The testis is a key male reproductive organ that produces gametes through the process of spermatogenesis. Testis morphologies, sperm phenotypes, and the process of spermatogenesis evolve rapidly in mammals, presumably due to the evolutionary pressure on males to give rise to their own offspring. Here, we review studies illuminating the molecular evolution of the testis, in particular large-scale transcriptomic studies, which were based on bulk tissue samples and, more recently, individual cells. Together with various genomic and epigenomic data, these studies have unveiled the cellular source, molecular mechanisms, and evolutionary forces that underlie the rapid phenotypic evolution of the testis. They also revealed shared  and species-specific spermatogenic gene expression programs. The insights and available data that have accumulated also provide a valuable resource for the investigation and treatment of male fertility disorders – a dramatically increasing problem in modern industrial societies. •The testis is a rapidly evolving organ, on both the transcriptomic and translatomic layer.•The force of sperm competition has shaped the evolution of this organ.•Insights from new data provide a resource for future investigations of testicular molecular evolution and male fertility. The testis is the male reproductive gonad in all bilaterian animals, including humans and other mammals. The function of the testis is to produce sperm, through the process of spermatogenesis, but also androgens, primarily testosterone. The testis has evolved rapidly in mammals, which is likely mainly due to positive selection associated with the force of “sperm competition”, which reflects the evolutionary pressure on males to be reproductively successful; that is, to fertilize female eggs and thus give rise to their own offspring . This prStudies in the past two decades have revealed that the rapid evolution of the testis is reflected at the molecular level. In particular the advent of RNA sequencing (RNA-seq) protocols has facilitated global large-scale cross-species investigations. Here, we discuss the exciting fundamental insights that these novel approaches have provided into the molecular basis of testicular evolution and the peculiar features of spermatogenesis.We set the stage by introducing the spermatogenic/testicular cell types and highlighting the peculiar chromatin dynamics of the autosomes and sex chromosomes during spermatogenesis. We then summarize how bulk tissue RNA-seq and ribosome profiling (or Ribo-seq) studies have shed light on the consequences of these chromatin dynamics but also on the extensive translational regulation that is occurring during spermatogenesis. We proceed by discussing insights into the molecular evolution of the testis obtained from cross-species comparisons of these data types, to then move on to describe how recent evolutionary single-cell RNA-seq studies have led to groundbreaking findings regarding the cellular source and evolutionary forces underlying the rapid evolution of the testis. Next, we delve into the intricate and intriguing patterns and mechanisms of sex chromosome evolution pertaining to spermatogenesis. We conclude our account by discussing overall implications of the recent large-scale genomics investigations of the testis and by identifying promising future research avenues.Spermatogenesis takes place in seminiferous tubules, which crowd the testis . SpecifiDuring spermatogenesis spermatogonia differentiate into spermatocytes, where meiosis takes place . The meiSpermatogenesis displays several unique and peculiar molecular chromatin features. Chromatin in spermatogenic cells is indeed massively remodeled during spermatogenesis. This process involves repackaging of the DNA initially around testis-specific histones and histone variants, then around transition proteins, and in the end around small protamines, which allow dense packaging of the DNA into the compact sperm head  Fig. 2)Fig. 2). Molecular biologists have been aware for decades that the testis expresses many or even most genes – more genes than other organs – and have therefore, for example, often resorted to the testis for cloning experiments. Initial analyses of RNA-seq data derived from bulk tissue samples confirmed this notion at a genome-wide scale , indicatRecent genome-wide investigations of mRNA translation based on Ribo-seq  – a highGlobal comparisons of gene expression patterns across species based on bulk tissue samples provided initial insights into the rates of expression evolution in different mammalian organs. Early work, which was using microarrays to compare gene expression levels of corresponding one-to-one (1:1) orthologous genes between humans and chimpanzees for several organs, already showed that the testis had the greatest divergence in gene expression levels among the investigated organs . Later sNotably, our recent work has brought the investigation of gene expression evolution from the transcriptome to the next expression layer – the translatome – based on Ribo-seq data for several organs (including the testis) from representative mammals . This stRecent high-throughput single-cell (sc) or single-nucleus (sn) RNA-seq technologies have enabled detailed investigations of the cellular and molecular evolution of organs. We thus recently performed an extensive evolutionary single-cell transcriptome study for testes from eleven species that cover the three major mammalian lineages  and birds (the evolutionary outgroup), and include seven primates  Fig. 4)Fig. 4). To trace the cellular source of the rapid evolution of the testis, we built expression trees for the different cell types based on these data and found that the total branch lengths of the trees, which reflect the amount of evolutionary expression change (akin to the aforementioned bulk RNA-seq work), vary substantially between cell types. Interestingly, while the rate of expression evolution is similar in Sertoli cells and diploid spermatogenic cells (and lower than that in other somatic cell types), it was found to be substantially higher in the post-meiotic haploid cell types , consistent with previous work and a recent inference based on data for three placental mammals . PairwisWe sought to trace the evolutionary forces underlying the rapid evolution of late spermatogenesis and reasoned that two non-mutually exclusive patterns of natural selection may account for this finding . First, Specifically, signatures of functional constraints along spermatogenesis were assessed based on patterns of the tolerance to functional mutations, mouse knockouts, and rates of amino acid altering substitutions in coding sequences of genes expressed in different spermatogenic stages. All of these analyses showed a progressive reduction of constraint towards late stages of spermatogenesis across species, typically with the strongest reduction in early spermiogenesis; that is, in round spermatids .On the other hand, an examination of the temporal expression pattern of genes whose encoded protein sequences have been shaped by positive selection revealed a significant increase in percentages of positively selected genes used during spermatogenesis, with a peak in round spermatids . MoreoveBut what are the fundaments underlying the dynamic changes of selective forces and patterns of innovation during spermatogenesis? Given that the breadth of expression across tissues and developmental processes (termed “expression pleiotropy”) was proposed to represent a main determinant of the types of mutations that are permissible under selection , we asseIn our study , we alsoNotably, integrated analyses of our data and known fertility phenotypes  unveiledFinally, we used our single-nucleus spermatogenic data to scrutinize expression patterns of sex chromosomal genes and their evolution across mammals . Two setOur analyses provided several intriguing insights into the expression of sex chromosome-linked genes and their evolution . First, Here we have reviewed cross-mammalian transcriptome studies that – initially at the bulk-tissue level and more recently at the level of individual cells – have unveiled details of the unique and complex biology and molecular evolution of the testis and the process of spermatogenesis that takes place in this organ. The available data also provide a rich resource not only for future investigations of the molecular evolution across mammals but also for studies of the biology of the testis and associated fertility disorders – a dramatically increasing problem especially in industrialized regions of the world . In the Nils Trost designed and contributed figures and co-wrote the manuscript.Noe Mbengue designed and contributed figures and co-wrote the manuscript.Henrik Kaessmann wrote the manuscript.German Research Council  and the 10.13039/501100000781European Research Council  to H.K.This review and the new research in our group covered at the end of this review by Murat et al. were supported by grants from the


The current work focuses attention on discussing the peristaltic flow of Rabinowitsch nanofluid through ciliated tube. This technical study analyzes heat and mass transfer effects on the flow of a peristaltic flow, incompressible, nanofluid via a ciliated tube. The governing non-linear partial differential equations representing the flow model are transmuted into linear ones by employing the appropriate non-dimensional parameters under the assumption of long wavelength and low Reynolds number. The flow is examined in wave frame of reference moving with the velocity  Narla et al.2 investigated the analysis of entropy generation in biomimetic electroosmotic nanofluid pumping through a curved channel with joule dissipation. Agoor et al.3 examined the binary powell- eyring nanofluid of peristaltic flow with heat transfer in a ciliated tube. Shit and Majee4 discussed a pulsatile MHD flow of blood signifying blood as a Newtonian fluid with temperature-dependent variable viscosity in an overlapping constricted tube under the influence of whole-body vibration. In a separate study, Shit and Majee5 examined the unsteady MHD flow of blood and thermal effect in an aneurysmatic artery using a finite difference approach. They documented that with increasing the magnitude of the Prandtl number, the Nusselt number enhances. Thermal radiation therapy is of significant importance in some medical procedures related to the cure of muscle spasm, myalgia (muscle pain), fibromyalgia and contracture. Maqbool et al.6 studied the effects of magnetic field and copper nanoparticles on the flow of tangent hyperbolic fluid through a ciliated tube. Tariq and Khan7 explained the behavior of second-grade dusty fluid flowing through a flexible tube whose walls are induced by the peristaltic movement. Ellahi et al.8 discussed the effects of heat and mass transfer on peristaltic flow in a non-uniform rectangular duct is studied under consideration of long wavelength and low Reynolds number. Nadeem et al.9 investigated the mathematical model for the peristaltic flow of nanofluid through eccentric tubes comprising porous medium. Shaheen and Nadeem10 analyzed the mathematical model of ciliary motion in an annulus is studied the effect of convective heat transfer and nanoparticle are taken into account. Iqbal et al.11 investigates the heat and mass transfer through curved channel with bi-convection. Main findings of the analysis discloses that the temperature of nanofluid decreases as radiation and viscosity varies. Abd-Alla et al.12 explained the effects of heat transfer and the endoscope on Jeffrey fluid peristaltic flow in tubes. Akhtar et al.13 construct polynomial scheme to find exact solution to the peristaltic flow of Casson fluid through elliptic duct. They focus their attention on the behavior of streamlines. Consideration of constant density force streamlines to be closed enough so that velocity get increased. Peristaltic flow of micropolar fluid through asymmetric channel with new type of interfacial thin film layer at the boundaries are studied by Mahmood et al.14. Tanveer et al.15 presented the analysis for peristaltic flow of Walter’s B fluid with internal heat generation. They applied numerical technique based on shooting method which express results in terms of interpolating function. Mansour and Abou-zeid16 studied the influence of heat and mass transfer the peristaltic flow of non-Newtonian Williamson fluid in the gap between concentric tubes. Awan et al.17 explained the numerical treatment for dynamics of second law analysis and magnetic induction effects on ciliary induced peristaltic transport of hybrid nanomaterial. Akbar and Butt18 investigated the concerns with the mechanical properties of a Rabinowitsch fluid model and the effects of thermal conductivity over it. In recent years, researchers have extensively focused on the peristaltic flow of Newtonian and non-Newtonian fluids , peristaltic flow with new parameters with or without endoscope has been discussed.Advances in fluids engineering and industrial sectors have aroused the interest of researchers in analysing mathematical models for non-Newtonian fluids. Non-Newtonian materials include slurries, coolants, lubricants, blood at low shear rates, ketchup, some paints, dirt, hygienic products, and many more. Several researchers have extensively studied the flow characteristics of such fluids due to their critical importance in the diverse fields of science and technology, including polymer solutions, viscoelastic suspensions, metal spinning, lubricants, plastics manufacturing, molten metal distillation, crystals, and food processing. Given its significance, a single constitutive model cannot encompass all non-Newtonian fluid aspects due to the diverse nature of fluid characteristics. The Peristaltic flow is a common method of fluid flow where flexible chambers are used to propel fluids through progressive waves of contraction and expansion. Akbar et al.Recently, significant interest has been developed in studying a peristaltic phenomenon due to its significant implications in biological sciences and biomedical engineering. In the current study, an investigation is carried out to inspect the peristaltic pattern of the nanofluid model in the presence of mass and heat phenomenon. The flow modelling is followed with the small Reynolds number hypothesis while the long wavelength is premised. The influence of various emerging physical parameters in the obtained solutions is observed. The obtained expressions are utilized to discuss the role of emerging parameters on the flow quantities. Numerical computations have been used to evaluate the expression for velocity, temperature, concentration, the gradient pressure, rise pressure and the friction force of various interesting parameters. Finally, the effect of various emerging parameters is discussed through graphs. Finally, the detailed computational results are compiled and discussed with the physical interpretation of our results. The graphical upshots for the velocity, temperature, concentration, the gradient pressure, rise pressure and the friction force are examined for influentrial parameters.The current analysis is performed to study the 2-dimensional peristaltic flow of Rabinowitsch nanofluid in an infinite tube with convective boundary condition. In addition, we also analyze the impact of nanofluid, thermal conductivity of fluid, the viscosity at constant concentration, thermal coefficient of nanofluid and heat source. For problem under consideration, geometry is exhibited in cylindrical coordinate system  representing radial, azimuthal and axial coordinates respectively. Furthermore, the fluid flow is caused by the metachronal wave, resulting from uniform cilia beating whereas the temperature and concentration at the wall are mentclass2pt{minimR, Z) where Z the axis of the tube, while R the radius of it see Fig. c.For the peristaltic flow of an incompressible nanofluid with iron oxide nanoparticles in a uniform tube, using the cylindrical coordinate  in flow in small diameter tubules, analysis can be completed by approximating the inertia-free flow. Additionally, if the tube length is finite and equal to an integral number of wavelengths along with a constant pressure difference at the ends of the tube, the flow may be steady in the wave frame of reference. The governing Eqs.  an an\documing Eqs.  in this The solutions of velocity, temperature and concentration with subject to boundary conditions  are giveThe gradient of the pressure:The volumetric flow rate:The rise of pressure:The force of friction:. The primary purpose of this section is to analyse the impact of pertinent parameters, including material parameters of Nanofluid, Nanofluid This article discussed the Rabinowitsch Nanofluid of peristaltic flow with heat and mass transfer in a ciliated tubeentclass1pt{minimase Figs. , 8 and 98.We disclose the influence of various parameters on temperature and heat transfer mechanism. Figure 32.Mass transfer cannot be ignored while dealing with heat transfer during multiple industrial and physiological fluid transport. Therefore, current subsection deals with the influence of different parameters on concentration profile. Figure 32.Figure z is plotted for various corresponding parameters. Fluctuating behavior is shown by pressure gradient attaining its maximum at 32.Figure 8.Figure Figure Figure Figure . The present investigation utilized nanofluid model in a tube to analyse the peristaltic flow of non-Newtonian fluid in a ciliated tube with heat and mass transfer. A thorough understanding of peristaltic flow regulation and malfunction is possible by incorporating numerous effects that mirror natural events, especially in small arteries. These discoveries shed crucial new light on the properties of peristalsis during blood flow in human circulatory system. The knowledge gathered from this study could help diagnose and treat vascular diseases and promote scientific research. The following is a summary of the main conclusions drawn from the model:Results obtained from the study indicate different flow behavior for the dilatant and nanofluid.Thermal conductivity: This phenomenon causes the temperature to fall during peristalsis. This indicates that the nature of heat transfer within the system influences temperature fluctuations.Coefficient of the viscosity at constant concentration: The model shows that fluctuating viscosity raises both velocity and temperature during peristalsis. This suggests that viscosity impacts the temperature and flow dynamics of blood.The graphical solutions of velocity depict that the flow has a maximum speed in the centre and it eventually decreases towards the duct walls.The temperature graphs reveal a parabolic graphical outcome and increasing manner in the temperature in the center of the tube.The concentration graphs reveal a parabolic graphical outcome and the concentration is minimum in the centre of duct whereas it enhances toward the duct walls.The results presented in this paper should prove useful for researchers in science and engineering, as well as for those working on the development of fluid mechanics.The Rabinowitsch nanofluid of peristaltic flow with heat and mass transfer in the ciliated tube is investigatedFinally, one can concludes that the optimum state of the cases under consideration is applied various emerging parameters as affect the nanofluid properties within the tube because of its utilitarian aspects in dealing the peristaltic flow with heat and mass transfer.


Vat photopolymerization (VPP) is an effective additive manufacturing (AM) process known for its high dimensional accuracy and excellent surface finish. It employs vector scanning and mask projection techniques to cure photopolymer resin at a specific wavelength. Among the mask projection methods, digital light processing (DLP) and liquid crystal display (LCD) VPP have gained significant popularity in various industries. To upgrade DLP and LCC VPP into a high-speed process, increasing both the printing speed and projection area in terms of the volumetric print rate is crucial. However, challenges arise, such as the high separation force between the cured part and the interface and a longer resin refilling time. Additionally, the divergence of the light-emitting diode (LED) makes controlling the irradiance homogeneity of large-sized LCD panels difficult, while low transmission rates of near ultraviolet (NUV) impact the processing time of LCD VPP. Furthermore, limitations in light intensity and fixed pixel ratios of digital micromirror devices (DMDs) constrain the increase in the projection area of DLP VPP. This paper identifies these critical issues and provides detailed reviews of available solutions, aiming to guide future research towards developing a more productive and cost-effective high-speed VPP in terms of the high volumetric print rate. In the 1980s, the first additive manufacturing (AM), also known as 3D printing, was the stereolithography printing technique to fabricate the prototype by adding the material layer by layer . Since tVat photopolymerization (VPP) is presently one of the most popular and in demand among AM technologies , which cThe idea of mass customization (MC) is now demanded in the era of Industry 4.0 by which the flexibility and personalization of custom-made products are combined with mass production ,22. The Concerning the present development of LCD and DLP VPP technologies to design a high-speed VPP in terms of the high volumetric print rate, a comprehensive review of the critical issues is necessary to point out the research directions where more focus is required. A comprehensive review of the separation force reduction and modification of the resin refilling methodologies has been carried out as these are among the main constraints to escalating the printing speed and printing area of LCD and DLP VPP. Additionally, the image projection issues of LCD and DLP VPP have been identified, and a constructive review has been made which can assist to recognize the improvement zone. Solving these issues make it feasible to bring out the DLP and LCD VPP as high-speed AM technology to accomplish the demand for mass customization with scalability.The development of high-speed VPP can be possible not only to increase the printing speed but also developing a large projection area of LCD and DLP VPP or increment the volumetric print rate that can reduce the production time per unit product. The volumetric print rate is an understandable parameter to judge the high-speed VPP from the industrial concern which can be calculated by multiplying the projection area and printing speed, shown in The vat depth is independent of the printing height, and the resin waste is less.Resin refilling happens automatically without any recoating process.The polymerization in the open air is difficult to control due to the oxygen inhibition effect. So, layer solidification is faster in the bottom-up method.The layer thickness is easier to control by the movement of the platform that is not dependent on the resin viscosity.The separation of the cured layer from the interface or constrained surface, caused by adhesion during photopolymerization, poses a significant challenge in bottom-up VPP processes. It can be seen from Different methods that have been proposed to solve the separation force issue still significantly hinder manufacturing capability, especially for a high printing speed and large-area printing. In addition, it is also essential to understand the mechanism  behind tAt first, it is necessary to understand the separation mechanisms which are primarily concerned with the adhesion characteristic between the rigid body and an elastic solid surface or liquid. The 3D-printed cured layer’s separation from the constraint surface can be elaborated as a laminated composite delamination process like mode-I fracture  ,39,42,45m. For the bilinear traction separation law (TSL)  ca ca84] ca2 [Polarizer films act like a filter that allows light in a particular pattern or orientation. These films (polarizer x and y) are oriented orthogonally to each other and placed LCD screens in between them b. Due to2 . This sy2 ,92.The packaging of LEDs or primary optics and the secondary optics c have anSilicone lens has been considered as primary optics in LED packaging which controls the emitting light efficiency and uniformity. A bio-inspired primary lens has been developed with periodic external nanostructures a. The ma2 nanoparticles are doped into the silicone lens, and developed five different dual-layer package structures to compare the result. Of these package structures, a thinner TiO2-doped silicone layer around the LED chip and a pure silicon lens on top  is a binary pulse-width light modulator, a core element of DLP VPP. It consists of millions of switchable microscopic mirrors arranged in a rectangular array equivalent to the projected image’s pixels. A schematic view of a single pixel of DMD with important components situated on a complementary metal-oxide semiconductor (CMOS) is shown in  company . DespiteEmami et al.  developeWithout using multiple DLP projectors or an additional exposure system, the delta mechanism has been implemented to increase the build size using a single projector ,135. ConA proper understanding of the separation mechanism is essential to estimate the separation force accurately whether it is solid–solid (DMT or JKR) or solid–liquid separation. For the solid–solid separation, the cohesive zone model (CZM) followed by the bi-linear traction separation law (TSL) has been used in most of the studies where crack formation occurs due to tension (mode I). It has been observed that soft material like hydrogel exhibits JKR-like separation while the higher stiffness of the interface is responsible for DMT-like separation. On the other hand, for solid–liquid separation due to dead zone, the analytical model of separation force has been developed based on the Navier–Stokes equation. The separation force is proportional to the fourth power of the radius of the printed part and inversely proportional to the third power of the dead zone thickness during solid–liquid separation.The interface modifications are the most focused area to reduce the separation force by creating an oxygen inhibition layer or dead zone. Polydimethylsiloxane (PDMS) has been used in most of the studies due to its oxygen permeability, even additives like silicon oil, perfluorocarbon, and vitamin E are also added to make a thicker dead zone. The CLIP and HARP technologies have been developed to maintain a constant dead zone thickness. However, the chemical stability of the dead zone against different monomers, the concentration of photoinitiators, and chemical additives are still uncertain. Additionally, maintaining the oxygen purity, and constant flow pressure in CLIP is indispensable otherwise the dead zone thickness will reduce drastically.The tilting mechanism has been used in several commercial machines where separation takes place due to shearing force instead of tension. Therefore, the required separation force is lower than the standard pulling process. However, this mechanism is difficult to apply for large-area printing because the tilting angle depends on the area of the vat. Furthermore, the repeatability, amplitude, and frequency of the vibration-assisted system should be explored in detail to reduce the separation force and surface roughness.During the separation, a vacuum is created between the cured part and the interface. The microand nano-sized channels of different shapes and sizes have been designed to increase the flowability of the resin into the vacuum. The surface roughness of the printed part due to the microchannel is one of the major concerns. Soft materials like hydrogel can also be another cost-effective solution to increase flowability. Chemical stability and JKR-like separation help to print large section areas at a minimum separation force. However, the thicker hydrogel (>4 mm) and water absorption tendency raise doubt about compatibility with the mass production scale.The monochrome LCD panel is essential to increase the printing speed and lifetime of the panel; however, the availability of large-sized monochrome LCD panels is still difficult. For increasing the optical efficiency and controlling the divergence of the LED backlight, the lens design plays an important role in primary and secondary optics. For the commercial lens array, the irradiance inhomogeneity of the LCD panel arises due to the intersection area among the secondary lens modules.Due to the area constraint and fixed pixel ratio of DMDs, multiple projectors methods  have been used to stitch the images to increase the printing area. Otherwise, a higher DoF mechanism has been added to the DLP projector or vat to increase the printing area by adjusting the focal length. However, obtaining the desired mechanical properties and surface roughness of the stitching zone is one of the main difficulties.The review has been carried out to identify the critical issues of high-speed LCD and DLP VPP and summarized the appropriate studies which can provide the solutions and direction for further research to bring out the LCD and DLP VPP as successful high-speed AM processes. The term high-speed VPP has been addressed as a high volumetric print rate  where boFurther studies on the cohesive zone model (CZM) for solid–solid separation can be conducted to incorporate the trilinear, parabolic, and exponential traction laws, to improve the correlation between numerical models and experimental results.Simultaneous consideration of separation force and resin refilling issues through the development of fluid-structure interaction (FSI) numerical model can help to understand and control the factors such as resin viscosity, printed part dimensions, and geometry, interface surface properties, dead zone thickness, especially for large-area printing.Development of ultra-slippery, low surface energy interface materials needs to be continued so they can maintain their surface properties after repetitive printing in different monomers and photoinitiator concentrations. Alternatively, exploring the hydrogel-like soft materials with various crosslinkers as interface materials could be promising.Investigation of LEDs’ primary optics lens designs needs to be explored further, specifically from a high-speed LCD VPP perspective. The different freeform shapes of secondary optics with BEF can be studied in more detail to enhance irradiance homogeneity and coherence.The concept of local dimming in mini/microLEDs can be applied to control the mask projection accurately with a reduction in power consumption and pixel blending effect in LCD VPP.Future research perspectives can focus on the following areas:These future research directions have the potential to address critical challenges and contribute to the advancement of high-speed VPP technologies, enabling their competitiveness with traditional manufacturing processes and expanding their application capabilities.


Microvascular decompression (MVD) is a widely adopted neurosurgery in treating cranial nerve diseases providing long-term pain relief. Improving surgical techniques has been a focus of recent studies. Venous structures such as the sigmoid sinus are essential to protect, and whose risk of destruction during surgery increases with size. The medical records of patients who went through MRI ahead of MVD surgery between Dec 2020 and Dec 2021 were reviewed. Section area of sigmoid sinus calculated from the MRI plane of auditory nerve showed a right dominance of the sinus. The improved method concerning the relationship between affected side and the dominant sigmoid sinus offered a better bone window and surgical field by planning the operation incision in advance. Intraoperative adjustment of the bone flap was avoided, and the risk of destructing the sigmoid sinus was reduced. Microvascular decompression (MVD) is recognized as the gold standard treatment for cranial nerve diseases such as primary trigeminal neuralgia (PTN), primary hemifacial spasm (pHFS) and glossopharyngeal neuralgia (GN) . After iVenous structures closely monitored are the sigmoid sinus and transverse sinus, whose exposure during MVD craniotomy marks the completion of the bone flap. Meanwhile, protection of venous structures during surgery is vital. Any destruction of the venous structures, especially on the dominant side, may lead to devastating effects. Dominance pattern of the sigmoid sinus affects venous flow rate, flow volume and other characteristics of the sigmoid sinus which are essential to evaluate before conducting MVD. Surgery on the cranial side of a dominant venous sinus with a large sectional area increases the difficulty and risk of operation. Thus, it is necessary to evaluate the dominant sigmoid sinus and to plan for the dimensions of the bone flap before surgical interventions. X-ray, computed tomography (CT), and magnetic resonance imaging (MRI) and angiography (MRA) has been widely adopted in preoperative planning of MVD to provide morphometric information on the posterior fossa and the neurovascular structures of the trigeminal nerve . MeanwhiWe retrospectively analyzed the medical records of 278 patients who underwent MVD surgery at our institute between Dec 2020 and Dec 2021. Cross-sectional areas of the sigmoid sinus were calculated from the magnetic resonance plane of auditory nerve.(1) Hospitalized due to primary trigeminal neuralgia or hemifacial spasm, (2) Received MVD surgical treatment, and (3). Underwent MRI examination before the surgery.Cases of a second surgery and anatomical pathologies were excluded.t| ≥ 1.96) indicates statistical significance. Data counts were tested by chi-square and index correlation was represented by Pearson correlation coefficient (Pearson’s r). A p-value less than 0.05  indicates statistical significance.Statistical analyses were carried out using SPSS 20.0 software. Results were presented in the form of average ± standard error (X ± S). Repeated measurement ANOVA was used for different times in the same measurement group. One-way analysis of variance was used to compare different groups. The t-test was used for inter-group or intra-group comparisons. A magnitude of t-value greater than or equal to 1.96 , however, the section areas of all groups yielded the same result that the right sigmoid sinus takes up higher percentages than the left. Right-side dominance was observed in both group a and b. This result was brought to attention when determining the location and length of the incision during preoperative preparation to protect the sigmoid sinus (see The difference between the sides was not statistically significant (inus see .We thereby improved the approach of line drawing in the subsequent treatments. The conventional drawing method was to determine the position of the transverse sinus and then draw the line according to the location of the mastoid root to design the surgical incision. In the improved method, having the relationship between the affected side and the dominant side determined, the location of incision was adjusted towards the dorsal if the relationship was ipsilateral, and was adjusted towards the ventral if the relationship was heterolateral, according to the thickness of the skull. Statistical data from 60 treated cases using the improved method are presented in According to The difference between the two groups was not statistically significant, given the limited sample size, but the advantage of the improved method based on these differences was evident. Planning the line of incision carefully based on different sizes and angles of sinuses achieved satisfactory surgical view. Intraoperative adjustments of bone flaps due to sinus protection were avoided. Comparing the bone flaps before and after implementing the improved method , 6, the Microvascular decompression relieves abnormal compression of a cranial nerve causing trigeminal neuralgia by isolating the trigeminal nerve root from the offending artery triggering the pain signals . It is aThe right dominant sigmoid sinus requires careful treatment during surgery. Preoperative design of the bone flap is a practical approach to prevent adjustment of bone flap dimensions. During operations, anatomical characteristics of venous sinuses can vary among individuals and should be identified carefully to avoid destruction to venous sinuses and restriction of bone window exposure . ClinicaIt should be noted that dominant pattern of the sigmoid sinus is based on the existing MRI records at our clinic, no statistical significance indicates limitation in the sample size. The pattern should be further validated in a larger cohort.In conclusion, surgical planning before MVD operation is essential to protect venous structures. Based on the right dominance pattern of sigmoid sinus, MRI examination serves to determine the relationship between the affected side and the dominant side in evaluating the positional and structural characteristics of the sigmoid sinus by individuals, to facilitate the retention of facial acoustic nerve in MVD surgery and to reduce the risk of glossopharyngeal nerve injury and cerebellum contusion. Such designs and improvements have yielded lower risks and good prognoses.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.CZ and YC contributed equally to the design and drafting of the manuscript. CjJ was in charge of data analysis and literature review. WX, JW, CgJ, and BW revised the manuscript. WL monitored the quality and integrity of this work. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Linitis plastica (LP) is a very aggressive and rare carcinoma with a scirrhous stroma that affects the submucosal and muscular layers of the stomach even without mucosal alterations. Lack of timely diagnosis is a crucial problem related to its prognosis and treatment. In this study, we investigated the LP-associated vascular pattern as a possible means to improve the diagnosis of these patients. During standard endoscopy, mucosal architecture, tortuosity and enlargement of vessels, as well as the presence of vascular leakage and efficiency of the blood flow were assessed in six LP patients using probe-based Confocal Laser Endomicroscopy (pCLE). In all LP patients, we detected abnormal changes in vasculature. The aberrant features of the vascular network were common to all LP patients examined and consisted of vessel enlargement, tortuosity, and leakage associated with the affected submucosal layer. This is the first study to highlight the presence of marked vascularization associated with LP, characterized by the presence of abnormal and non-functional vessels, similar to what is observed in neoplastic tissues. Therefore, the analysis of LP by pCLE may provide a new endoscopic approach and strategy to better define these patients. Linitis plastica (LP) is an aggressive and rare carcinoma with a scirrhous stroma involving the submucosal and muscular layers of the stomach . The sprThe probe-based Confocal Laser Endomicroscopy (pCLE) enables in vivo analysis of tissue microarchitecture and precise identification of areas suitable for biopsy sampling by enhancing contrast and magnification of the diseased tissues at the cellular level –7. High-With the aim of developing new approaches to improve LP diagnosis, in this study, we used the pCLE technique for the first time to determine whether these lesions are also characterize by aberrant vasculature similar to gastric cancer.For this study, we consecutively enrolled six patients  who underwent endoscopy for diagnostic work up in 2019–2020 at the Oncological Gastroenterology Unit of the CRO-IRCCS, National Cancer Institute of Aviano (PN), Italy. Based on biopsy specimens, patients (“1-6LP”) were diagnosed negative for gastric cancer, although the endoscopic features were macroscopically suggestive for LP. pCLE was used to guide biopsy sampling and define vascular architecture. All patients consented to endomicroscopic pCLE analyses by signing the informed consent form. The methods used were in accordance with the standards of the WMA Declaration of Helsinki. The study was approved by the Institutional Board of the CRO-IRCCS (IRB no. CRO-2014-03).The pCLE analyses were performed using a GastroFlex UHD probe  during gastroscopy (Olympus series 180) and immediately before endoscopic ultrasonography (Olympus series 160) as previously described , 13. AftGastric cancer was classified according to the Lauren classification , and thepCLE could not detect neoplastic features in the gastric mucosa of all examined LP patients. The gastric pit pattern showed reduced but regular pits with dilated openings as observed in atrophic gastritis . AccordiAlthough confocal endomicroscopy excluded neoplastic mucosal infiltration, pCLE was useful in revealing the features of vascular architecture in this type of gastric cancer. The vessel architecture was abnormal and mainly consisted of enlarged, distorted and highly permeable microvessels. Figure The lack of timely diagnosis is a crucial problem related to the prognosis and treatment of LP. Because of their peculiar spread pattern, LP tumors occasionally cannot be distinguished from atrophic gastritis on endoscopy. Endoscopy of the upper gastrointestinal tract reveals only the mucosal layer, and superficial biopsies may be negative in this case. Because tumor cells generally migrate throughout the submucosa without seriously affecting the gastric mucosa, it is difficult at an early stage to detect LP-derived cancer cells by gastrointestinal series or conventional endoscopic biopsies. Indeed, analyses of endoscopic biopsies in all LP patients who participated in this study were inadequate to correctly diagnose the disease. The use of pCLE, a well-established endoscopic tool to improve diagnosis in gastrointestinal diseases , was helRecently, we thoroughly investigated the vascular features of locally advanced gastric cancer by evaluating the use of pCLE for the analysis of intratumoral angiogenesis and demonstrated that the functional and structural angiogenic parameters of the tumor blood network were fully detectable with this innovative endoscopic technique . The vasA major limitation of this study is that it is a qualitative analysis performed on a small number of patients, although this disease is quite rare, especially in Western countries. On the other hand, we believe that the strength of this study lies in the innovative use of this endoscopic technique, which, unlike other techniques currently used, can provide not only structural but also functional information about the tissue. Nevertheless, to our knowledge, this is the first report showing the use of the pCLE technique for the analysis of LP patients, as well as the first time that a thorough analysis of the LP-associated vasculature is outlined. Given the promising results of this study, we envision that the use of pCLE may open new perspectives not only to improve diagnosis but also to better understand how vascular characteristics may influence the biological behavior of gastric disease.


The importance of the microbiome in aquaculture species is widely acknowledged. The fish gut microbiota is essential for host fitness, modulated by diet and environment, and affects animal physiology. The gut microbiome optimizes nutrient uptake and immunomodulation and enhances host resilience against infectious diseases. Understanding microbiome dynamics in aquaculture species is vital in promoting animal health and industry sustainability.In this Research Topic of Frontiers four original papers and one review paper were accepted. This editorial provides an integrated summary of those papers’ main discoveries and clues.2) and reduce the amount of ammonia excretion caused by feeding. Additionally, studies show that carp excrete less ammonia when fed on demand compared to being fed the same amount twice daily by hand. In the study by Mes et al. comparing the growth and nitrogen excretion of demand-fed carps with batch-fed carps, the authors found that the feeding regime had a significant impact on nitrogen balance and that carp can excrete N2 at a rate in the same order of magnitude as the amounts of nitrogen that were found unaccounted for in the calculated balance. The authors suggest that N2 production by symbiotic branchial nitrogen cycle bacteria is likely a universal feature that needs to be considered to fully understand nitrogen balance in fish and the functional role of their microbiome.Two of the papers address mainly the problem of nitrogenous production/accumulation in rearing systems, especially with carnivorous fish species, like common carp and grouper, and strategies to mitigate toxicity and reduce the nitrogen load in aquaculture conditions. The amount of ammonia that fish produce and excrete responds to various factors, including their food intake and the protein content of their diet. Researchers have found that fish can host nitrogen-cycle bacteria in their gill cells, which can aid in the production of dinitrogen gas  failed to compete for resources. Including probiotics led to better results in fish growth parameters in the treated groups. Although this study strongly suggests the bioremediation capacity of probiotics, it also makes obvious the necessity to conduct further studies to fully comprehend and evaluate the extent of the dysbiosis effect on the natural microbial community in the water and fish gut.The accumulation of toxic nitrogen forms in rearing environments is a significant concern in intensive aquaculture systems. Asian fish farmers commonly use fishponds to rear grouper, relying on stable water quality achieved by using environmental heterotrophic bacteria to break down excess waste. However, overfeeding or keeping fish at high densities can increase organic matter to dangerous levels by accumulating ammonia and nitrites, which makes crucial the development of pond culture technology that meets farmers needs and ensures animal health. In the study by Liao et al. the authors studied the effects of the “Fishery-photovoltaic Integration” (FPVI) aquaculture system on the growth rate and ecological environment of shrimp, using Penaeus monodon as a model species. They characterized the bacterial community structures in water, effluent, and intestinal environments using 16S gene sequencing. The results showed that the microbiota composition under the FPVI system promotes the healthy growth of shrimp by regulating intestinal function and preserving intestinal homeostasis. Additionally, the microbiota regulates nitrogen transformation in the water, ensuring the stability of the water environment throughout the 105-day experiment period with a reduction in antibiotic resistance genes observed within the FPVI pond. The findings suggest that the FPVI aquaculture model holds significant potential for future development and testing with other aquaculture species and rearing systems.In the paper by Wei et al. studied the effect of exercise on a novel hybrid of Megalobrama amblycephala  and Ancherythroculter nicrocauda , which showed quick growth, disease resistance, and anti-stress capability but needed improvement in fillet quality. By allowing the fish a short-term (12–16 days) swimming exercise at a constant moderate speed in circular flumes, the authors observed increased muscle fibre density, decreased muscle fibre diameter, and improved muscle texture. The exercise significantly increased gut bacterial community richness and diversity and altered the composition of gut microflora, as confirmed by 16S gene sequencing analysis. At the phylum level, the relative richness of Proteobacteria, Firmicutes, and Bacteroidetes was increased in the exercised groups, while that of Fusobacteria decreased. Functionally, these alterations can boost glucose, nitrogen cycling, metabolism, and the cycling of protein-rich compounds. Including the reported alterations at the genus level, the results suggest that short-term swimming exercise also increases intrinsic antimicrobial resistance and promotes the denitrification capacity of this hybrid species.A higher diversity of gut microbes leads to better metabolic health in humans and other mammals. Exercise, even in moderation or short-term, can diversify intestinal microorganisms and restore the balance of beneficial and harmful microbes. The use of motor stimulation in fish aquaculture as part of environmental enrichment strategies is a current concern. Kumar et al. opened other perspectives to studying fish microbiota, using Zebrafish (Danio rerio) as a model species in the context of human pathologies. In a comprehensive survey of the literature, the authors highlight aspects that justify the use of Zebrafish as a valuable tool to identify microbial enterotypes in fish and humans and investigate the link between the gut microbiome and physiological homeostasis of cardiovascular, neural, and immune systems. Zebrafish can be reared germ-free under gnotobiotic husbandry practices, with the apparent advantages of directly investigating specific host-microbiota interactions. The review demonstrates the significant overlap between Zebrafish and mammalian gut microbiota composition and the physiological responses of gut bacteria in both models. The paper supports the idea that sustained improvements in methodology to unravel host-microbe interactions using Zebrafish as a tool will benefit both mammalian and aquatic microbiota research.Finally, the review paper by


In recent years, scientific research into the therapeutic potential of psychedelic compounds has experienced a resurgence of interest. New studies have shown promising results, supporting the use of psychedelic drugs in treating various psychiatric disorders, including treatment-resistant depression, post-traumatic stress disorder, and even alcohol addiction. The FDA has recognized 3,4-methylenedioxymethamphetamine (MDMA) as a breakthrough therapy to treat symptoms of post-traumatic stress disorder. At the same time, interviews with recreational MDMA users have documented experiences of emotional intimacy while using MDMA, often without the desire for penetrative sex. However, some people have reported that MDMA increases their sexual arousal and specifically use it to enhance their sexual performance. This study aims to analyze current and planned research on the psychophysiological effects of entactogens on human sexuality. With their prosocial potential, the pharmacokinetic and neuroendocrine effects of entactogens may recreate the subjective experience of emotional intimacy, the initiation of intimate relationships, or even feelings of ‘falling in love’ with previously neutral individuals while under the influence of entactogens. This includes MDMA-induced sexual arousal-like effects observed through subjective behavioral perceptions of desire and arousal and specific physiological markers such as oxytocin and prolactin. Modern MDMA-assisted psychotherapy (MDMA-AP) protocols are transparent and follow strict ethical guidelines. However, despite these proposed ethical principles, little consideration has been given to the potential neurobehavioral effects of entactogens on the sexuality of participants in MDMA-AP protocols. The psychophysiological and sexual effects of entactogens should be discussed more openly in current MDMA-AP protocols, including the potential experience of the phenomenon of sexualized pharmacotransference. The field of psychedelic research is currently experiencing a remarkable renaissance. After decades of restrictive regulations and societal stigma, scientific investigations into the therapeutic effects of psychedelics have resumed, unveiling a promising new direction for mental health treatment.Studies on the effects of entactogens on humans are few and very scattered, especially regarding the impact of these substances on human sexuality. On the other hand, entactogens, especially 3,4-methylenedioxymethamphetamine (MDMA) also called ecstasy, have been used since the 1970s for recreational purposes and sexual enhancement but also for augmentation of the psychotherapeutic process .The philosophical change of the perception concerning the role of the psychiatrist in the PAP and especially in the MDMA-AP process applies to several elements: duration of the pharmacological treatment, the structure of psychedelic application sessions, the interpretation of the altered states of consciousness, mystical experiences and spirituality, the role of music and artistic expression, and finally the personal experience with the use of psychedelics Table .Table 3MThe researchers, participants, and universities face conflicting interests and incentives, which is strictly important in the context of avoiding missteps in the introduction of psychedelics to the set of psychiatric methods without a thorough understanding of all the effects that psychedelic substances have on humans .To assess the state of knowledge concerning the effects of entactogens on sexual human functions, a systematic review of the literature using PubMed database has been conducted. The updated search for the scope of this mini-review was performed on the 1st of July 2023 with the following keywords  AND . The author has received 148 records most of which 143 did not meet the criteria for describing the psychophysiological effects of MDMA on human sexuality.Given the absence of enough results in the PubMed Database author decided to search for the clinical trials registers. In the EU Clinical Trial Register using the following keywords: (entactogen OR MDMA OR methylenedioxymethamphetamine), the search did not return any results. In the database clinicaltrials.gov using the same topic, we have received 96 results.For the scope of this mini-review, we have decided to further analyze the clinical trials concerning the neurophysiology of entactogens (MDMA) in humans considering the Phase 1 clinical trials conducted on healthy participants. The primary purpose of this analysis was the evaluation of the advancement of the research on the physiology of entactogens in terms of their impact on human sexuality. We have analyzed the primary and secondary outcomes of these trials in terms of the assessment of the effects of MDMA on sexual functions or the ability to engage in intimate relationships.Of the 96 clinical trials registered, 17 concerned Phase 1 studies on healthy volunteers, while other studies concerned the assessment of the impact of MDMA on selected psychopathological symptoms in people with mental health problems , combat stress disorder, mood disorder, anxiety disorder, substance-related disorders, alcohol use disorder, amphetamine-related disorders, drug addiction, social anxiety in autistic adults, anorexia nervosa restricted type, binge-eating disorder, adjustment disorders, OCD, and schizophrenia .Whereas from the first phase or early first phase studies, only three studies were indirectly designed to assess the effects of MDMA on the evaluation of the preferences of the partner of the conversation under the influence of MDMA or placebo (NCT05123716) and self-reported feeling of connectedness and affective touch received from the familiar and unfamiliar person (NCT05948683).The first study was conducted between 2021 and 2022 and was planned to evaluate the effect of drugs on personal interactions in the same-sex pair partner design. The protocol proposed the subjects’ engagement in a 45-min semi-structured conversation with a novel partner under the influence of MDMA and with another partner under the influence of a placebo. At the end of each session, participants were supposed to rate their feelings about the partner, preferences about the partner, and the evaluation of the feelings of closeness to the subject under the influence of MDMA and placebo on the test day.The aim of the second study on the prosocial effects of MDMA was to test the hypothesis that MDMA produces greater prosocial effects when administered in the presence of a familiar, compared to an unfamiliar person. In this study, it was proposed to investigate whether the prosocial effects of MDMA are greater when interacting with a partner to whom the participant feels close and more connected, compared to an unfamiliar partner. To establish familiarity in one of the study groups, the study proposed a procedure during which two same-sex partners, who were initially strangers, were supposed to engage in a 45-min conversation with a ‘small talk’ condition or ‘deep talk’ condition that could produce feelings of connection, being understood and liking their partners (NCT05948683). The protocol of the study, planned to be conducted between 2023 to 2024, did not give any details concerning the method of assessment of the affective touch that participants of the experiment were supposed to receive from partners of a neutral or in-depth conversation.The third study conducted between 2019 and 2021 was also designed the evaluation the change in responses to affective touch but in a group of individuals with a range of autistic traits. Participants were supposed to complete an affective touch task during which time they were asked to rate pleasantness of touch (NCT04053036) at the point after receiving 1.5 mg MDMA and 6 weeks after the drug administration.In all three studies, the assessment of the effects of MDMA on the feeling of intimacy or sexual arousal was addressed only indirectly by evaluation of the feeling of connection, liking the partner of the conversation, or the evaluation of the affective touch. Experiments were designed in same-sex couples, possibly to avoid the risk of subjects engaging in intimate relationships or inducing experiences that might be interpreted as sexually related.Users of MDMA  commonly report experiencing unique psychological effects, including heightened empathy and increased prosocial feelings . These ‘On the other hand, these two socio-emotional processing alterations could facilitate both positive social interactions with strangers and interactions with a psychotherapist , 44 and In conclusion, it should be emphasized that none of the randomized controlled studies published so far on the socio-emotional effects of MDMA, nor even any planned studies available in the register of controlled trials, assess the impact of MDMA on intimate relationships and human sexual functions.MDMA is recognized among drug users for its positive social-emotional effects, such as increased feelings of empathy, interpersonal closeness, and sociability –47. FurtResearch concentrated on the evaluation of the motivations of MDMA users in naturalistic settings has shown that one of the main motivations for using this substance is sexual enjoyment  or sexuaIn McElrath et al.’s study, the majority of respondents had used MDMA six months before the interview, with a significant percentage having consumed the drug on 100 or more occasions . Most reA study investigating the experiences of young women (aged 18–29) from New York found that MDMA use was associated with heightened both sexual aspects  and sensual aspects . However, these experiences were more commonly categorized as sensual. A majority of women who engaged in sexual activity after the application of MDMA believed that the drug did not lead to risky sexual behavior. Nevertheless, some women reported engaging in sexual behaviors they might not have otherwise engaged .The results of a study involving 679 nightclub attendees (ages 18–25) indicated a strong association between MDMA use and heightened perceived sexual effects, including perceived sexual attractiveness of oneself and others, sexual desire, length of intercourse, and sexual openness . FurtherIn the study conducted by Zemishlany, the effects of MDMA on various aspects of sexual response were assessed in a small group consisting of 35 healthy recreational MDMA users (20 men and 15 women aged 21–48) . The stuThere are also descriptive reports from small groups of adult couples who have used MDMA for relationship enhancement . These cThe protocols of psychedelic-assisted psychotherapy are transparent and strongly relate to the ethical rules characterizing most of the therapeutic processes of various schools of psychotherapy. The ethical guidance of psychedelic-assisted psychotherapy introduced strict rules of no physical contact with participants during the session, strict respect of sexual boundaries, and examining the sexual countertransference by the therapists . AlthougThe protocols for psychedelic-assisted psychotherapy can be considered short-term therapeutic approaches that include a limited number of preparatory and integrative sessions.In the protocol for MDMA-assisted psychotherapy used in clinical trials conducted by the Multidisciplinary Association for Psychedelic Studies, it is a requirement to have two psychotherapists present, one of each gender, during the preparatory and integrative sessions (as outlined in the MAPS Code of Ethics) . It can On the other hand, during integrative sessions, the patients are expected to process the effects of the psychedelic experience with the therapist. The therapist’s neutral behavior during these sessions might be interpreted as friendly or even as bearing signs of closeness and intimacy, especially under the influence of previous MDMA use. The prosocial effects of entactogens, which enhance feelings of emotional closeness and connection, have been preliminarily described in the studies conducted thus far. Hence, it appears particularly important for MDMA-Assisted Psychotherapy (MDMA-AP) therapeutic protocols to include psychoeducational elements that can prepare participants for the possibility of sensory experiences that they may interpret as related to intimacy or sexual experiences with unclear meanings. Therapeutic protocols should also guide how therapists should conduct themselves during integrative sessions if patients wish to better understand any sexual sensory experiences that may have arisen during the application of entactogens or other psychedelics. the pharmacotransference process.Since the socio-emotional effects of MDMA are associated with feelings of connection, oneness, and even intimate bonding, the application of MDMA could induce a specific subcategory of transference feelings, i.e., eroticized transference that could be called The risks of the development of sexual, eroticized transference during the application of MDMA in clinical settings were not sufficiently addressed at the current stage of work on these protocols. Little is known about methods of facilitating the resolution of the possible sexual ‘pharmacotransference’ during MDMA-AT sessions.According to Thorsten Passie, the behavioral effects of entactogens resemble experiences that mimic the physiology of the sexual response cycle along with the phases of excitement, plateau, orgasm-like culmination, and reflection. The phenomenological features of the psychological state induced by MDMA, in turn, show some similarities with features of the post-orgasmic state. In addition, MDMA also induces a prominent increase of prolactin plasma levels with a similar time kinetic compared to the post-orgasmic prolactin increase . More reFrom the point of view of evolutionary psychology, human sexual response with orgasmic culmination is understood as a powerful stimulus that through positive reinforcement may increase the chances that the copulation will occur again with the same partner. The effect of orgasm on the development and shaping of partner preferences may involve catalysis of the neurochemical mechanisms of bonding . Partnerpharmacotransference’ and ‘pharmacocountertransference’ regarding both participants of the MDMA-AT process, i.e., patient and psychotherapist [At the current stage of research on entactogens, we cannot rule out that these substances affect changes in the perception of other people’s behavior as intimate behavior or modify the subject’s behavior into sexually motivated behavior. Therefore, during the further development of the psychotherapeutic methods based on entactogens, it is worth considering the possible risk of inducing eroticized ‘herapist , 70. At Based on naturalistic reports of MDMA-related physiological effects, some aspects of MDMA application experience could be interpreted as related to intimacy or sexuality by sensitive or ‘hyper-sensitive’ patients.High sensitivity to the application of entactogens may apply in particular to women who did not have former contact with MDMA. In the study of Liechti et al. concerning 74 subjects  with no prior contact with MDMA, the psychoactive effects of MDMA (75–150 mg) were more intense in women than in men. In women, MDMA-induced perceptual changes, thought disturbances, and fear of loss of body control were more frequent and intense .Therefore, the aspects related to the sexual dimorphism of the response to entactogens and the psychosexual physiology that accompanies their application should be taken into account in further work on the development of MDMA-AP protocols.Amid the contemporary resurgence of psychedelics as potential medicinal tools for addressing various conditions, the narrative surrounding MDMA has transformed. It has shifted from being perceived as a perilous street drug to a groundbreaking therapy in the realm of mental health. Nevertheless, the tale of MDMA remains somewhat incomplete, often framed within a binary discourse that pits its recreational misuse against its psychotherapeutic and medical applications . DespiteAs presented in Table Controlled laboratory studies, employing well-defined psychological constructs, play a pivotal role in unraveling how these substances yield their therapeutic benefits. However, it is crucial to acknowledge that there exist significant methodological disparities between clinical studies aimed at investigating therapeutic outcomes and laboratory studies designed to probe the underlying processes that may account for these therapeutic effects .In this mini-review, we have tried to examine the basic assumptions concerning the story of the therapeutic use of MDMA, the circumstances of its popularization as a street drug, and its removal from legal therapeutic methods at the stage of the early development of psychedelic-assisted psychotherapy. We have also outlined the challenges faced by clinicians who want to continue working on the development of MDMA protocols, both in individual in group settings.We have revealed that at the current stage of the development of studies on MDMA, there are no planned studies listed in the International Register of Clinical Trials that would be specifically dedicated to exploring the sexual effects of MDMA.Based on naturalistic reports of MDMA-related physiological effects, many aspects of clinical MDMA application need better understanding and in-depth research in controlled settings.Understanding human sexual behavior requires continued research and a balanced approach to the simplicity of the definitions of sexual response with normal and abnormal arousal, desire, performance, and orgasm with the array of exceptions to those definitions that characterize sexual function and dysfunction in real people . AccordiWhen designing research into the social-emotional effects of entactogens, the philosophical underpinnings of researching human sexuality and the complicated history of these substances doubly complicate the process of conducting these studies. The foundational assumptions surrounding the narrative of MDMA’s therapeutic usage, its journey from being a street drug to its exclusion from legal therapeutic practices, have hindered the evolution of psychedelic-assisted psychotherapy methods in their early stages. On the contrary, current efforts to employ MDMA within clinical contexts for the treatment of post-traumatic stress disorder and to expand its potential applications to other psychiatric conditions have made significant progress , 75. NevMany clinical trials involving new psychiatric drugs utilize the Arizona Sexual Experience Scale (ASEX) to evaluate sexual function . This fiThe challenges of translating findings from recreational and street drug use to clinical settings are demanding but essential. This calls for a blend of rigorous laboratory and clinical research that bridges the scientific methodology with the insights derived from ‘street discoveries’ regarding the effects of entactogens on human sexuality. On the flip side, this unique opportunity for further in-depth research in a scientific setting on a substance previously used extensively for recreational purposes and studied in naturalistic contexts should not be missed.Neglecting topics related to the assessment of the effects of entactogens on intimate relationships and sexuality in planned or future clinical research on entactogens might have unforeseen consequences for patients participating in entactogen-assisted therapy protocols. One of the risks highlighted in this review pertains to the potential development of ‘pharmacotransference,’ a topic not yet explored in the scientific literature within this context. Conducting randomized trials that incorporate entactogens with a substance-based intervention augmented by psychotherapeutic intervention demands meticulous attention during study design and result interpretation. The widespread adoption of psychotherapeutic methods enhanced with entactogens for specific psychiatric disorders necessitates extensive research into the psychophysiological and sexual effects of these substances, drawing insights from studies conducted on healthy volunteers.


Acute abdominal pain in pregnant women may complicate the diagnostic process of acute abdominal pain because of anatomical and physiological changes and limitations of computed tomography examinations related to radiation exposure. Here, we present the case of a 35-year-old female in her 10th week of pregnancy who was seen in the emergency department with unilateral abdominal pain and gross hematuria. Ultrasound detected only hydronephrosis and failed to identify ureteral stones, but magnetic resonance imaging revealed a diagnosis of idiopathic renal hemorrhage and intraductal ureteral hematoma, not ureteral stones. Although magnetic resonance imaging for pregnant women has the disadvantages of prolonged scan time and difficulty in image interpretation, no harm or complications to the mother or fetus have been reported. Magnetic resonance imaging may be considered in assessing acute abdominal pain in pregnant women, especially when the diagnosis is uncertain, based on shared decision-making with the patient and assessing the clinical situation and availability. The approach to investigating acute abdominal pain during pregnancy is essentially the same as that used for the non-pregnant approach. Although acute abdominal and pelvic pain may be more common during pregnancy, several challenges to diagnosis arise because of pregnancy, such as pregnancy-related anatomical and physiological changes, obstetric complications, and fetus-related conditions Ureteral stones are the most common non-gynecologic cause of abdominal pain among pregnant women Herein, we describe a suspected ureteral stone as the cause of acute right lower abdominal pain in a pregnant woman. Ultrasound examination revealed hydronephrosis. However, because of the difficulty in differentiating between ureteral stone and physiologic causes of hydronephrosis, we proceeded with MRI without contrast, which led to a timely diagnosis of idiopathic renal hemorrhage, a rare condition of occult hematuria. Our case demonstrates the usefulness of MRI for diagnosing acute abdominal pain in pregnant women.The patient was a 35-year-old woman with a history of 2 miscarriages. At the time of consultation, the patient was in her 10th week of pregnancy through artificial insemination. She was taking 100 mg of aspirin per day. She presented to the emergency department at night with a chief complaint of gross hematuria and right lower abdominal pain, which had developed 2 days prior. Physical examination revealed positive tenderness of the right lower abdomen and costovertebral angle (CVA) tenderness on tapping. Abdominal ultrasound showed hydronephrosis in the right kidney but no visible stone lesions in the pyelonephritic transition zone. Information was provided to the patient and family regarding the high possibility of a ureteral calculus, which could not be confirmed via ultrasound. The physician presented the patient and family with recent evidence on the safety of MRI for pregnant women and the usefulness of MRI for abdominal pain disease, including ureteral calculi, without risk of radiation exposure. Through shared decision-making, we proceeded with MRI without contrast, aligning with the patient's desire for a diagnostic examination.MRI showed hydronephrosis of the right kidney and a 4 cm lesion with low signal on T1- and T2-weighted images  and high signal on diffusion-weighted images in the lesion in the renal pelvic-ureteral junction . SymptomFrom MRI images and radiology reports and the patient's clinical symptoms, a diagnosis of idiopathic renal hemorrhage and suspected intra-ureteral hematoma was made by the urologist, and the patient was followed up on an outpatient basis. Aspirin was discontinued at the time of the first follow-up. The patient's symptoms improved, with resolution of the occult urine blood within 4 weeks and negative urine cytology. There was no recurrence of hematuria.In this case, we described our use of MRI for a close abdominal examination of a woman at 10 weeks of pregnancy. MRI was effective for differentiating idiopathic renal hemorrhage, a rare condition, from ureteral stones. Idiopathic renal hemorrhage, also known as "essential hematuria" or "chronic unilateral hematuria," is characterized by intermittent or persistent gross unilateral hematuria from the upper urinary tract The most frequent cause of idiopathic renal hemorrhage is a hemangioma or microvascular rupture ,8. HematIn summary, although the use of MRI in diagnosing acute abdominal pain in pregnant women is still not widespread, our case demonstrates the usefulness of MRI for the timely diagnosis of acute abdominal pain, even for the rare condition of idiopathic renal hemorrhage. Further evidence through case reports and research is warranted to validate this clinical use of MRI. Education regarding the appropriate use of MRI will also need to be considered.Our institution does not require ethics approval for reporting individual cases.Written informed consent was obtained from the patient for the use of her anonymized clinical information in the publication of this case report.


Teaching Point: Spontaneous rupture of the anterior tibial tendon at the ankle joint may mimic a tumor. A 75-year-old man presented with spontaneous soft tissue swelling at the left ankle joint anteriorly. Longitudinal sonogram of the tibialis anterior tendon (TAT) of the left ankle joint showed a retracted, irregular, hypoechoic, and swollen proximal part of TAT and pre-existing tendinopathy. There was focal discontinuity of the TAT between superior and inferior retinaculum .Magnetic resonance imaging (MRI) confirmed a full-thickness tear of the TAT with slight retraction of the tendon on sagittal fat-suppressed (FS) T2-weighted Image (WI) . Axial FTAT courses at the medial compartments of the superior and inferior retinacula. It inserts at the medial cuneiform bone and the base of the first metatarsal bone. Dorsiflexion of the foot is its primary function. Diagnosis of TAT rupture should be suspected clinically if a triad of a ‘pseudotumour’ of a ruptured tendon, loss of tendon contour, and reduced dorsiflexion is present .Spontaneous rupture occurs predominantly in the elderly with pre-existing tendinopathy. The tear can go clinically unrecognized because of preserved active dorsiflexion of the foot – although significantly weakened – due to residual integrity of the digitorum longus and hallucis longus tendons.Patients may present with a focal soft tissue swelling above the anterior aspect of the ankle joint, because of tendon retraction. Although careful comparative clinical examination may suggest the diagnosis, by revealing a tendon gap, imaging is often required to confirm the diagnosis of tendon rupture and to exclude the diagnosis of a soft tissue tumor.Ultrasound shows focal tendon thickening and heterogeneity, with loss of the normal fibrillar pattern above the level of the tendon tear and absence of the tendon between the superior and inferior extensor retinaculum. Power doppler may show hypervascularity. Proximal tendon thickening with increased signal intensity on T2-WI, and tendon discontinuity at the level of the tibiotalar joint are the diagnostic imaging features on MRI.Treatment is usually conservative in elderly patients with extensive comorbidities. The use of an ankle-foot orthosis, bracing, and shoe adaptations are recommended.In conclusion, although diagnosis of TAT rupture depends on the clinical triad, elderly patients with spontaneous TAT tears may only present with a soft tissue swelling at the ankle joint, which may be misinterpreted as a soft tissue tumor. Imaging is pivotal to define the pseudotumoral nature of this lesion.


A peripheral ossifying fibroma (POF) is a benign, localized lesion that originates from the periosteum or periodontal ligament after traumatic or calculus irritation. The lesions typically manifest in females throughout their second and third decades of life. The diagnosis of a POF is challenging from both clinical and histological standpoints, as it exhibits overlapping features with numerous other clinical entities. This case describes an unusual occurrence of POFs in the anterior maxilla of a 66-year-old female patient who is edentulous at this jaw, but the last two teeth of the lower jaw affect it. The radiographic evaluation revealed no discernible alterations within the bone structure. The diagnosis of POFs was determined through histological investigation. The microscopic examination revealed scattered immature osteoid dystrophic calcified depositions in deep positions, whereas the overlying stratified squamous epithelium manifested frictional keratosis (hyperplasia). The stromal fibroblasts of the collagenous stroma displayed ovoid, normochromatic nuclei, without atypia. Interestingly, the particular importance of this POF case indicates the possibility of an atypical formation in terms of age and location suggesting the role of local chronic irritation as the most critical parameter. Regardless of the initial causative factor, which may be the remnants of the periodontal ligament, the periosteum, or the gingival fibroblasts, ultimately mechanical trauma constitutes the crucial prerequisite so that reactive hyperplasias may be induced. A peripheral ossifying fibroma (POF) is a non-neoplastic gingival growth that is considered to be of reactive origin. The POF accounts for 2% of all oral lesions . The iniA 66-year-old female patient was referred to the Department of Dentoalveolar Surgery, Surgical Implantology and Radiology, School of Dentistry, Aristotle University of Thessaloniki, Greece, complaining about the presence of a tumor in the upper jaw, opposite of the last two remaining teeth in the mandible. Before the examination, the patient provided written informed consent. This form was approved by the School of Dentistry, Aristotle University of Thessaloniki and was in accordance with the Helsinki Declaration for research and patient’s ethics. Subsequently, the patient was examined thoroughly. The clinical examination revealed a pedunculated tumor, with hard, slightly elastic in palpation and a slightly whitish discoloration of the surface Figure , exactlyThe orthopantomography (OPG) examination did not reveal any involvement of the maxillary bone Figure .The surgical excisional biopsy took place in the Department of Dentoalveolar Surgery, Surgical Implantology and Radiology completed by the use of sutures. The stepwise surgical procedure is displayed in Figure The tissue specimen was preserved in formaldehyde and submitted to histopathological examination in the Department of Oral Medicine/Pathology of the same Institution. The microscopic examination revealed scattered immature osteoid dystrophic calcified depositions in deep positions, whereas the overlying stratified squamous epithelium manifested frictional keratosis (hyperplasia). The stromal fibroblasts of the collagenous stroma displayed ovoid, normochromatic nuclei, without atypia Figure .The clinical and histological findings settled the diagnosis of POF. POF development is associated with the periodontal ligament or periosteum, and its location is limited to the soft tissues positioned above the alveolar crest . In our In summary, it is a challenge in clinical practice to distinguish between various reactive gingival lesions, especially during the early phases. Irrespective of the specific surgical approach utilized, it is imperative to address the underlying causes and conduct histological analysis of the tissue to validate the diagnosis. Regardless of the initial causative factor, which may be the remnants of the periodontal ligament or the periosteum or the gingival fibroblasts, ultimately mechanical trauma constitutes the crucial prerequisite so that reactive hyperplasias may be induced.


Editorial on the Research TopicInnovative approaches in drug discovery and developmentIn December 2022, the US House of Representatives has passed the FDA Modernization Act of 2022, which eliminates the animal-testing mandate for drug development and replaces this strategy with 21st-century methods grounded on human biology. This historical policy development reboots our drug development paradigm and drives us into a new era of drug discovery. The transition from bench to bedside has been long, and the number of drug withdrawals has increased to historic highs. Therefore, large investments are being made in translational research to find innovative tools that accelerate the drug discovery processes. During the last few years, we have seen many technological advances across the pharmaceutical industry that show tremendous potential to push the frontiers of pharmaceutical research to new vistas. In particular, the fusion of many engineering disciplines into the medical and pharmaceutical industries allows using the engineering principles to solve problems in biology and medicine ushering in a new era of technological breakthroughs for sensing and manipulating molecules, cells, tissues, and organs.This Research Topic includes four papers that address the current innovation at the frontiers of pharmaceutical research and development.Achieving enhanced drug delivery, efficacy and reduced toxicity effects of existing and new drug entities are crucial objectives in the pharmaceutical and medical device industries. The current trend in cardiovascular disease management has evolved significantly due to the improvement in both surgical and percutaneous revascularization techniques, which became the preferred therapeutic strategy in many clinical subgroups. To date, animal studies remain to play a vital role in validating the safety and efficacy of medical devices and biomaterials during the bench-to-clinic translation stage. However, the results obtained from these studies can be sometimes inconsistent and may fail in human studies.in vitro or ex vivo models to accelerate the translation to the clinical stage. For instance, the evaluation of non-stent cardiovascular drug delivery systems is lacking ex vivo models capable of testing pharmacokinetic performance in humans. Cooper et al. developed an ex vivo system to quantify the acute drug transfer of catheter-based drug delivery devices  into explanted carotid arteries. To validate the ex vivo measurements, parallel experiments were also performed in a pig model. Overall, the results demonstrated no significant differences between ex vivo and in vivo outcomes for the two tested drug delivery devices. This system would reduce the time and expense associated with in vivo testing of vascular devices, particularly in measuring and quantifying vessel drug retention.Therefore, there is a real need for human-based ex vivo and in vitro models, computer-aided drug design (CADD) and in silico methodologies are increasingly used in various stages of drug discovery and development which significantly reduce the costs and time. Verma et al. used CADD to investigate the potential antifungal effect of the 1, 2, 4-triazine and its derivatives and if it can protect humans from infection with Candida albicans by employing the molecular docking and molecular dynamics simulation and aiming at inhibition of Candida albicans CYP51. It was found that each drug has a high binding affinity for CYP51 proteins and is involved in non-covalent interactions and hydrogen bonds with their active residues and surrounding allosteric residues which establish a strong candidature of 1, 2, 4-triazine and its derivatives as a potential drug target against fungal infection.Besides in vitro tools for solving key issues in drug discovery and bridging the gap between in vivo and in vitro studies. These humanized microphysiological models have shown rapid progress during the last few years as indispensable tools for recapitulating human physiological key-parameters, hence enabling the translation of the preclinical findings at the Pre-Investigational New Drug Application (Pre-IND) stage. In his opinion paper, Nahle provides a dozen reasons why organ-on-a-chip systems are better at modeling human physiology, drug-organ interaction and diseases. The paper highlights the key-findings of the recent study by Ewart et al. (Organ-on-a-chip has emerged as a promising technology to provide reliable t et al.  and commKhalil and Onyango discusses the effect of patent expiry on the performance of innovator multinational pharmaceutical companies in a low-middle income country, such as Kenya. The study focuses on the effect of generic products manufacturing and competitive market pressures, price changes, and changes in sales volumes and profitability of innovator multinational pharmaceutical companies after patent expiry. Qualitative and quantitative techniques were used to collect relevant data via survey questionnaires and in-depth interviews with regional managers, general managers, and directors of eight participating companies. The results of the study depicted a significant effect of patent expiry on the generic production and subsequent decline in the performance of multinational innovator companies in the pharmaceutical industry. This study also recommends the multinational innovator companies operating in low-income countries to develop strategic policies that encourage collaborative manufacturing with generic companies to share revenues.Finally, the study by We will see more advanced technologies infuse into the lab practice over the next few years and more innovations will continue to emerge, and it is exciting to think how drug discovery will develop in the near future.


The present study aims to report the first case of chronic neck sinus post-thyroidectomy caused by oxidized regenerated cellulose (ORC). A 55-year-old female patient underwent a total thyroidectomy operation. Three months after the surgery, the patient presented with persistent purulent discharge and sinus at the site of the drain. A CT scan of the neck showed a fistula tract, deep-neck fluid collection, and bilateral paratracheal high-density lesions at the thyroid bed, suggesting infected foreign bodies. The patient underwent surgery, during which the mesh of the ORC was found nonresorbed at the paratracheal space. The treatment involved neck exploration with the removal of all retained material and excision of the sinus tract. The patient had a favorable outcome following the surgical excision of the sinus tract and the removal of retained hemostatic materials. Further research is needed to explore the risk factors and preventive measures for neck sinus formation to enhance the safety and outcomes of thyroidectomy. Thyroidectomy is a common surgical procedure, and it is associated with potential complications such as bleeding, infection, hypocalcemia, and recurrent laryngeal nerve injury . ChronicA 55-year-old female patient was admitted to Saint George Hospital and diagnosed with toxic multinodular goiter and Graves' disease. The patient underwent total thyroidectomy surgery. After the surgery, a collection was noted at the drain site one week postoperatively Figure . The colFurther review of the operative report revealed that ORC had been used for hemostasis on both sides at the conclusion of the thyroidectomy surgery. Given the possibility of retained hemostatic material causing chronic inflammation and infection, the decision was made to explore the neck for a persistent non-healed fistula. The patient was taken to the operating room, where the fistula opening was probed, and methylene blue was injected to identify the tract and the feeding collection Figure . The preChronic sinus tract formation in the neck following thyroid surgery has been reported in the literature ,8. SeverMaintaining a sterile environment during surgery is critical to minimizing the risk of infection and other complications. To achieve this, healthcare providers assess the sterility of equipment used in the initial surgery (including the drain and ORC), remain vigilant to detect and address breaks in sterility during the procedure, and administer preoperative antibiotics. These important steps help optimize patient outcomes by reducing the likelihood of postoperative complications. This finding is consistent with previous reports of retained material causing complications following surgery and underscores the need for healthcare providers to monitor patients carefully for signs of infection and other complications ,12. WhilThis is the first report of the occurrence of chronic sinus formation secondary to the use of ORC during thyroid surgery. This highlights the need for both surgeons and patients to be aware of this possible complication. While infection and nonabsorbable sutures have commonly been implicated as causative factors, our presented case suggests that nonresorbable ORC mesh used as a hemostatic agent during surgery may contribute to chronic sinus formation. Effective management of this condition requires a comprehensive neck exploration, meticulous removal of all retained material, and excision of the sinus tract. These findings significantly advance our understanding of the potential mechanisms underlying neck sinus formation post-thyroidectomy and highlight the importance of vigilant monitoring and timely intervention in managing this infrequent yet significant complication. Further research is needed to explore the risk factors and preventive measures for neck sinus formation, ultimately enhancing the safety and outcomes of thyroidectomy procedures.