that sets them apart from other stem cell populations.Overall, the molecular signature of quiescent stem cells is a complex and highly regulated network of gene expression, epigenetic modifications, and metabolic processes that work together to regulate stem cell behavior. Understanding the molecular mechanisms that govern quiescence in stem cells is critical for the development of new therapies for a range of diseases and conditions .Epigenetic modifications play a critical role in regulating the behavior of quiescent stem cells. These modifications refer to changes in gene expression that occur without changes to the underlying DNA sequence, and they can be influenced by a variety of environmental factors.Epigenetic modifications play a critical role in regulating the behavior of quiescent stem cells. Understanding the mechanisms that govern these modifications will be essential for the development of new therapies that target quiescent stem cells for tissue repair and regeneration .Histone modifications are critical epigenetic regulators of gene expression in quiescent stem cells. In quiescent cells, histone modifications help to maintain stem cell properties and regulate the transition from quiescence to proliferation.Histone modifications are important regulators of gene expression in quiescent stem cells. Understanding the specific mechanisms by which these modifications regulate stem cell behavior will be critical for the development of new therapies for tissue repair and regeneration.Chromatin remodeling is an important process in the regulation of gene expression in quiescent stem cells. Chromatin remodeling involves the physical reorganization of chromatin structure, which can influence the accessibility of DNA to transcription factors and other regulatory proteins.Chromatin remodeling is an important mechanism for regulating gene expression in quiescent stem cells. Understanding the specific mechanisms by which chromatin remodeling complexes regulate stem cell behavior will be critical for the development of new therapies for tissue repair and regeneration.DNA methylation is a critical epigenetic modification that regulates gene expression in quiescent stem cells. DNA methylation involves the addition of a methyl group to the cytosine residues of DNA, usually in the context of a CpG dinucleotide. This modification can influence gene expression by altering the accessibility of DNA to transcription factors and other regulatory proteins.Overall, DNA methylation is an important regulator of gene expression in quiescent stem cells. Understanding the specific mechanisms by which DNA methylation regulates stem cell behavior will be critical for the development of new therapies for tissue repair and regeneration.The study of quiescent stem cells is a rapidly developing field with exciting future perspectives. One area of research that holds great promise is the development of new therapies for tissue repair and regeneration. Quiescent stem cells have the potential to differentiate into a variety of cell types, making them ideal candidates for cell-based therapies to treat a wide range of diseases and injuries. One challenge in the field of quiescent stem cells is the development of methods to activate quiescent stem cells and promote their proliferation and differentiation. A better understanding of the epigenetic modifications and signaling pathways that regulate quiescence and activation will be critical for developing such methods. Another area of research with future perspectives is the role of quiescent stem cells in aging and age-related diseases. Aging is associated with a decline in stem cell function and a decrease in the number of quiescent stem cells. Understanding the mechanisms that regulate stem cell quiescence and how these mechanisms are disrupted with age may lead to new therapies to improve stem cell function in aging populations. The study of quiescent stem cells also has implications for cancer research. Quiescent cancer stem cells have been implicated in tumor recurrence and resistance to chemotherapy. Understanding the mechanisms that regulate quiescence in cancer stem cells may lead to the development of new therapies to target these cells and improve cancer treatment outcomes.The study of quiescent stem cells has broad implications for regenerative medicine, aging research, and cancer biology. Continued research in this field will undoubtedly lead to new insights and developments that have the potential to transform medicine and improve human health .


In patients with schizophrenia, numerous studies have shown a relationship between negative symptoms and cognitive deficits  and a similar impact of these domains on different clinical features such as onset, course and prognostic relevance. However, this relationship is still today subject of scientific debate.The aim of the present study is to conduct a systematic review of the literature on data concerning the relationships between neurocognition and social cognition deficits and the two different domains of negative symptoms – avolition-apathy and expressive deficit.A systematic review of the literature was carried out following PRISMA guidelines and examining articles in English published in the last fifteen years (2007 - March 2022) using three different databases . The included studies involved subjects with one of the following diagnoses: high risk of psychosis, first episode of psychosis, or chronic schizophrenia. Other inclusion criteria of the reviewed studies included: evaluation of at least one neurocognitive or social cognition domain and at least one negative symptom using standardized scales; analysis of the relationship between at least one neurocognitive or social cognition domain and a negative symptom.Databases search produced 8497 results. After title and abstract screening, 395 articles were selected, of which 103 met inclusion criteria. The analysis of retrieved data is still ongoing. Preliminary evidence highlighted: a correlation between social cognition and negative symptoms, in particular with the “expressive deficit” domain; a positive correlation between the severity of negative symptoms and that of neurocognitive deficits (in particular with the “processing speed” domain); an association of verbal working memory deficits with alogia and anhedonia.The study of the relationship between negative symptoms, neurocognitive deficits and social cognition could contribute to the understanding of the aetiology of psychotic disorders and therefore to the identification of therapies for the improvement of overall functioning and quality of life. The studies analysed so far show some interesting associations between cognition and negative symptoms, but the presence of often inconsistent results, partially attributable to the different conceptualizations of the various domains of negative symptoms adopted, hinders the generalization of the results.None Declared


Social desirability bias is often speculated to influence survey responses but seldom studied in healthcare. The objective was to explore whether social desirability scores (SDS) or the presence of interview observers is associated with inaccurate recall and overestimation of antenatal care (ANC) services.Longitudinal validation study comparing recalled receipt of ANC services and nutrition components of ANC against direct observations of care. An adapted short form Marlowe-Crowne questionnaire was used to generate an SDS, and the presence of interview observers was treated as a separate exposure. We assessed accuracy and overestimation of recalled receipt of ANC services against observed receipt using log-binomial regression, adjusting for age, education, first-pregnancy and socioeconomic status.Rural Southern Nepal with recruitment from five government health posts.401 pregnant women.Social desirability scores did not significantly predict accuracy or overestimation of most types of ANC care except counselling on nausea. Higher SDS was associated with more accurate recall ) and less overestimation ). The presence of mothers-in-law or husbands during interviews was associated with greater overestimation of the number of ANC visits received by more than three visits ) and ), respectively. Those interviewed with friends present tended to overestimate the receipt of counselling on nausea, avoiding alcohol and not smoking.The presence of observers can lead to overestimation of the receipt of ANC care and support the conduct of interviews in private settings despite challenges of doing so in village contexts. Findings that the SDS did not predict the accuracy of most types of ANC care might reflect a reality that such questions may not be sensitive from a social-norms perspective. Additional local adaptation of SDS is recommended. The effect of social desirability bias and the presence of interview observers on response accuracy was evaluated against the gold standard of observed receipt of antenatal care services.The tool used to assess social desirability was adapted for comprehension for the local population in rural Nepal but has not been validated for that context.Interviewers noted the presence of others at any point during the interview, and not specifically during specific portions of the interview, likely attenuating estimates of the relationship between the presence of others and validity of reported services receipt.The WHO recommends a number of nutrition interventions in pregnancy, including iron-folic acid (IFA) supplements, counselling on healthy eating and physical activity, and in certain contexts calcium, micronutrient supplements and balanced energy and protein supplements.2Many survey-based coverage indicators come from self-reported data, and a growing number of studies have explored the validity of responses to questions about the receipt of nutrition interventions delivered through antenatal care (ANC).5Social desirability bias (SDB) is a common type of response bias that reflects the tendency of respondents to reply in a manner that may be viewed positively by social peers or that is consistent with social norms and expectations. SDB is generally thought to be greater for questions that are perceived as sensitive or subject to judgement such as those related to sexual practices or family planning.8Survey-based scales to measure social desirability were developed in the field of social psychology in the 1960s beginning with the 33-question Marlowe-Crowne scale.14SDB has been frequently described as an area of potential concern in nutrition-related studies collecting data about diet, physical activity and self-reported weight, but few studies have directly quantified the strength of association between social desirability scores and these domains.Adapt and test a modified short-form version of the Marlow-Crowne SDS in rural Nepal.Explore whether social desirability or the presence of other adults during interviews helps to explain previous findings related to overestimation of the receipt of services.Explore whether social desirability or the presence of other adults during interviews is associated with inaccurate recall of ANC and associated services.Tarai) of Nepal located in Province 2, the province with the lowest rates of ANC coverage in Nepal. According to the 2016 Demographic and Health Survey, only 36% of the women in Province 2 received all four recommended ANC visits, far below the national average of 59%.20This study took place in Sarlahi District, an area in the southern plains  to women who complete all four visits.This study was a part of a larger effort to validate coverage indicators for various nutrition services through ANC, described in detail elsewhere.10.1136/bmjopen-2022-071511.supp1Supplementary dataQuestions from a short-form Marlowe-Crowne social desirability index  were traCorrelations between different items of the social desirability index were explored after reverse coding negatively keyed questions, and most were found to be positively associated with one another . Tests oEnrolment criteria for the parent study included currently pregnant, married women aged 15 years or older, who (a) resided in the study area, (b) visited one of the five health posts for their first ANC visit and (c) had the intention to return to these study sites for subsequent ANC visits. All interview questions were translated and back-translated by Nepali/English speakers familiar with the study context. These questions were pretested, and minor changes were made to help facilitate comprehension in the local context. Both Maithili-speaking and Nepali-speaking interviewers conducted the interviews following training exercises designed to standardise the approach to translation. Interviewers were trained to replicate usual survey conditions. This included asking respondents to answer questions themselves even if a family member had tried to answer it for her and repeating or rephrasing questions in a simpler way if respondents were confused or responded with ‘I don’t know’.The study started in December 2018 and reached full enrolment by November 2019. Direct observations of ANC visits were nearly completed by March 2020 when a shutdown for the COVID-19 pandemic interrupted all non-emergency health services in Nepal. Data collection for the postpartum 6-month visit was started in September 2019, but COVID-19-related shutdowns caused delays. The mean number of days that passed from delivery to the postpartum data collection visit was 252 with an SD of 75 days. Precautions taken to prevent the spread of COVID-19 included masking by interviewers and respondents, handwashing with soap provided to interviewees, holding interviews outdoors when weather permitted and maintaining a distance of more than 6 feet during data collection.We examined whether SDS or the presence of other adults during interviews was associated with the accuracy or overestimation of recalled receipt of specific ANC services using log-binomial bivariate and multivariable regressions to directly estimate risk ratios or log-Poisson models in the case of model non-convergence.This research conformed with the principles embodied in the Declaration of Helsinki. The institutional review boards at Johns Hopkins Bloomberg School of Public Health and the Nepal Health Research Council both approved this study including permission to collect and resume data collection during the COVID-19 epidemic. Signed consent was obtained from all participants. Patients and the public were not involved in the design, conduct, reporting or dissemination plans of this research. Dissemination and discussion of study design and results are made to a national committee and a local district committee.The research questions were not informed through direct consultation of patients’ priorities, experience or preferences. However, many members of our local research team are from the local population where the research is conducted and were involved in pretesting, questionnaire development and recruitment. Findings will be disseminated to national and local stakeholders through meetings and local presentations.Of the 441 women enrolled in the study, 396 were included in our analysis after accounting for exclusion criteria described in About half of women overestimated the number of IFA tablets they received by at least 30 tablets and over a third overestimated the number of ANC visits by at least one visit . About aThe presence of any other adult was significantly associated with overestimation of receipt of counselling on managing nausea as well as overestimation of the number of ANC visits. MILs were present during about a quarter of all interviews. Their presence was associated with significant overestimation of the receipt of deworming tablets ) and more than doubled the risk of overestimating the number of ANC visits by three or more visits ) . InteresWomen interviewed in the presence of MILs were less accurate in estimating the number of ANC visits but more accurate in recalling the receipt of counselling related to avoiding alcohol consumption in pregnancy. Women tended to be less accurate when estimating the number of ANC visits or receipt of IFA in front of their husbands .We also examined how the receipt of help from observers to answer questions during the interview may have affected the accuracy of recall of services . AssistaPrevious studies exploring the validity of questions asking respondents to self-reported receipt of ANC services have raised SDB as a possible type of error that might affect coverage estimates.The effects of SDB are complex,25 26However, it is unclear why higher scores on the SDS were positively associated with more accurate recall of counselling on management of nausea. One possible explanation is that the counselling focused only on women that complained of nausea and not all women.In contrast to questions about the simple receipt of services during ANC visits, questions about the number of ANC visits or IFA consumption could be more subject to SDB because they relate to a woman’s initiative in seeking services or taking supplements and because there is likely positive sentiment around the benefits of services for women and their babies. This could explain the finding that the presence of MILs and/or husbands during the interview was associated with a significantly greater overestimation of the number of ANC visits. Cognitive testingIFA coverage is an important indicator for global monitoring of nutrition interventions; it is included in the Global Nutrition Monitoring Framework and an indicator for the Countdown to 2030.4Our study is the first that we are aware of to test a SDS in the context of rural Nepal, though SDSs have been used in urban IndiaA strength of our study is that we used direct observation to assess the receipt of services in clinics. However, the tool used to assess social desirability has not been validated in a rural context and was only slightly adapted for comprehension by respondents in our area. One adaptation we made to improve comprehension by the study population was to reformat the SDS tool from statements into questions. Ultimately, however, it is not clear how well the scale was able to capture socially desirable response tendencies in this context. Our study used a recall period of approximately 6 months, which may have facilitated more accurate recall of receipt than typically is assessed in surveys such as the DHS, which currently administers ANC modules to women up to 2 years postpartum. The implications of different recall periods for SDB are unclear. Additionally, the enumerators noted the presence of others at any point in the interview and not specifically during the questions about receipt of services; without more detailed information about observer presence when the questions were asked, it is difficult to attribute findings specifically to SDB.These findings reinforce the guidance often given during survey training to conduct surveys without others present, though doing so in practice is often challenging in rural village settings where norms around privacy differ. As we found that the SDS was not well correlated with overestimation or lack of accurate recall, there was no need to correct for SDB. Given that the generalisability of our study to other contexts including other parts of Nepal is uncertain, we recommend further studies be conducted in other contexts to develop and validate SDSs and use them to better understand the effects of SDB on estimates of services use.


The study of hominin genomes has provided insights into human evolution and reproductive functions. The hominin genome is the complete set of genetic material that is present in the cells of hominins, a group of primates that includes modern humans and their extinct relatives. It consists of approximately three billion base pairs of DNAs that are organized into 23 pairs of chromosomes . The geOne of the most significant findings from the study of hominin genomes is the evidence of interbreeding between early modern humans and Neanderthals. Genetic analysis has shown that Neanderthal DNA makes up approximately 1-4 % of the DNA in non-African populations . This iThe study of hominin genomes has also shed light on the evolution of reproductive functions in humans. For example, genetic studies of the genomes of Neanderthals and modern humans have identified several genes that are involved in reproductive biology, including those that influence fertility, sperm motility, and the development of testes and ovaries . Some oSome of these genes have undergone rapid evolution in humans, suggesting that they may have played a role in the adaptation of our species to different environments and lifestyles . AnotheMoreover, the identification of genetic variants associated with fertility and reproduction in ancient hominin genomes has important implications for modern human health. For example, genetic studies of the genomes of Neanderthals and modern humans have identified variants associated with reduced fertility, which may have contributed to the extinction of some early human populations. A study published in 2016, examined the DNA of Neanderthals and found that they had a higher number of harmful mutations in genes related to male fertility compared to modern humans . AdditiIn conclusion, the study of hominin genomes has provided insights into human evolution and reproductive functions. The discovery of interbreeding between early modern humans and Neanderthals, as well as the existence of new hominin species like the Denisovans, has challenged our understanding of human origins and the process of speciation. The genetic analysis of FOXP2 and Y chromosomes has revealed how changes in our genome have influenced the evolution of language and migration patterns in early humans. Discovery of more fossils and ancient DNA would be critical in refining the understanding of human evolution and deciphering the existence of infertility like physiological ailments.The authors declare no conflicts of interest.Not applicable.


Mycobacterium avium subsp. paratuberculosis (MAP), is a chronic progressive granulomatous enteritis mainly affecting domestic and wild ruminants worldwide. Although paratuberculosis could be prevail in Ethiopia, there is a scarcity of epidemiological data on paratuberculosis in the country. Thus, this study was conducted to estimate the prevalence of paratuberculosis based on gross and microscopic lesions in cattle slaughtered at ELFORA Abattoir, central Ethiopia. Small intestines and associated lymph nodes of 400 apparently healthy cattle which were slaughtered at ELFORA export abattoir were examined for gross and microscopic lesions of paratuberculosis. The microscopic lesions were classified into four grades (I-IV) based on the type and number of cells infiltrated into the lesion. The prevalence of paratuberculosis was estimated on the basis of gross as well as microscopic lesion of paratuberculosis.Paratuberculosis, caused by The prevalence of paratuberculosis was 11.25%  on the basis of gross lesion. However, relatively lower prevalence  was recorded based on microscopic lesion. The gross lesions were characterized by intestinal thickening, mucosal corrugations and enlargement of associated mesenteric lymph nodes. On the other hand, the microscopic lesions were characterized by granuloma of different grades ranging from grade I to grade III lesions.The present study indicated the occurrence of paratuberculosis in cattle of Ethiopia based on the detection of gross and microscopic lesions consistent with the lesion of paratuberculosis. The result of this study could be used as baseline information for future studies on the epidemiology and economic significance of paratuberculosis. Mycobacterium avium subsp. paratuberculosis (MAP) which is a facultative intercellular acid-fast bacillus (AFB) belonging to the genus Mycobacterium. MAP is an extremely slow growing mycobactin-dependent organism that replicates within the macrophages of both the gastrointestinal tract and associated lymphoid tissues [Paratuberculosis (PTB), commonly known as Johne’s disease (JD), is a chronic progressive granulomatous enteritis of ruminants. It also affects a wide variety of domestic and wild life species worldwide , 2. It i tissues . Contami tissues . Cattle  tissues . Intraut tissues .Paratuberculosis induces a significant economic and health problem worldwide, especially in the cattle industry. Economic losses occur due to decreased in milk production 15–16%), low carcass yield %, low ca, decreasParatuberculosis occurs in most part of the world and its incidence is rising from time to time . It has In contrast to these industrialized countries, the exact sanitary situation of most African countries with regards to paratuberculosis is unknown but the occurrence of the diseases is suspected in most countries and the disease has been confirmed in a few countries of Africa. There are very few studies carried out to date, which leaves a big information gap on a very important disease of livestock. Only case reports and limited prevalence studies covering small areas in a few countries are available . For exaPrior to this study, Temesgen and Gemehu in 1995 reported a case of paratuberculosis from Ethiopia based on the history of diarrhea cases lasted for two years and clinical examination  althoughThe study was conducted from September 2013 to July 2014 at Bishoftu ELFORA export abattoir in central Ethiopia. ELFORA export abattoir is located at Debre Zeit Town 47 km southeast of Addis Ababa. Currently the abattoir is one of the modern export abattoirs in Ethiopia and is exporting meat of small ruminants to Middle East countries  and African countries , But the cattle slaughtered in the ELFORA export abattoir are used for local consumption. During the study on average 400 and 500 sheep and goats respectively, were slaughtered at this abattoir per day. On the other hand, on average 70–85 cattle were slaughtered per week based on local market needs.Bos indicus) and only males with variable body condition scores and age groups.Animals used for the study were cattle slaughtered at ELFORA export abattoir. The study cattle were purchased from different zones of the country particularly Borana, Arsi, Bale, Gondar, Jimma and southern Ethiopia. All study animals were local breed  and on the associated intestinal lymph nodes as previously described by Hailat . All chaHistopathological examination was performed according to a protocol described by Bancroft . Tissue Data from gross examination and laboratory results were entered into Microsoft Excel 2010 spread sheets and the prevalence of bovine paratuberculosis was calculated in percentage. Animal prevalence was defined as the number of cattle found positive for paratuberculosis lesion per 100 animals examined.The prevalence of paratuberculosis on the basis gross pathology was 11.25% . Thus, of the 400 cattle examined for the gross lesion of paratuberculosis, 45 cattle had intestines and/or lymph nodes with gross lesions compatible with the lesion of paratuberculosis. The gross lesions were characterized by thickening and corrugations of the intestinal mucosa, or enlargement of associated intestinal lymph nodes. Grossly, the intestinal wall was thickened in its different parts particularly at the ileoceacal junction. When thickened parts of the intestine were opened they showed corrugations and elevations which did not disappear on stretching . Thus, the 45 cattle which were positive for gross lesion of paratuberculosis were further examined for microscopic lesion using Hematoxylin-Eoesin stained sectioned tissues of which eight animals had microscopic lesions consistent with the microscopic lesion of paratuberculosis. The microscopic lesions were characterized by an increase in the thickness and congestion of the intestinal mucosa due to inflammatory cells infiltrations. Out of the eight cattle with microscopic lesions, two cattle showed severe thickness and corrugation of the mucosa which were formed longitudinal and transverse ridges that could not be reduced by stretching . The prevalence of paratuberculosis was estimated on the basis of gross as well as microscopic lesion of paratuberculosis.The prevalence of paratuberculosis recorded in the present study on the basis gross lesion was 11.25%, which was similar with the prevalence of the study conducted earlier in Canada  while itMacroscopically a variety of gross lesions which were normally associated with paratuberculosis were observed in the ileum. Thickening and corrugations of the ileum were obvious in the last portion of the ileum particularly at the ileoceacal junction. In severely affected cases, there were diffuse thickenings along with transverse and longitudinal corrugations of the intestinal wall making irregular folds –42. CongThe prevalence of paratuberculosis recorded in the present study was 2% on the basis of microscopic lesion. This microscopic lesion-based prevalence was comparable with the prevalence reported by the study conducted earlier in Pakistan , while iThe grade III lesion found in 2 cattle had diffuse infiltration of epithelioid cells, macrophages and multinucleated giant cells in the last portion of the small intestinal ileum and their associated lymph nodes. The grade III lesions observed in the present study corresponds most closely to those of the multibacillary form of paratuberculosis which is in agreement with the earlier by other authors , 44–48. Grade II lesions had the same pathological pattern of grade III, except that the severity of the lesions was moderate with few epithelioid cells, but there were more lymphocyte infiltrations. While the grade I lesions had less cellular infiltrations which was consisted more of lymphocytes and some scattered macrophages. This observation is consistent with the observation made earlier by other researcher . PreviouThe study is not without limitation as it was based on gross and microscopic lesions of paratuberculosis confirmation of the diagnosis using identification of the etiologic agent (MAP) or it is nucleic acid using molecular typing was necessary although this could not be done because of resources.This study indicated the occurrence of paratuberculosis in cattle of Ethiopia on the basis of gross and microscopic lesions. This study was the first in pathologically detecting lesions consistent with the lesion of paratuberculosis although only one study reported the seroprevalence of paratuberculosis earlier. Thus, the result of the present study highlights the need for additional studies to establish its epidemiology and economic significance of partatuberculosis in the country.


Following the publication of this article , concernThe University of California, Davis confirmed that author DPW admitted to manipulation of the data underlying the results presented in Fig 2.PLOS Genetics Editors issue this Expression of Concern to notify readers of the above issues.The authors are working with PLOS to try and address these issues. Meanwhile, the


The use of a stent to coil an aneurysm can alter the position of the main blood vessel and affect blood flow within the sac. This study thoroughly examines the impact of stent-induced changes on the risk of MCA aneurysm rupture. The research aims to assess the effects of coiling and vessel deformation on blood flow dynamics by comparing the OSI, WSS, and blood structure of two distinct MCA aneurysms to identify high-risk areas for hemorrhage. Computational fluid dynamics is used to model blood flow. The results indicate that aneurysm deformation does not always decrease the risk of rupture, and coiling is more effective in occluding blood flow than aneurysm deformation. If there is a residual neck or unoccupied neck remnant, growth, recanalization, and rupture may occur, making treatment essential5.In the United States, the rupture of intracranial aneurysms is a significant challenge, as 30,000 cases of ruptured aneurysms are reported in US patients each year. The rupture of an aneurysm can lead to death or debilitation, and endovascular coils are the primary conventional treatment technique used to obstruct aneurysms and reduce the risk of rupture. Previous reports suggest that the quality of coiling plays a crucial role in reducing the risk of aneurysm rupture, particularly in the aneurysm ostium region, which experiences high-velocity impinging blood flow due to poor filling7. This technique substantially decreases the blood flow into the sac and makes a framework for thrombus establishment9. The application of the stent is helpful for the efficient coiling of the cerebral aneurysm11. The usage of the polymer foam as coils results in optimistic long-standing healing based on the in vivo studies. On the other side, the filling of the aneurysm could effectively have been done by the usage of a stent since this permits the coiling of the aneurysm with higher density14. In addition, the usage of the stent allows higher coiling near the neck area which is susceptible to rupture by the reason of the high flow rate.The usage of shape polymer foam is suggested as one of the reliable methods for occlusion of the aneurysm18. The recognition of the blood hemodynamic under impacts of the stent-induced deformation offers valuable information for surgeons for estimation of long-term treatment of the aneurysm22. The post-interventional impacts of stents have been investigated in limited research and results considerably vary based on the types and shapes of aneurysms27.The side effect of stent usage is the deformation of the parent vessel which also has a great impact on the performance of the occlusion of blood stream into the main sac areaIn this study, the hemodynamic analyses of the MCA aneurysms have been performed to reveal the impacts of the stent on the rupture risk of the saccular aneurysm after the deformation of the parent vessel. To study the hemodynamic impacts of the aneurysms, computational fluid dynamics is applied for the analysis of the bloodstream inside the MCA aneurysm at two stages of deformations. In addition, the influence of coiling porosity is also investigated after the deformation of the parent vessel.28.It is confirming that all methods were carried out in accordance with relevant guidelines and regulations. Besides, all experimental protocols were approved by of the Ca’ Granda Niguarda Hospital and it is confirmed that informed consent was obtained from all subjects and/or their legal guardian(s). All study are approved by Ca’ Granda Niguarda Hospital ethics committee32. The transient form of Navier–stokes is used for the modeling of blood flow through the vessel and sac section35. The one-way FSI model is used to apply the impacts of the vessel interaction under the impacts of blood pressure39. This technique is extensively used for the simulation of deformable domain where fluid has impacts on the solid wall42. Computational technique has been used in different applications of engineering44 and medical devices46. In this approach, the pressure force on the vessel would result in the defamation of the sac and vessel. The bloodstream is assumed transient with cardiac cycle and non-Newtonian28. Casson model is applied for the calculation of the blood viscosity29.The simulation of blood hemodynamics inside the MCA aneurysm with/without deformation by stent is done via computational fluid dynamics28. This figure also demonstrates the applied boundary condition for the chosen aneurysms. Inflow blood is applied by mass flow rate pattern  under the impacts of deformation and coiling is displayed in Fig. To understand the role of deformation on the hemodynamic of the MCA aneurysm, Fig. OSI index is critical for the evaluation of the aneurysm rupture. Figure The results of mean OSI on sac wall for different coiling porosities under impacts of deformations are presented in Fig. In Fig. The impacts of stent-induced deformation on the hemodynamics of two distinctive MCA aneurysms are fully investigated in the present research. This study examined and explored the role of endovascular coiling when the parent vessel is deformed by the implementation of stents on the parent vessel near the sac. The modeling of the bloodstream in vessels and aneurysms is done via the computational fluid dynamic technique. The blood flow feature and WSS of aneurysm are compared to disclose the influence of coiling after post-interventional deformation. Presented results show that the effects of MCA aneurysm deformation are not always favourable for occlusion of the blood entrance. A comparison of coiling and deformations indicate that the coiling of an aneurysm would effectively reduce the risk of MCA aneurysm rupture.