Identifying key anatomical features of the hypospadiac penis is crucial to better understanding this pathology and guiding surgical reconstruction plans, thereby achieving superior functional and cosmetic outcomes.To Assess the feasibility and precision of penile ultrasonography (PUG) in determining key structural features for hypospadias cases .Twenty-five children with hypospadias were assessed using PUG prior to surgical repair and then again under general anesthesia. Preoperative images were acquired using ultrasonography in sagittal and transverse planes, then later compared with anatomical findings obtained during surgical repair of urethral hypoplasia.Median patient age was 1.2 years (range 0.5–12) and hypospadias types included coronal 17/25 (68%), mid-penile 5/25 (20%), and proximal penile 3/25 (12%). Distinct layers of the corpus spongiosa and mucosal layer, Buck fascia, tunica albuginea, glans, corpora cavernosa, and penile skin were delineated so that their spatial inter-relationship could be assessed. Distal extent of the spongiosal component of the urethral plate was determined by the mid-glans B-B line. The extent of urethral hypoplasia identified by PUG was relatively similar to measurements obtained intraoperatively.PUG is a feasible and accurate approach to evaluating penile configuration in children with hypospadias. Distal extent of the spongiosal component of the urethral plate was accurately determined, hence PUG could potentially be used to improve surgical planning and appraisal of current repair procedures. Hypospadias is a common malformation of the penis in which abortive development of the ventral axis and corpus spongiosum leads to a range of short- and long-term effects –3. DelinSeveral tools have been used to compare the anatomy of hypospadias and normal phallus, including histological staining , elastogThe aim of this study was to determine the exact configuration of the spongiosa in cases of hypospadias. Distal extent of the spongiosa beneath the urethral plate was also assessed to better understand the healing process following TIP urethroplasty.Consecutive hypospadias patients less than 18 years old were included in the study and evaluated by PUG by the surgeon to determine spatial relationships between the corpora cavernosa (CC), corpora spongiosa (CS), hypospadias meatus, and glans penis (GP). These measurements were followed by intraoperative reporting of the extent of urethral hypoplasia , and urethral defect [distance from spongiosal bifurcation to the level of the imaginary line between the two glanular knobs (B-B line)], using metal surgical calipers with no magnification, which were then compared with PUG findings . EthicalDegree of penile curvature was measured under artificial erection using a mobile application (Angle Meter 360 by ALEXEY KOZLOV) using a standardized approach with the following definitions; point Y at the mid-axis of the penile shaft at the level of maximum curvature, point X at the mid-axis at the level of the tip of the glans, and point Z at the mid-axis at the level of the pubic bone . PatientUltrasonographic examination was performed using ultrasound linear probe (Phillips IU 24 SWE–High Frequency Linear 6–12 MHz) under general anesthesia with patients in supine position and flaccid penis in the pre-pubic area immediately prior to commencing surgical repair. PUG was performed using acoustic gel and direct skin contact along the ventral surface of the penis to allow two transverse captures at the levels of the peno-scrotal junction and midway between the hypospadiac meatus and the B-B line. This was followed by capturing a longitudinal view with two metal landmarks defining the B-B level and the hypospadiac meatus (guided by their acoustic shadows). The sagittal view of the PUG is over the midline of the ventral aspect of the penile shaft and glans with a window of 3–25 mm in range in a sagittal view. The transverse view of the PUG is done with a depth window 3–25 mm.Objective quantification of urethral plate quality was performed using the plate objective scoring tool (POST) , 13. Brip-values presented were two-tailed, and p-values < 0.05 was considered as statistically significant. All Statistical analyses performed using statistical packages SPSS version 27.0 .Descriptive statistics were used to summarize and determine the sample characteristics and distribution of various considered parameters related to ultrasonographic evaluation of the hypospadias penis in children. The normally distributed data and results were reported with mean and standard deviation (SD), whereas median and interquartile range (IQR) were used in non-normal data distribution. Categorical data were summarized using frequencies and percentages. General and penile anthropometric parameters values of the studied patients measured across three independent groups  were compared using Pearson Chi-square or Yates corrected Chi-Square tests as appropriate  and one-way analysis of variance (ANOVA) or Kruskal–Wallis test as appropriate (for quantitative outcome measures). All statistical p < 0.0001, 0.003, respectively). While determination of the extent of urethral hypoplasia was not precise by physical examination, both intraoperative and PUG assessment were relatively more similar.Between January 2022 and May 2022, a total of 25 children with coronal , mid-penile , or proximal hypospadias  were included in this study. General characteristics of the study cohort are summarized in The CC is a relatively hypoechoic cylindrical structure  lined byIn this study we show that PUG is a feasible and useful tool that enables high precision evaluation of hypospadias in children. PUG successfully determined the different structures within the hypospadias penis as well as the two-dimensional spatial relationships between them. This methodological study of feasibility and sensitivity of ultrasonography of the penis in cases of hypospadias in children has several clinical implications. It can facilitate the preoperative risk stratification based on defining the exact of the urethral hypoplasia  and thusTubularised incised-plate urethroplasty was popularized by Snodgrass in 1994, since this technique made tubularisation of shallow and narrow plates more amenable , althougvia formation of a neourethra that is wholly lined with epithelium. To achieve this, grafting of the dorsal incised (GTIP) area using the inner prepuce has been described by several surgeons (Urethral wound healing is perceived to be a multifaceted and active process that includes multiple different cell types at each stage . The inisurgeons –28. HoweInitial experiences with ultrasound evaluation of the urethra in the late 1980s were described separately by McAninch et al. . CurrentThe relatively small number of patients examined in this study could be considered a limitation, as was the involvement of a single measuring surgeon, which prevents us from assessing inter-observer variability. Although sequential performance of eye, ultrasonographic and intraoperative assessment could potentially be considered adequate for such feasibility study, no formal blinding scheme was conducted. Future studies that consider larger numbers of patients and evaluating surgeons interobserver variability and reproducibility will therefore be required to enforce these findings.We showed that PUG is a feasible and accurate technique to evaluating penile configuration in children with hypospadias. Distal extent of the spongiosal component of the urethral plate was precisely defined, hence PUG could potentially be used to improve surgical planning and appraisal of current repair procedures.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Institutional Review Board, Project # 1837587, Sidra Medicine, Doha, Qatar. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.TA conceptualized the idea, collected the data, and analyzed and wrote the manuscript.The author declares 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.


Polarization-dependent scattering anisotropy of cylindrical nanowires has numerous potential applications in, for example, nanoantennas, photothermal therapy, thermophotovoltaics, catalysis, sensing, optical filters and switches. In all these applications, temperature-dependent material properties play an important role and often adversely impact performance depending on the dominance of either radiative or dissipative damping. Here, we employ numerical modeling based on Mie scattering theory to investigate and compare the temperature and polarization-dependent optical anisotropy of metallic  nanowires with indirect  and direct  bandgap semiconducting nanowires. Results indicate that plasmonic scattering resonances in semiconductors, within the absorption band, deteriorate with an increase in temperature whereas those occurring away from the absorption band strengthen as a result of the increase in phononic contribution. Indirect-bandgap thin ( Early investigations in plasmonics focused on the so-called ’epsilon-negative’ metals because of their strong plasmonic response driven by the large negative real part of their dielectric permittivity9. However, excessive dissipation in metallic nanostructures, especially in the near-infrared (NIR) regime, has led to a quest for semiconductor materials with low losses that act as dielectrics in the NIR regime away from their absorption band edge12. Studies on Mie resonances in noble metal and dielectric nanowires have been reported previously15, but thus far there have been no systematic studies on the polarization dependence of Mie resonances in metallic or semiconductor nanowires that would also account for their temperature-dependent dielectric permittivities. Furthermore, most attention has been on the generation of dark anapole modes using cylindrical metamaterials characterized by near-zero scattering efficiencies and high absorption efficiencies resulting in significantly enhanced near-field energy16. Anapole modes have been shown to arise from electrodynamic out-of-phase charge-current distributions that do not radiate or interact with external fields as a result of destructive interference of radiation produced by spatially overlapping and co-excited electric, toroidal or magnetic modes that suppresses scattering in the far field18. However, the temperature and polarization dependence of anapole modes in single cylindrical nanowires has not been studied thus far.Polarization-dependent scattering anisotropy offers an important tool, among others, to control incident radiation on the mesoscale using sub-wavelength nano- or microstructures for applications in directional nanoantennasHere, we present results for temperature and polarization-dependent Mie resonances in metallic (Au), and indirect (Si) and direct (GaAs) bandgap semiconductor nanowires. We then identify anapole modes in the semiconductor nanowires and study their temperature and polarization dependence. In the discussion of the results, we first analyze polarization and temperature-dependent scattering and absorption efficiencies. This is followed by a discussion of the results in the limit of thin wires, polarization and temperature dependence of anapole modes, and, a comparison of radiative to dissipative damping as a function of temperature and polarization. The last section, Theory and Methods, briefly outlines the analytic solution to the polarization-dependent scattering from long nanowires and the computation of the temperature-dependent dielectric permittivites for Au, Si and GaAs that were employed to obtain the results presented here.Briefly, our results indicate that plasmonic resonances degrade at elevated temperatures in both Au and semiconductor nanowires (within the absorption band edge) regardless of the polarization of the incident radiation. The indirect bandgap thin Si nanowires present lower absorption efficiencies for both the perpendicular (TE) and parallel (TM) polarizations at short wavelengths in conjunction with high scattering efficiencies for the TM mode making them suitable as highly efficient scatterers. Results also point to the existence of higher-order anapole states in both Si and GaAs nanowires. The anapole modes observed for the TM polarization exhibit a large redshift with increase in temperature while those for the TE polarization are observed to be resilient to temperature changes.We first examine and compare the polarization and temperature dependence of the scattering and absorption efficiencies for the Au, Si and GaAs cylindrical nanowires as a function of their radii.Figures mentclass2pt{minimFano resonances arising from all three lower order modes, against a broad background of zeroth and first-order resonances, are observed in the case of the thicker  Au nanowires present a largely featureless broad band absorption at the longer wavelengths accompanied by broad resonances at shorter wavelengths , the ratio ure Fig. . This ismentclass2pt{minimFor the TM polarization of the incident radiation in Au nanowires the broad scattering efficiencies exhibit maxima at the edges of the wavelength range under consideration Figs. a–c. The entclass1pt{minimay-scale for the ratio For Si nanowires, the The thin , and indirect (Si) and direct (GaAs) bandgap semiconductor nanowires. Similar to nanoparticles23. Here, in our results for the thin Si nanowires, it is just the zeroth order TM mode Scattering resonances in the case of the TE polarization of the incident EM radiation for the nanowires occur at shorter wavelengths as a consequence of confinement along the radial direction of the cylindrical nanowires. Plasmonic resonances that occur within the absorption-band edge of the semiconductor nanowires at shorter wavelengths and those for the Au nanowires are observed to deteriorate at elevated temperatures regardless of the polarization of the incident EM wave. In contrast the phononic contribution to the dielectric resonances in semiconductor nanowires that occur away from the absorption band edge, however, serves to strengthen them at elevated temperatures. This augurs well for applications in thermophotovoltaics and high temperature insulators wherein the broadband reflectances shall actually increase with rising temperatures and result in enhanced performance at elevated temperatures. The thin  nanowire. Additionally, we also report high scattering efficiencies in conjunction with low absorption for a single thin Si nanowire system with just the zeroth order TM mode in contrast to the use of more complex multilayered cylindrical geometries needed to engineer coincident multimode scattering resonances23.To summarize, we have shown the existence of temperature resilient anapole modes for the perpendicular polarization of the incident radiation in the 19. The analytical solution is derived by solving the wave equation for the electric and magnetic fields of a plane electromagnetic wave incident on an infinitely long cylindrical scatterer. The infinite cylindrical scatterer and the non-absorbing surrounding medium  model to compute the dielectric permittivity for Au in the wavelength range 25. Here, T and b depends on the normalized temperature coefficients 30 and Green25. Kramers-Kronig analysis31 is then employed to calculate optical constants using measured reflectance E is a dimensionless quantity. The refractive index  in Eq.  depend osing Eq. .Supplementary Information.


Immunotherapy is an effective cancer treatment that activates the immune system to target and destroy cancer cells. The emerging use of a form of immunotherapy referred to as immune checkpoint inhibitors is often limited by the development of immune-related adverse events. This often leads to the discontinuation of treatment and limits good outcomes. In this review, we summarize the spectrum of immune-related adverse events of the gastrointestinal system with a focus on their management and emerging therapies.Immune checkpoint inhibitors (ICI) are a form of immunotherapy that have revolutionized the treatment of a number of cancers. Specifically, they are antibodies targeted against established and emerging immune checkpoints, such as cytotoxic T-cell antigen 4 (CTLA4), programmed cell death ligand 1 (PD-L1) and programmed cell death 1 protein (PD-1) on CD8-positive T cells, which promote the destruction of tumor cells. While the immune checkpoint inhibitors are very effective in the treatment of a number of cancers, their use is limited by serious and in some cases life-threatening immune-related adverse events. While these involve many organs, one of the most prevalent serious adverse events is immune checkpoint inhibitor colitis, occurring in a significant proportion of patients treated with this therapy. In this review, we aim to broadly describe the immune-related adverse events known to occur within the gastrointestinal system and the potential role played by the intestinal microbiome. The development and subsequent utilization of immune checkpoint inhibitors (ICIs) have revolutionized the management of a growing number of malignancies, including metastatic melanoma, renal cell carcinoma, non-small cell lung cancer and hepatocellular carcinoma ,2,3,4. AThe immunological events that result in the development of irAEs following the commencement of immunotherapy have for the most part remained elusive. Recent and emerging evidence appears to have uncovered the origins of the immunological ‘big bang’ of the tissue resident memory (Trm) pool of the GI mucosa . The TrmThe most common irAE of the gastrointestinal system is ICI colitis, with a recent systematic review highlighting an incidence of up to 40% ,11. The The main hallmark and presenting feature of ICI colitis is diarrhea . Other aThe management is generally guided by the severity of symptoms according to the common terminology criteria for adverse events (CTCAE)  12]. Pa. Pa12]. For patients who develop grade 2 or greater diarrhea or colitis, management involves the commencement of corticosteroid therapy and ceasing ICI therapy. Prior to the commencement of immunosuppressive therapy, it is recommended that other causes for diarrhea are excluded, such as infection, pancreatic insufficiency and coeliac disease. It has been shown that the severity of symptoms does not correlate well with either the severity of colitis or response to treatment . The comThe microbiota is a complex ecological community of commensal, symbiotic and pathogenic micro-organisms found within the gastrointestinal tract. They are thought to play an important role in both maintaining health and increasing the risk of development of certain diseases, such as clostridium difficile colitis and inflammatory bowel disease .faecalibacterium and firmicutes were more likely to develop colitis through upregulation of dendritic cells (DC) and antigen-presenting cells (APC), promoting the proliferation of T cells that enhance the blocking effect of ICI [Ruminococcaceae, Enterococcus faecium, Klebsiella pneumoniae, Veillonellaparvula and Akkermansia muciniphilia have been shown to increase response to ICI therapy via multiple mechanisms of immune modulation across a number of studies [Early observations that treatment with ICI often resulted in intestinal inflammation through dysregulation of mucosal immunity prompted further research into the role of the microbiome . Subsequt of ICI . Bacterot of ICI . These rt of ICI . The prot of ICI . Other b studies . The ove studies ,26,27.Helicobacter Pylori (H. pylori) has established itself is one of the most common chronic infections of the stomach and likely achieves this status through the establishment of an immunosuppressive environment both locally and systemically. Recent studies have demonstrated the role H. pylori infection may play on the effectiveness of ICI therapy [H. pylori had better responses to ICI therapy in reducing tumor volumes following treatment compared with H. pylori-infected mice [H. pylori seropositivity was associated with reduced survival in cancer patients following treatment with ICI. As the first study to demonstrate the important role H. pylori infection may play in the effectiveness of ICI therapy, it raises the possibility that H. pylori serology or confirmation of histological diagnosis may play an important role in treatment planning and selection of therapies. It is possible that eradication of H. pylori therapy may influence treatment outcomes positively. The microbiome of the stomach may play a vital role in modulating the immune system that rivals the colonic bacterial population. therapy . Oster eted mice . AnalysiIt is not only the bacterial organisms themselves but the presence of various metabolites that may play a role in regulating the activation of T cells. Short-chain fatty acids (SCFAs) such as butyrate and propionate have been shown to induce proliferation and differentiation of T regulatory cells, leading to higher levels of CTLA-4 and potentially increasing sensitivity to ICI therapy ,31,32. TThe commencement of corticosteroid therapy should not be delayed while awaiting endoscopic assessment and is often commenced while awaiting other investigations such as stool culture to exclude infection in combination with antibiotic therapy . The AmeUp to a third of patients fail to respond to or have worsening symptoms of colitis after initiating corticosteroid therapy, with consideration given to early initiation of second-line immunosuppressive therapy . InflixiVedolizumab is a monoclonal antibody that binds to the GI-specific integrin α₄β₇, thereby reducing the trafficking of lymphocytes into the intestine. The largest study of the use of vedolizumab in ICI colitis demonstrated excellent response rates of 94.1% in steroid refractory patients receiving between 1–6 doses of vedolizumab at a dose of 300 mg .A small number of patients (15–19%) requiring biologic therapy will be non-responders . There iThe calcineurin inhibitors cyclosporin and tacrolimus inhibit T-cell activation by inhibiting the release of interleukin-2 and have proven effective in the management of inflammatory bowel disease, with cyclosporin demonstrating similar efficacy in anti-tumor necrosis factor therapy in patients with severe ulcerative colitis . In a reMycophenolate mofetil (MMF), which is the prodrug of mycophenolic acid, is a direct inhibitor of T and B lymphocytes. There is a single study demonstrating the use of concomitant MMF with corticosteroid therapy, with combination therapy proposed to shorten the recovery time of colitis and reduce the incidence of colitis flare following corticosteroid wean . DiarrheOther therapies have been described in case reports for the successful management of refractory ICI colitis, including tofacitinib and ustekinumab; however, there are no safety data in this cohort, and their use should be considered experimental and as a last resort in those wishing to avoid surgical management ,52,53.p < 0.001), with severe (grade 3 or 4) colitis occurring in as many as one in five patients. These rates are consistent with data from a recent systematic review and meta-analysis also reporting the development of colitis in 40% of patients with IBD exposed to immune checkpoint therapy [Inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn’s disease share similar clinical characteristics to ICI colitis. Patients with IBD can be at increased risk for the development of malignancies and may require therapy with checkpoint inhibitors; therefore, it is important to understand the unique and inherent risks posed to this patient cohort and the need to consider preventative strategies to the development of ICI colitis. In a multi-center retrospective study, Abu-Sbeih and colleagues analyzed the outcomes of 102 patients with IBD receiving ICI therapy . They re therapy . In the The safe recommencement of immunotherapy following the successful treatment and remission of ICI colitis is largely guided by retrospective studies. Abu-Sbeih et al. reported 167 patients who resumed immunotherapy following ICI colitis . A recurTreatment strategies aimed at the prevention of ICI recurrence following the recommencement of immunotherapy has been explored in small case series. It is suggested that infliximab used in combination with immunotherapy is safe and may promote successful steroid tapering and prevent the recurrence of ICI colitis . HoweverH. Pylori infection and the use of non-steroidal anti-inflammatory medications. Once a diagnosis is made the initial treatment of choice is a proton pump inhibitor (PPI), which has been shown to lead to the complete resolution of upper gastrointestinal symptoms in 88% of patients with esophagitis [H. pylori infection may play in the development of ICI gastritis and the potential benefit of eradication therapy.Gastritis and esophagitis caused by ICI therapy is rare, occurring in 3% of patients with upper gastrointestinal symptoms . The diaphagitis . In thosThere are scarce data on the management of PPI and steroid refractory upper gastrointestinal inflammation due to immune checkpoint inhibitors. The use of infliximab and vedolizumab has been described in cases of ICI gastritis refractory to corticosteroids with complete clinical and endoscopic remission of upper gastrointestinal inflammation .After commencing immunotherapy, the development of right upper quadrant pain with nausea, vomiting, diarrhea and fever should raise the suspicion of immune-mediated cholecystitis. Currently, there is no way of making a definitive diagnosis without histological confirmation, and hence the treatment of cholecystitis in patients on immunotherapy should follow the traditional management of non-immune-mediated cholecystitis. Management of cholecystitis in patients on immunotherapy has been described in a case series which includes the use of antibiotics, intravenous fluids, cholecystectomy and percutaneous cholecystostomy .The management of ICI-related cholecystitis with corticosteroids is associated with reduced survival, and their use is not recommended . ExpectaInjury to the pancreas has been noted to occur in up to 4% of patients being treated with immune checkpoint inhibitors . This maPatients should be monitored for and managed for the development of longer-term complications, including pseudocyst formation, chronic pancreatitis, diarrhea and diabetes .The development of diarrhea and abdominal pain following the commencement of ICI therapy should raise the suspicion of rare gastrointestinal irAEs in cases where colitis is excluded. Patients with positive coeliac serology (tTG-IgA) should be commenced on a gluten-free diet, which has been shown to improve symptoms and coeliac antibody titre . In patiImmune checkpoint inhibitor hepatitis should be suspected in patients on immunotherapy who present with abnormal liver function tests. There are no specific biomarkers available, and it remains a clinical diagnosis that requires exclusion of other causes of liver injury, including viral hepatitis, biliary obstruction, other drug-induced liver injury and hepatic metastases.The incidence of ICI hepatitis is reported to occur in 1–17% of patients, with rates as high as 25% when ipilimumab and nivolumab are used in combination . Most paThe degree of hepatotoxicity is graded according to the common terminology criteria for adverse events (CTCAE) on a scale of 1–5 , which iFor patients with grade 1 hepatitis, ICI therapy can be continued with close monitoring of liver enzymes with at least weekly blood tests. Corticosteroids should be commenced in patients who develop grade 2 hepatitis, with the suggested dose of 0.5–1mg/kg/day of oral prednisolone as first-line therapy. Immunotherapy should be withheld at the commencement of corticosteroid therapy with the option of recommencing therapy should the hepatitis improve to grade 1 or less.In patients with either grade 2 hepatitis who fail to improve with oral prednisolone therapy or in grade 3 or higher hepatitis, ICI therapy should be discontinued indefinitely, hospital admission should be planned for intravenous glucocorticoid therapy and the consideration of liver biopsy should be made on a case-by-case basis. Multiple pathologic subtypes have been described in ICI hepatitis, including panlobular lymphocytic hepatitis, cholangitis, bile duct injury and fibrin ring granulomas . In gradCurrently, most of the available evidence for managing irAEs of the GI system is derived from case studies, case series and retrospective data. There is a need to support and inform both current and future management guidelines with prospective studies. In many cases, these studies are currently underway, and the results are awaited.With the increasing use of ICI therapy, it is imperative that clinicians are able to promptly recognize the occurrence of irAEs of the GI system so that timely management can be implemented. Clinicians should be aware of the general management principles, including when to cease immunotherapy and taking the opportunity to recommence ICI therapy where it is safe to do so. The severity of colitis, which can rarely be fatal, and the use of immunosuppressive therapy must be balanced with the risks of underlying disease progression. A patient-centered approach supported by a multidisciplinary team is paramount to improving outcomes. The complexity of caring for patients with GI irAEs will necessitate the development of collaborative care teams that involves a coordinated approach between the oncologist, gastroenterologist and allied health clinicians to achieve the best outcomes in patient care.


Purpose: Report of a successful case of endovascular recanalization of an occluded superficial femoral artery (SFA) using Fiber Optic RealShape (FORS) technology. Case Report: A 79-year-old male was referred for evaluation of multiple ischemic pretibial ulcers of the right lower extremity. Computed tomography–angiography (CTA) imaging confirmed significant stenosis of the right common femoral artery (CFA) and an occlusion of the SFA from its origin to the Hunter’s canal. The patient was treated with a hybrid surgical procedure: an endarterectomy of the CFA and SFA origin was performed combined with an endovascular recanalization of the occluded SFA using FORS technology. During recanalization, the FORS guidewire slowly twisted subintimally around the occluded lumen of the SFA, maintaining the created corkscrew shape after pre-dilation with the percutaneous transluminal angioplasty (PTA) balloon and subsequent stenting. Conclusions: FORS technology can be successfully used during recanalization of an occluded SFA without the use of fluoroscopy. The corkscrew shape formed during recanalization in this case was retained during PTA balloon pre-dilation and stenting; this potentially improves hemodynamics and thereby reduces the risk of in-stent restenosis. However, expanding patient series and longer follow-up data are needed to increase the understanding of the feasibility and effectiveness of using FORS in the treatment of peripheral arterial occlusive disease. Exposure to fluoroscopy during endovascular procedures poses risks to both the patient and the treatment team ,2,3. In A 79-year-old male was referred for evaluation of multiple ischemic pretibial ulcers (W1I3fI1) of the right lower extremity (Rutherford stage 5 classification). The patient had a history of smoking, cerebrovascular disease, hypertension, renal insufficiency, and endovascular recanalization of the right common iliac (CIA) and left external iliac artery (EIA) combined with bilateral thromboendarterectomy (TEA) of the common femoral artery (CFA). The photoelectric plethysmography toe-arm index was 0.34 and duplex ultrasound showed patency of previously placed stents in the CIA and EIA, however a flow-limiting stenosis in the right CFA and occlusion of the SFA were observed. Computed tomography–angiography (CTA) imaging confirmed significant stenosis of the right CFA and occlusion of the SFA from its origin to the Hunter’s canal.2, and the fluoroscopy time (FT) was 1046 s.The treatment team decided to treat the abovementioned vascular lesions in a hybrid surgical procedure: an endarterectomy of the CFA and SFA origin combined with an endovascular recanalization of the occluded SFA using FORS technology. The patient provided informed consent for the procedure. The CFA was approached via a standard surgical approach and the atherosclerotic plaque was removed via open endarterectomy with venous patch closure. Subsequently, the venous patch was punctured and a 6F sheath was placed over a standard guidewire. Digital subtraction angiography (DSA) was performed and confirmed the SFA occlusion . FurtherAfter the procedure acetylsalicylic acid 80 mg daily was added to clopidogrel 75 mg once daily and continued for three months after which only clopidogrel was continued. After the procedure, wounds healed within 6 weeks and duplex ultrasound after 6 months confirmed patency of the treated segment without restenosis.This report presents the first ever described case of successful recanalization of an occluded SFA using FORS technology. Using 3D visualized FORS-enabled devices, it was apparent during recanalization that the guidewire slowly twisted subintimally around the occluded lumen of the SFA. In addition, during pre-dilation with the PTA balloon and placement of the SE stents, these devices maintained the corkscrew shape formed during recanalization.2, and an FT of 557 s. Predilation treatment with DCBs, stent placement, and control DSAs accounted for the remainder of the procedural radiation exposure parameters. While FORS was used in the majority of the time to create the recanalization tract (56 min), the amount of FT was relatively lower during FORS usage (103 s) than when FORS was not used (454 s). Additionally, during FORS usage, the AK and DAP were 2 mGy and 0.82 Gy/cm2 and can be attributed to the use of DSAs used to create roadmaps and ensure the accuracy of the FORS devices during recanalization. The use of FORS technology therefore enables the practitioner to perform these types of procedures while reducing radiation exposure and thus the potential health risks associated with it, such as DNA damage and long-term health effects. Moreover, FORS technology provides feedback on the force applied to the guidewire, in addition to standard tactile feedback. Excessive force on the guidewire will impair its optical signal, exceeding the boundary conditions for reconstruction of the shape of the guidewire. Therefore, the FORS technology visualizes the entire guidewire as a dashed line rather than a solid line during the period when excessive force is applied to it  for recanalization of chronic total occlusions of the femoro-popliteal tract was first described by Bolia et al.  and aimsDuring predilatation of the recanalized SFA pathway with a PTA balloon and subsequent placement of the SE stents, these devices showed a similar corkscrew shape as the FORS guidewire during recanalization. Although the fact that the corkscrew shape is not necessary for the consequence of the FORS characteristics, this corkscrew configuration may provide hemodynamic benefits as spiral laminar flow appears to be the preferential arterial flow pattern . Since rWhile the use of FORS-enabled guidewires during recanalization provides improved 3D perception of the trajectory and recanalization could be performed with laser-light navigation instead of using fluoroscopy, there are also limitations to their use. For example, the current FORS software (Release 1) is unable to visualize a narrow looped (<6 mm radius) FORS guidewire without the use of fluoroscopy. As a result, FORS visualization of the FORS guidewire is only possible if the guidewire is advanced with the tip facing forward which may increase the risk of perforation during recanalization. In addition, only the 0.035 inch angled hydrophilic FORS-enabled guidewire with a working length of 120 cm is currently available. As a result, the FORS technology is currently not applicable when performing recanalizations below the knee. Further development of the current guidewire and increasing the number of available guidewires and catheters is therefore necessary to broaden the application of FORS.This report is the first to describe a case of a successful recanalization of an occluded SFA using FORS technology. As a result, with the exception of creating a re-entry, the recanalization was performed without using fluoroscopy. The deployed SE stents adopted a corkscrew shape similar to that of the guidewire during recanalization, potentially improving hemodynamics and reducing the risk of in-stent restenosis. However, expanded patient series and longer follow-up data are needed to increase understanding of the feasibility and radiation dose reduction effectiveness of using FORS in the treatment of peripheral arterial occlusive disease.


The phenomenon of burnout generates the most interest due to relation to complete or partial disengagement of emotions, cognitive impairment, impairment of long-term and working memory. The neurophysiological mechanisms of emotional burnout remain insufficiently studied. Data related to gender specific characteristics of burnout formation are contradictory.To establish the gender related EEG markers of burnout was our aim.621 volunteers  aged 18 to 24 years participated in this study. EEG was registered during the resting state . The interhemispheric and intrahemispheric average coherence across all EEG segments in all frequencies from 0.2-45 Hz was estimated. Psychological testing was performed before the registration of EEG. To determine the level of burnout formation the Boyko`s Syndrome of Emotional Burnout Inventory (SEB) was used.The Resistance phase of emotional burnout was formed in 139 women and 42 men. Development of Resistance stage in female includes formation of new intrahemispheric connections predominantly in the left frontal region  and the midline frontal-central axis . At the same time new intrahemispheric links in men under Resistance stage development are formed mainly in the right frontal region .Connectivity patterns displayed gender-related variations that are associated with the difference in the alterations in the attention focusing, working memory, and emotional processes under burnout formation.No significant relationships.


Deep learning has promoted the development of cutting-edge robotic systems with the ability to automatically mine concepts from complex tasks in an open-ended manner. Many novel algorithms and efficient architectures of deep learning with trainable components have achieved remarkable performance in various domains such as machine learning and robotic devices.Most of the current deep learning methods focus on a single-view perception of objects without fully considering the intrinsic characteristics of data through which objects can be described by heterogeneous views. These heterogeneous views contain complementary knowledge and information that can further improve the representation learning of data. With developments in the easier access of heterogeneous view data promoted by deployments of edge-computing robotic devices, deep heterogeneous-view perceptions distilling knowledge from various views are increasingly attracting more attention. At the same time, heterogeneous view data contains more private information than single view data. Mining large-scale heterogeneous view data inevitably raises the issue of privacy. With the emergence of deep heterogeneous view perceptions, privacies hidden in data are at risk of being leaked more easily. Thus, utilizing the perceptions of deep heterogeneous view data knowledge whilst preserving privacies is also becoming central to neural computing.This Research Topic collects five high-quality articles reporting the latest applications of privacy-preserving deep heterogeneous learning. Below is a review of the articles published in this collection.Ma et al. focuses on the privacy protection of robot location-based services. The authors propose a Q-learning particle swarm optimization algorithm in mobile crowdsensing. This new method can make attackers unable to distinguish the specific tasks of users and cut off the association between users and tasks to protect location privacy. The superiority of the method was evaluated on real data.1. The paper by Lyu and Sun aims to improve the recognition of emotion by robots. The authors introduce a global and local feature fusion method for the recognition of the dance emotion. The new method integrates the global information extracted by long and short-term memory with local information extracted by linear prediction coefficients to enhance the recognition of emotions. This method was evaluated on benchmark data.2. The paper by Zhang et al. focuses on image classification in robots. The authors propose a novel CapsNet neural network based on the MobileNetV2 structure. The new neural network leverages the dynamic routing mechanism and the attention mechanism for accuracy and robustness. This method was evaluated on the cifar-100 benchmark dataset.3. The paper by Zhang and Liu aims to improve shadow detection in robots. The authors have designed an unsupervised domain adaptation adversarial learning network with a convolutional block attention module. This new method utilizes hierarchical domain adaption along with boundary and entropy adversarial branches to improve shadow detection. This method was evaluated on the ISTD dataset.4. The paper by Shen et al. focuses on the recognition of emotion by robots. The authors introduce a linear predictive Meir frequency cepstrum coefficient and bidirectional long short-term memory for recognition of the dance emotion. The new method was evaluated on public datasets and obtained better results compared to six state-of-the-art motion recognition methods.5. The paper by The author confirms being the sole contributor of this work and has approved it for publication.


The high mortality of coronary heart disease (CHD) among Czech men—one of the highest worldwide—began to decline in 1991 soon after the abolition of government subsidies to all foodstuffs rich in animal fat. As participants in the WHO MONICA Project, we were able to analyze the CHD risk factors just before and after this major economic change. We had previously documented that the originally subsidized prices decreased animal fat consumption and consequently non-HDL cholesterol concentrations in the population. By the early 1990s, no progress had been made in the treatment of acute myocardial infarction, statins were unavailable as was not the currently more effective antihypertensive therapy. Our recent research proved a close relationship between cholesterolemia and proinflammatory macrophages in adipose tissue and accelerated macrophage polarization with increased palmitate and palmitoleate contents in cell membrane phospholipids. By contrast, the proportion of proinflammatory macrophages decreases with increasing presence of n-3 fatty acids in the cell membrane. The combination of non-HDL cholesterol drop and a decreased proportion of proinflammatory macrophages due to replacement of alimentary fat decreased CHD mortality immediately. Coronary heart disease (CHD) mortality has been decreasing continuously in the industrialized nations since the mid-1960s, first in the USA . The subThe late 20th century brought completely new perceptions of the importance of lifestyle change, primary prevention, and treatment of established coronary heart disease . With thNew substantial information about progression of coronary atherosclerosis has been published within the last two decades, documenting the interplay of intravascular levels of cholesterol-containing lipoprotein particles  and immuWe have documented earlier ,14 that Data related to CHD mortality as well as CHD treatment were provided by the Institute of Health Information and Statistic of the Czech Republic based on individual death certificates. Biochemical and anthropological data of the Czech general population were obtained from a representative 1% random population stratified sample of residents from six regions of the Czech Republic in the 1st and 2nd WHO MONICA surveys conducted in 1988 and 1992, respectively. In these surveys, 2570 and 2768 individuals aged 25–64 years were examined with response rates of 81% and 73%, respectively.Total cholesterol, triglyceride, and HDL cholesterol fractions of living kidney donors (LKDs) were determined from fasting blood samples obtained immediately before surgery (prior to anesthesia) using an enzymatic method . High-sensitivity C-reactive protein was measured by immunoturbidimetric assay using a Cobas Mira Plus Autoanalyzer . All parameters were analyzed in a lipid laboratory participating in the CDC Atlanta, GA, USA control system and serving as a control laboratory within the WHO MONICA project.All 154 individuals (enrolled between July 2014 and December 2020) were fully informed about the process of kidney donation and transplantation. All participants signed informed consent forms in relation to adipose tissue sampling. Samples of VAT were obtained intraoperatively to be immediately cooled and transferred to the laboratory. The method of adipose tissue processing has been described in detail earlier [Based on our results published earlier , we defin = 43). The other minor FAs (<2%) were pooled to saturated (SAFA), monounsaturated (MUFA), and n-3 and n-6 polyunsaturated fatty acids (PUFA), accordingly.The extraction, separation, and methylation of adipose tissue phospholipids have been described in detail earlier . Total lr, which was calculated with the Pearson method, including the p-value. All tests were two-tailed and the level of significance was set at 0.05. Statistical analyses were performed using Prism 6 .Our data are presented as means with standard deviations for continuous variables. The correlations of the proportion of PIMs to non-HDL cholesterol and different FAs were documented using the coefficient of correlation During the 1960s and 1970s, CHD mortality in the Czech general population was still increasing in contrast to the progressive downward trend seen in the industrialized Western countries. This trend in CHD mortality ranked the Czech Republic among countries with the highest CHD-related death rates worldwide. During the early 1980s, CHD mortality in men  somewhatBased on data obtained from the Institute of Health Information and Statistics of the Czech Republic and those released by the Czech Society of Cardiology, acute treatment of CHD remained rather unaltered during this period . PrimaryOn the contrary, a major economic change came into effect on 1 January 1991 in the form of universal price liberalization. The Czech government decided to deregulate all prices, not only those of steel or corn, to realistically reflect those on the international market while also stopping subsidies to meat, meat products, milk, and dairy products . As a result, and to give an example, the price of butter doubled and, consequently, its consumption decreased from 10.2 kg/capita per year in 1989 to 5.3 kg in 1992. Generally, the economic change and abolition of subsidies to animal products placed immediate pressure on the budgets of the majority of families. The concentration of non-HDL cholesterol dropped by 14% in the population sample and the distribution curve of cholesterol concentration was shifted to the lower concentration  between high. Correspondingly, anti-inflammatory adipose tissue macrophages with the CD14+CD16-CD36low phenotype shows a mirror-like pattern. In addition to these two main subfractions, adipose tissue contains several intermediate subfractions representing an average 15 ± 2%. Our preliminary data [p < 0.0001) with an r2 value of 0.1288 was found. As is evident from the shift of the curve of distribution of cholesterol concentrations, the decrease in the proportion of PIMs occurred in the whole population sample  and increase in PUFAs  reflected these price changes. We took advantage of the participation of our institutions in the large epidemiological WHO MONICA study and related parameters were analyzed in a representative population sample. The first MONICA survey was conducted just before the economic changes and the second survey was conducted just after the economic changes, making the drop in non-HDL cholesterol concentrations as well as the shift in cholesterolemia in the whole population sample clearly evident .An older concept of atherogenesis already assumed qualitative changes in the endothelium of the inner arterial lining, which increases the rate of inflow of cholesterol-carrying lipoproteins  together with inflow of circulating monocytes. The presence of cholesterol-carrying particles in the subendothelial space higher than the physiological requirement of the arterial wall cells accelerates scavenging of these particles in local macrophages by specific receptors. On the one hand, cholesterol accumulation (when reverse cholesterol transport becomes inadequate) leads to foam cell production and sets off the process of atherogenesis. On the other hand, a decrease in cholesterol inflow to the artery may start a reversal of atherosclerosis and reduce the likelihood of atherosclerosis-related complications . In addiAt the same time, a substantial decrease in the prevalence of obesity from 25 to 20% BMI > 30) was demonstrated in the MONICA analysis. Adipose tissue hypertrophy is connected with substantial proinflammatory changes, so one may assume that systemic subclinical inflammation also decreased. Systemic inflammation may have been influenced by the diet change per se, as demonstrated previously . This ef was demoTherefore, we suggest that our data demonstrate an immediate effect of dietary modifications on coronary plaque stabilization and, consequently, reduced likelihood of CHD-related clinical complications and reduced CHD mortality, in agreement with the relevant data . Based oAlthough statin treatment has been shown to be most effective in decreasing the incidence and severity of atherosclerosis-related clinical complications, there is still a proportion of individuals dying from acute myocardial infarction while on high-dose statins. This residual risk is due to the relatively high levels of remnant particles of triglyceride-rich lipoproteins. Their atherogenic effect was best documented by the Copenhagen General Population Study . These rThe metabolic pathways that influencs the potential synergy of diet-induced decreased lipoprotein concentrations and adipose tissue inflammatory status in CHD mortality are intricate . DecreasAs it is, we are unable to explain the unusual proinflammatory effect of palmitoleate on adipose tissue. A plausible and possible explanation is that palmitate is the end product of FA synthesis from a non-lipid substrate and a locally produced saturated molecule, whereby palmitate converts in a one-step process (by stearyl CoA dehydrogenase) to locally acting palmitoleate. However, data regarding palmitoleate local effects are still lacking.A limitation of this paper is that the initial data and confirmation of the decrease in intravascular cholesterol levels were obtained three decades ago, whereas the above data about inflammation are the result of recent research. It is obvious that only our recent adipose tissue inflammation data put the older epidemiological data into context, enabling a better understanding of the complex issue of decreased cardiovascular mortality. We would like to underline that the above changes clearly show that even “well meant” subsidies may not necessarily have a beneficial impact on society but may be outright counterproductive or even harmful.In conclusion, we hypothesize that the sudden economic change led to a substantial diet change and an immediate decrease in atherogenic lipoproteins together with decreased proinflammatory status of adipose tissue. The synergy of both these beneficial changes enhanced the stability of pre-existing coronary plaques in a proportion of the population and immediately reduced CHD mortality.


The science of chemical biology has matured greatly in the past decade to provide enormous insights into the chemical basis of cellular and biological processes and to exploit the resulting knowledge for the development of novel research tools and compounds in across fields such as medicine, agriculture, veterinary science and biology. Such advances have been made possible by not only the acquisition of new chemical and biophysical techniques and instrumentation including cryo-electron microscopy but also superbly skilled application of these.Avalon et al. report the use of bioinformatic tools to develop predictive models of the biosynthesis of the marine polyketide natural product, palmerolide A. Enzymatic reactions and organic synthesis interpretations were based on homology analyses. Together, these led to the identification of a biosynthetic gene cluster from an Antarctic microbial species that is ultimately responsible for the stepwise synthesis of the polyketide.In this dedicated Research Topic, eleven leading international researchers of chemical biology together with their teams present their latest results across a wide spectrum of research. These showcase the contribution that current or novel chemical biological methods and technology make towards the better understanding of the chemical basis of biology. Application of such expertise and resources is wide and varied as exemplified by the following examples. Fang et al. focus on the design and synthesis of a series of calix (4) arene derivatives as antimicrobial agents that biomimic the structural properties and biological activities of antimicrobial peptides . Following the introduction of cationic hydrophilic moieties and after further structural optimization, a lead compound was obtained with potent activity against Gram-positive bacteria while having low toxicity towards mammalian cells. Such rational peptide drug design on novel natural product templates affords a promising path towards addressing AMR.The development of new antibiotics is essential given the increasing development of antimicrobial resistance (AMR). Here, Wodzanowski et al. were an attempt to better understand the molecular mechanisms whereby the human immune system can differentiate between pathogenic bacteria and the commensal bacteria of the microbiome . A comprehensive chemical biology platform was established in which biorthogonal chemistry was used to differentially label the cell walls of two different species of bacteria. Then, a hydrogel-based synthetic matrix was developed and employed to encapsulate monocytes and macrophages for subsequent measurement of the invading bacteria and a reflection of pathogen invasion and homeostatic maintenance.The reported studies of Mackinnon et al., in this special Research Topic describes an effort to develop novel inhibitors of hydroxy acid oxidase 1 (HOA1) as an alternative approach to treat primary hyperoxaluria . They report the use of X-ray crystallography for the discovery and optimization of six low-molecular-weight active site fragments. Two of these were shown by biophysical analyses to be of suitable potency while devoid of substrate competition that make them suitable for further possible drug development.The fourth manuscript, by Lin et al. report their ongoing efforts to develop novel glucose-responsive insulin analogues which represent a primary goal in the better management of fluctuating blood glucose levels in type 1 diabetes and some type 2 diabetes . Using elegant chemical peptide synthesis, they prepared an insulin analogue that contains two fluorophenylboronic acid (FPBA) moieties at the C-terminus of the A-chain of insulin glargine. In turn, they showed that this led to an increase in the baseline glucose-dependent solubility of insulin without potency reduction. This finding augurs well for the development of novel insulin-based therapies for diabetes. Crystal Chan et al. also use chemical peptide synthesis to prepare a series of analogues of Peptide5, a connexin43 inhibitor, that regulates both cellular communication with the cytoplasm and cell to cell communication . The goal was to develop greater in vivo stability as well as to increase the peptide’s potency. From these studies, design criteria were established which enabled the production of improved analogues that were suitable for further optimization.de Grip and Ganapathy focuses upon rhodopsin proteins, a superfamily of photoreceptors that are essential to multiple elements of light-sensitive animal physiology (de Grip and Ganapathy). Discussions include spectral and structural properties of these proteins together with the current and future applications of engineered rhodopsins in fields as diverse as bioelectronic and biomimic nanotechnology, optogenetics, and cell factories.G-coupled receptors are a fascinating and important class of cellular signal transducers which are also primary drug targets for many therapeutic interventions. The review by Zhao et al. review the use of chemoenzymatic synthesis strategies to prepare homogenous complex-type N-glycans for use in the preparation of well-characterized glycopeptides . Despite significant gains in synthetic efficiency, much more remains to be done to achieve higher, reliable and reproducible yields of these essential core oligosaccharides.Post-translational modifications (PTMs) of peptides and proteins is a key cellular process that adds significant structural and functional diversity. Glycosylation is probably the most common PTM but is highly complex and difficult to study. The manuscript by Landrieu et al. provide a comprehensive treatise on the putative role of protein aggregation (amyloidosis) in neurological disease or systemic diseases such as type 2 diabetes . The biophysical study of the ultrastructural organization of such aggregates has provided sophisticated and discriminating detail of the molecular features that govern the development and features of fibril (amyloid) formation. The role of chemical biology tools in such studies is highlighted with several examples including of protein engineering methods and biorthogonal chemistry for the introduction of protein chemical modifications. Amyloid-beta oligomers (AβO) are one of the most-studied protein aggregates given its still-unconfirmed role in Alzheimer’s disease onset and development. Hilt et al. report the synthesis of a class of bifunctional stilbenes and of measurements via a range of sophisticated chemical biology tools of their ability to modulate the conformational toxicity of the aggregates . They show that the ability of these designed small molecules to intervene with neuronal AβO strongly suggests a potential therapeutic application for Alzheimer’s disease.In another review, Zhou et al., describes the isolation and chemical characterization of six novel bibenzyl small molecules (three pairs of enantiomers), blestrinsD-F, from the tubers of Bletilla striata. Use of a range of analytical techniques including 1D/2D NMR led to their structural elucidation . One of the compounds showed prominent inhibitory activity against three different Gram-positive bacteria which augurs well for further development as a novel antibiotic.The final paper in this Research Topic, by Together this excellent collection of manuscripts highlights the continuing and powerful role chemical biology makes in our understanding of complex cellular processes. The contributions that the development and utility of novel chemical biology research tools produce are amply illustrated. The work described in the manuscripts also shows the acceleration towards translation to the design and production of research diagnostics and potential medicinal therapeutics and agricultural applications. It is hoped that the reader will enjoy and appreciate this Research Topic.


Computational modeling and simulations have long been recognized as key tools for a detailed characterization of ion channel functionality, which is pivotal for a deeper understanding of several physiological and pathophysiological processes. This is particularly relevant in light of the currently available computational resources that finally allow studying the complex molecular mechanisms driving conduction, selectivity, and gating. Still, the need to provide a direct link with experimental measurements calls for advanced simulation frameworks, including enhanced sampling techniques and/or multiscale models, while adequate analysis tools must be devised to cope with an ever-increasing amount of data. Articles on this Research Topic reflect the close interplay among these aspects and provide insight into advances in computational simulations in the field of ion channels both from a methodological and application standpoint.Drosophila melanogaster (dOrai), Zhang et al. showed that increased pore hydration in the gain-of-function L210F mutant facilitates channel opening with respect to the wildtype (WT) channel, regardless of activator binding. The dOrai gating mechanism was instead explicitly investigated through enhanced sampling by Guardiani et al. A complex allosteric propagation mechanism going from the activator binding site to the inner helices was revealed through contact map analysis, which was recapitulated into a gating mechanism involving a “steric brake” and the formation of vacuum bubbles inside the pore. Contact map analysis, complemented with network analysis, was also exploited by Costa et al. for highlighting the molecular determinants underlying the inactivation mechanism of the voltage-gated potassium channel Kv1.2. The approach allowed the authors to identify two distinct allosteric pathways coupling the voltage-sensing domain and the pore domain to the selectivity filter, where channel inactivation is expected to occur. The allosteric pathways were compared with those obtained from nine mutants known to impair the inactivation mechanism, supporting their hypothesis.Gating and allosteric activation of the Orai protein belonging to the calcium-release activated calcium (CRAC) channel family is an example of complex molecular mechanisms that can be untangled through computational approaches. By performing repeated sub-microsecond-long molecular dynamics (MD) simulations based on the Orai crystal structure from Fuladi et al. adopted a combination of all-atom and hybrid resolution schemes, which allowed them to simulate double-membrane systems up to the sub-micrometer length scale. By comparing the dynamics of the WT and A134P mutant, the authors showed that the mutation significantly affects the mechanical properties of the strands, including lateral flexibility and persistence length. Rationalizing the impact of mutations on the dynamics and function of a member of the superfamily of pentameric ligand-gated ion channels (PLGICs), the Glycine Receptor (GlyR), was instead the subject of the contribution by Mhashal et al. Through the integration of bioinformatics tools and structural analysis, the authors identified three mutations reported in human tumors linked to the disruption of glycinergic currents that were expected to impact GlyR conformation. Then, by mapping the MD trajectories on a low-dimensionality space capturing the conformational variability encoded in several functional states of the channel, they highlighted a divergent behavior of the mutants with respect to the WT. This example emphasizes the role played by sophisticated analysis tools both in planning and interpreting simulation results. In this context, Raffo et al. presented a novel analysis method for the geometrical characterization of the shape and dynamics of ion channels which does not rely on user-dependent parameters, like the pore axis, and that is specifically devised for processing MD trajectories.The system size required to correctly describe the molecular assemblies under investigation is critical to consider when facing ion channel modeling. For studying the claudin-15 strands and their role in tight junctions, Garofalo et al. characterized the binding mode of the small-molecule modulator retigabine to the Kv7.2 channel through an elaborate computational framework involving homology modeling, MD simulations, and ensemble docking. Specifically, they showed that retigabine can bind multiple functional states of the channel and provided molecular insights into the ligand-induced activation process. The importance of channels as pharmaceutical targets was also underscored by Aledavood et al. In their Review, the authors provide a comprehensive picture of the structural and mechanistic aspects related to the function of the M2 proton channel of the Influenza A virus, and how this knowledge can be exploited for computer-aided drug design, especially in light of the emergence of resistant strains.Modulation of channels’ dynamics and functionality through ligand binding is another aspect of ion channel research that can benefit from advances in computational simulations. For example, Lin and Luo presented a systematic benchmark of widespread approaches to single-channel permeability calculation applied on a carbon nanotube as a small-conductance ion channel model. Comparing results obtained from enhanced sampling methods like umbrella sampling and milestoning on the one hand, and out-of-equilibrium steady-state flux under applied voltage on the other, they discuss the advantages and drawbacks of the different techniques, providing useful guidelines for further investigations in the field. Finally, a bottom-up multiscale approach was developed by Horng et al. to study the longtime controversial mechanism of K+ permeation through the prototypical KcsA channel. The proposed method is based on a kinetic model fed with rate constants obtained from enhanced sampling. In this way, they managed to estimate current-voltage and current-concentration characteristics, providing a link between atomic structures and single-channel experimental data.Ion permeation is perhaps the most distinctive feature of ion channel functionality that poses specific challenges to modeling and simulations. Overall, the studies presented in this Research Topic demonstrate the liveliness of computational methods in the field of ion channels and how methodological advances in simulations and analysis frameworks are fostering a better understanding of the molecular mechanisms responsible for their functionality.


The eukaryotic organisms that constitute the kingdom fungi have, for a long time, been of pharmaceutical and industrial interest as they serve as natural sources of important bioactive secondary metabolites. Compared to other plant-derived active products, biochemicals from fungi represent an underexplored source despite the historical contribution of this kingdom to the discovery of antibiotics , immunosuppressants , antifungal drugs , cholesterol-lowering statins, anti-migraine ergot alkaloids, among others. In spite of being proven sources of pharmaceuticals, only a fraction of the described species of fungi has been screened for drugs. Most fungi studies are focused on the late-diverging fungal phyla (Ascomycota and Basidiomycota), while other phyla remain mostly un-investigated.Edible and medicinal mushrooms are one of the most widely studied fungi for their biologically active compounds. Another group that has been of interest is the endophytic fungi, particularly those that grow in marine habitats. Recent studies have reported bioactive compounds from these endophytic fungi . A uniquBegum et al. explored the potential antidiabetic activity of the phytochemical constituents of Morchella conica. M. conica is a popular wild edible mushroom in parts of Asia and Europe. By targeting the Protein tyrosine phosphatase 1B (PTP1B), an important regulator in the insulin signalling pathways associated with insulin resistance, the authors set out to, not only seek a new potential antidiabetic drug source, but also a unique target for which no commercial antidiabetic drug currently exists. Compared to controls, extracts of M. conica potently inhibited PTP1B in vitro, while significantly decreasing blood sugar levels in diabetic-model mice. These results were accompanied by positive markers of improved renal and hepatic functions. Expanding the frontiers of diabetic treatment through novel biomolecular mechanisms that counter insulin resistance is a worthwhile adventure. The potential of bioactive secondary metabolites from fungi to achieve this feat is worth further research.In this current edition, Aspergillus terreus. In the study conducted by Sakaida et al., a bioactive secondary metabolite isolated from A. terreus (+)-terrein demonstrated in vitro suppressive activity against the phosphorylation of PKCα/βII that is typically induced by the receptor activator of nuclear factor-κB ligand (RANKL). RANKL plays important role in bone resorption and the suppression of its activity has been one of the core therapeutic targets for the prevention and management of osteoporosis. For example, denosumab, an approved drug for the treatment of osteoporosis, works by suppressing osteoclastic activities through the inhibition of RANKL. As a monoclonal antibody, denosumab is not just the only approved drug in the class, it is associated with a wide range of adverse effects including immunosuppression and increased risk for systemic infection. However, RANKL inhibition is still one of the pharmacologically prudent ways of preventing and treating osteoporosis compared to bisphosphonates-mediated osteoclastic inhibition. Sakaida et al. have shown that (+)-terrein modulates different processes including the suppression of the nuclear factor of activated T-cell 1 (NFATc1) which regulates osteoclastogenesis. In translating these in vitro biomodulation to potential anti-osteoporotic activity, the authors demonstrated that the administration of (+)-terrein in mice significantly improved bone density, bone mass, and trabecular number.Another endophytic fungus that features in this special edition is Sakaida et al., A. terreus as a source of a bioactive compound highlights the continuing discovery of new chemical compounds with potential therapeutic and pharmaceutic utility. While the current study focuses on the potential benefit in osteoporosis (+)-terrein has been evaluated for several other potential utilities including cancer and inflammatory diseases.From this study by An et al. demonstrates the continuing ability of various fungi to produce secondary metabolites through the exploration of endophytic relationship with other plants. The study showed the biotransformational ability of Panax bipinnatifidus, from where the authors isolated 93 representative morphotype strains of fungi, out of which a 26 exhibited antibacterial/antifungal activity. The enormity of the potential of fungi to continue to serve as sources of antibiotics is still underappreciated. While bacterial resistance to the existing antibiotics has been a concern in pharmacotherapy, the evolutionary ability of the fungi to manufacture bioactive substances of varying and unrelated chemical structural backgrounds can continue to offer hope against infectious diseases.The study by Ye et al. explored the chemistry and biodiversity of the endophytic fungus Ilyonectria robusta. This study reported the isolation and characterization of five new isopimarane diterpenoids possessing the unique skeletons of 19-nor-isopimarane or isopimarane. Two of the new compounds, robustaditerpene C and robustaditerpene E exhibited immunosuppressive activity against cell proliferation of B and T lymphocytes respectively. The recent applications of compounds with immunomodulatory potentials in the management of emerging disease states further underscore the potentials of endophytic fungi in generating novel, sustainable and potent bioactive “lead” molecules.Polyporus umbellatus as a result of the symbiotic relationship with Armillaria mellea were reported by Mei Xing et al. in this special edition. Armillaria melea, a saprophytic fungus with facultative and parasitic activity is capable of infecting and establishing a symbiotic relationship with Polyporus umbellatus. This relationship plays critical role during the formation and development of the sclerotia, the part of P. umbellatus with medicinal properties. Metabolomic and transcriptomic techniques were used to determine the difference between metabolites found in the infected and uninfected parts of the separated sclerotia cavity wall of A. melea. A total of 118 metabolites between the two groups were differentially expressed and identified. The pathways of metabolism suggested that carbohydrates, fatty acids as well as steroids were highly enriched and active during the infection of the sclerotia part of P. umbellatus by A. melea. In comparison to that of the control group, the content of polyporusterone A and B, and that of ergosterol in A. melea infected P. umbellatus were increased by 75.0%, 20.0%, and 32.2%. Series of enzymes that played significant functions in the last steps of the biosynthesis of ergosterol, were upregulated in A. melea infected P. umbellatus. It appears, that A. melea drives the modification of the chemical components of P. umbellatus sclerotia.Furthermore, metabolomic and transcriptomic changes in the sclerotia of During the past decades, several novel compounds with diverse biological activities have been identified and isolated from fungi. As a kingdom that comprises over 1.5 million species, with only a few thousand explored so far, fungi still represent a vastly untapped reservoir of chemical backbones and actual bioactive for potential therapeutic uses. The diversity in the ecology, morphology and physiology of fungi makes them more scientifically vital for pharmaceutical research. One of the major challenges in this regard is the reliance on only culturable and fast-growing fungi for drug screening. The application of genetic engineering for cloning unculturable fungi into heterologous fast-growing hosts can expand the exploratory opportunities in fungi-sourced drug discovery research.


The research and clinical application of the noninvasive brain stimulation (NIBS) technique in the treatment of neuropathic pain (NP) are increasing. In this review article, we outline the effectiveness and limitations of the NIBS approach in treating common central neuropathic pain (CNP). This article summarizes the research progress of NIBS in the treatment of different CNPs and describes the effects and mechanisms of these methods on different CNPs. Repetitive transcranial magnetic stimulation (rTMS) analgesic research has been relatively mature and applied to a variety of CNP treatments. But the optimal stimulation targets, stimulation intensity, and stimulation time of transcranial direct current stimulation (tDCS) for each type of CNP are still difficult to identify. The analgesic mechanism of rTMS is similar to that of tDCS, both of which change cortical excitability and synaptic plasticity, regulate the release of related neurotransmitters and affect the structural and functional connections of brain regions associated with pain processing and regulation. Some deficiencies are found in current NIBS relevant studies, such as small sample size, difficulty to avoid placebo effect, and insufficient research on analgesia mechanism. Future research should gradually carry out large-scale, multicenter studies to test the stability and reliability of the analgesic effects of NIBS. Neuropathic pain (NP) was defined by the International Association for the Study of Pain (IASP) in 2008 as “pain caused by a lesion or disease of the somatosensory nervous system” . And theBased on the principles of electromagnetic induction and electromagnetic conversion, TMS, including single-pulse TMS and rTMS, alters the motor potential of cortical nerve cells by stimulating the magnetic field generated by coil transients, which affects intra-brain metabolism and neuroelectric activity . CompareThe guidelines of the International Federation of Clinical Neurophysiology and the European Federation of Neurological Societies supported the specific analgesic effect of HF-rTMS stimulation in the primary motor cortex (M1) of NP . MoreovePain was common and present in 10%–45.8% of stroke cases . PSP impThe influence of the site of the stimuli around the motor cortex on the analgesic effect is also the focus of research . M1 is tCentral neuropathic pain is a common and disabling symptom in individuals with SCI; it affects 75%–81% of SCI patients, and one-third reported severe pain that worsens their mood state . CNP affParkinson’s disease is a common chronic progressive neurodegenerative disease among middle-aged and elderly people and is characterized by motor and non-motor symptoms. More than 90% of patients with PD experienced non-motor symptoms; among which, the most common was pain with an incidence of 40%–85%, and it seriously affected the quality of life of patients . The curMultiple sclerosis is a disease caused by an inflammatory demyelinating process in the central nervous system (CNS) and a leading cause of disability in young adults with substantial economic and social burdens . Many coCurrently, the mechanism of rTMS is found to be related to synaptic plasticity, neural regulation, and response .Repetitive transcranial magnetic stimulation acts on the synapses of neurons and causes axons to be depolarized and transmitted down-line, which then leads to changes in the nerve cell body, cell permeability, and excitability and results in brain plasticity. Central sensitization refers to the abnormal increase in the excitability or synaptic transmission of central pain-related neurons, including the increase in the spontaneous discharge activity of neurons, the expansion of the sensory domain, the reduction of threshold value to external stimuli, and the enhancement of response to suprathreshold stimuli, which amplify the transmission of pain signals . The maiThe exudation of mast cells, macrophages, and other immune cells; sympathetic nerve excitation; and vascular dilation after nerve injury or disease make the peripheral nervous system and CNS produce histamine, NGF, IL-10, tumor necrosis factor (TNF)-α, and other pro-inflammatory cytokines and then cause NP . MechaniTumor necrosis factor-α expression in the central nervous system contributes to the induction of NP in rats . The claRepetitive transcranial magnetic stimulation could promote nerve cell proliferation in healthy, depressed, and stroke rat models. Transcranial direct current stimulation is an approach that induces neuroplasticity and modulates cortical excitability by applying a weak direct current over the scalp of subjects . tDCS isThe tDCS guidelines published by the International Society for Neuropsychopharmacology indicated that the use of tDCS to stimulate the left M1 region was highly effective in improving NP and was therefore a level B recommendation . The guiPatients with CPSP may have skin temperature changes because of autonomic nervous system dysfunction. Therefore, the physiological changes in patients with CPSP can be evaluated by measuring the skin temperature difference between the pain area and contralateral area . Bae et The increased excitability and reactivity of spinal dorsal horn neurons caused by the dysregulation of the central inhibitory mechanism is an important cause of pain following SCI . Fregni Some evidence showed that tDCS did not provide any pain relief to longstanding NP after SCI . The anaTranscranial direct current stimulation manages PD through brain stimulation by very weak currents to activate neurons into an excitable state . A growiTranscranial direct current stimulation has been gradually used in the clinical of spasticity and pain in MS . Poorly The effect of tDCS in reducing CNP may be related to increased sympathetic nerve activity, decreased blood flow, and decreased or interrupted transmission of the connection between sympathetic nerve fibers and pain-transmitting nerve fibers .Transcranial direct current stimulation is thought to work by changing the excitability of nerve cells as electricity passes through brain tissue . The curThe subsequent effects of the cessation of tDCS stimulation may be related to the regulation of synaptic plasticity and connect ability by regulating neurotransmitter activity . SynaptiThe activation of purinoceptor 4 (P2X4) receptors in the microglia is a sufficient and necessary condition for NP . The P2XTranscranial direct current stimulation modulates the activities of brain regions directly under the stimulating electrode, as well as a network of brain regions that are functionally related to the stimulated area. The relevant NIBS studies still have several shortcomings, which may be important causes of the inconsistency in research results and difficulties in clinical application. First, most studies have small sample sizes . Studies with a limited sample size may lead to the poor stability of the results and the inability to reliably reveal the true analgesic effect of NIBS because of the subjective characteristics of pain scores and differences in pain sensitivity among individuals. Future research should gradually carry out large-scale, multicenter studies to test the stability and reliability of the analgesic effects of NIBS.Second, the current research on the analgesic effect of brain stimulation is not sufficient and in-depth. The analgesic research of rTMS is limited to CPSP, and the attention to other pain types is insufficient. The parameters used in the study of tDCS are relatively single, and the effect of stimulus parameters on analgesia is not clear. The effect of stimulation parameters on the regulation of analgesic effect should be comprehensively investigated. Micro-neuron discharge and neurotransmitter release can be integrated, as well as macro-brain response signal and somatic nervous system signal changes, through cross-species studies.Third, understanding analgesic mechanisms rely on comparisons with analgesic loops found in other analgesic areas in the past without substantial evidence. Additionally, the influence of the placebo effect cannot be excluded because some experimental designs did not set a placebo group and only examined the changes in pain indexes before and after stimulation. Scale measurement or behavioral experiments can be carried out in multi-experimental and placebo groups to reveal the analgesic circuits of NIBS. In addition, the current assessment of the analgesic effect of different combinations of technologies is insufficient, and the interaction between NIBS and analgesic drugs is less considered. Combining different approaches may enhance analgesic effects by considering differences in pain-avoidance mechanisms.In this article, the analgesic effects of common NIBS techniques on CNP are described in detail, and their respective analgesic mechanisms are discussed. The stimulation parameters for rTMS to produce an analgesic effect are stimulation frequency of 5–10 Hz, RMT of 80–90%, 5–10 times, and current intensity of 2 mA, 20–30 mins a time, 5–10 times is the common parameter of tDCS. The most popular stimulation area of analgesia is the M1 region for rTMS and tDCS. In addition, DLPFC has also been used as a target for NP improvement for tDCS. Although tDCS stimulation of the DLPFC region has been found to reduce pain caused by MS, current guidelines do not mention improving NP by stimulating DLPFC. tDCS with different parameters acting on the DLPFC region to reduce NP induced by various diseases needs further study.Repetitive transcranial magnetic stimulation analgesic research has been relatively mature and applied to a variety of CNP treatments . The anaX-QW and YF conceived the review. Q-HY drafted the manuscript and searched the literature to identify eligible trials. S-HD and Y-CW extracted and analyzed the data. Y-HZ revised the tables in the drafted manuscript. All authors approved the final manuscript.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.


Portal vein thrombosis (PVT), particularly the presence of portal cavernoma, was traditionally considered a relative contraindication for transjugular intrahepatic portosystemic shunting (TIPS) due to the technical difficulties in accessing and maneuvering the portal vein and avoiding the high risk for bleeding periportal collaterals. However, the last decade has seen a surge in the number of studies—mostly case reports and small series of patients—demonstrating that TIPS is not only technically feasible in the vast majority of these patients but also provides effective and long-term control of symptoms associated with portal hypertension in cases refractory to the standard line of therapy. The present article aims to provide a concise but exhaustive overview of the role and the standard and technically difficult TIPS placement scenarios in patients with chronic non-malignant PVT and with and without underlying liver disease. The review is strategically punctuated by exemplary instances from the authors’ experience. Portal vein thrombosis (PVT) refers to the obstruction of the portal venous blood flow due to a thrombus in the lumen of the vein. The splenic and superior mesenteric veins can also be variably involved in this context. PVT is estimated to affect 1–2% of the world population, and its prevalence continues to increase . AscitesVariceal bleeding in chronic non-cirrhotic PVT can be successfully managed by vasoactive drugs and endoscopic band ligation, which have low morbidity but requires repeated visits and adherence to long-term surveillance protocols or by portosystemic shunt surgery. The latter provides good control of bleeding, helps improve growth retardation in children, ameliorates hypersplenism, and protects against the future development of gastric and ectopic varices. It also helps control the worsening of portal cavernoma cholangiopathy but could be associated with surgical mortality. It is sometimes not feasible due to the non-availability of a satisfactory blood vessel that precludes vascular reconstruction . In 8–12In patients with chronic PVT due to cirrhosis, treatment options and therapy goals differ from the non-cirrhotic group, which includes not only the management of symptomatic portal hypertension but also an improved chance of LT candidacy or transplant-free survival. Typical indications for endovascular intervention include recurrent variceal hemorrhage, refractory ascites, and hepatic hydrothorax. Asymptomatic patients who do not need LT can be observed to develop complications requiring interventions ,8.Since chronic non-cirrhotic PVT leads to prehepatic portal hypertension, and intrahepatic resistance is often relatively normal, several studies have explored the role of PVR without placing a TIPS stent in these patients . This apPercutaneous variceal embolization, although effective in the acute setting with 70–90% success rates, does not take care of the underlying portal hypertension, and a high incidence of re-bleeding (37–65%) remains a concern ,11,12. MWhile TIPS has become an established treatment modality in managing cirrhotic patients with variceal bleeding or difficult-to-treat ascites, placement of the TIPS stent in patients with chronic PVT and portal cavernoma formation is technically challenging and, until some years ago, was considered a contraindication.TIPS involves creating an artificial conduit between the hepatic and portal veins to decrease the portal pressure and resolve the associated complications of portal hypertension. The procedure has traditionally been performed under fluoroscopic guidance with or without wedge portography or carbon-dioxide angiography to delineate the portal venous branches . Both thA standard transjugular approach with real-time transabdominal or intravascular ultrasound guidance remains one of the preferred approaches to TIPS in chronic PVT . SimultaInitial attempts at TIPS in patients with portal vein thrombosis utilized the transhepatic approach . BrieflyThe tract between the portal vein and IVC is then balloon dilated, and the portal vein is accessed from the jugular approach to stent deployment. The advantage of the transhepatic approach is that accessing the portal system via this shorter route through the liver under image guidance is considered relatively easier compared to the longer transjugular route wherein a longer needle has to be manipulated through the metallic cannula. However, concern for access site complications remains, especially in patients with coagulopathy and ascites. With the advent of intravascular ultrasound and the trans-splenic approach, the transhepatic route is less commonly utilized.A significant proportion of patients with portal cavernoma do not have a visible native portal vein on imaging. Thus, alternative routes had to be devised for the placement of TIPS. The trans-splenic approach remains the mainstay for such patients. Originally described in the late 1980s, the trans-splenic route was traditionally associated with high rates of hemorrhagic complications . HoweverThe rest of the procedure is completed via neck using a standard technique. The trans-splenic access site is plugged in to avoid bleeding complications. This approach can also be used in patients with partial thrombosis of the splenic vein at the splenoportal confluence in whom accessing the splenic vein from the transjugular route is difficult .Recent studies have described the percutaneous transmesenteric approach to access the portal vein via the antegrade route ,22. For Large, relatively less tortuous periportal collateral veins communicating with the superior mesenteric vein or splenic vein inferiorly can sometimes be used to create TIPS in patients who had a failure of TIPS via other approaches. These collaterals and the possible route through which they can be accessed via any of the three hepatic veins can be evaluated by preprocedural imaging .However, accessing a suitable collateral vein is often difficult and risks extrahepatic portal vein laceration and hemoperitoneum. An infographic summary of chronic PVT and its pertinent clinical and therapeutic features is shown in Reports of TIPS in portal vein thrombosis have been markedly heterogeneous. A significant proportion of these studies have included both cirrhotic and non-cirrhotic patients in the cohort with different degrees of portal vein thrombosis of varying chronicity. Moreover, the presence or absence of portal cavernoma has not been universally mentioned. The approaches used for TIPS have also been diverse.In one of the earlier studies on TIPS in chronic portal vein thrombosis, Senzolo et al. reported the outcomes of endovascular treatment in a heterogeneous cohort of 28 patients . The stuIn another study on TIPS in 17 patients with chronic non-cirrhotic PVT using the transjugular approach, a technical success rate of 76.5% was reported . The cumThe percutaneous transhepatic route with balloon or snare assistance for the placement of TIPS in chronic PVT has been described in several recent studies. One of these studies reported outcomes in 18 patients with cirrhosis and chronic PVT . The autIn a series of 44 pretransplant cirrhotic patients with complete (100%) or near-complete (95%) chronic PVT, 30% of whom had portal cavernoma, technical success rates of 98% were reported with 5-year portal vein patency rates of 89% . The autOther studies reporting outcomes of TIPS in pretransplant patients have also been promising. In a retrospective analysis of 35 patients receiving TIPS for chronic obliterative PVT before LT, it was found that TIPS demonstrated efficacy in resolving PVT and simplified the surgical aspects of LT, allowing for end-to-end portal vein anastomoses . AnotherTwo meta-analyses of TIPS in cirrhotic PVT have shown that the placement of TIPS alone improved PVT owing to improved portal hypertension and restored PV flow ,31. PostOne of the largest studies on the role of TIPS in chronic non-cirrhotic PVT was reported recently in a group of 39 patients . All theIn acute PVT, experts recommend a minimum of six months of anticoagulation therapy and a longer duration when the thrombus extends to the mesenteric veins, and life-long in the presence of an underlying confirmed prothrombotic state . There aMultiple technical modifications to the standard TIPS approach in patients with chronic PVT have been reported in recent years. Given the high rates of technical and clinical success described in these studies, the presence of portal cavernoma should not be considered a contraindication to TIPS. However, the potential risks involved with the procedure and the relatively inferior long-term patency rates mandate that the procedure be offered only to patients with severe recurrent complications of portal hypertension or portal cavernoma cholangiopathy that are not responding to standard medical and endoscopic therapy and who are not candidates for shunt surgery or portal vein recanalization. In patients with cirrhosis, TIPS can be utilized to manage the complications of portal hypertension and improve LT candidacy. Referral to centers with substantial experience in TIPS procedures would be desirable to optimize the clinical outcomes. Long-term clinical effects of TIPS in young patients with non-cirrhotic chronic PVT and associated cardiomyopathy need additional studies. In addition, the role of adjuvant anticoagulation in augmenting TIPS patency merits further investigation.


Background: Metabolic syndrome is widespread in patients with schizophrenia receiving long-term antipsychotic therapy. Dopamine D2 receptors play an important role in mediating both the therapeutic actions of antipsychotics and their side effects. The present study examined the association of two polymorphisms of the DRD2 gene with metabolic syndrome in patients with schizophrenia. Methods: We examined 517 patients from several regions of Siberia (Russia) with a clinical diagnosis of schizophrenia. Genotyping of two single nucleotide polymorphisms rs1799732 and rs4436578 of the dopamine D2 receptor gene (DRD2) was performed in a population of 471 patients. The results were analyzed using chi-square tests. Results: Functional polymorphism rs1799732 of the DRD2 gene is associated with drug-induced metabolic syndrome in women with schizophrenia. Conclusions: Our results show that the DRD2 gene may be involved in the pathogenesis of metabolic disorders in patients with schizophrenia. Further analysis of possible genetic markers will allow for personalized treatment with minimal side effects and optimal efficacy. This which seems relevant in light of the recent focus on improving the quality of life and ensuring a high level of social adaptation of patients with schizophrenia. DRD2) and the occurrence of the cardiometabolic effects of antipsychotics. Assigning a role to dopaminergic neurotransmission in the development of obesity is quite logical. Dopaminergic pathways ascending from the midbrain play an important role in promoting reward-oriented behavior   . We founThe mechanism by which the functional polymorphism rs1799732 affects the cross-sectional prevalence of the metabolic syndrome is unknown. In prolactinomas, hyperprolactinemia is often accompanied by obesity, metabolic syndrome, and insulin resistance ,64,65,66Unfortunately, in the clinical setting, pharmacogenetic information is rarely used to personalize treatment. However, given the progress in molecular genetic research, it seems inevitable that pharmacogenetic testing will ultimately play a decisive role in the prescription of antipsychotics and other psychotropic drugs. Further research is needed on genetic markers in relation to the development of side effects of pharmacotherapy, which in the future will allow for personalized treatment of patients with minimal side effects and optimal efficacy.The main limitation of our study is its cross-sectional nature. We applied an observational and trans-sectional design; our patients were treated with a variety of first and/or second-generation antipsychotic drugs. We cannot be certain about the previous long-term stability of medication intake causing the metabolic effects. It is desirable to follow up on the emergence of metabolic syndrome in pre-genotyped individuals. Then differences can also be decoupled from differences in treatment duration. The major advantage of our study, however, is the considerable size of the patient population and the natural character of its composition. This makes it likely that the receptor occupancy of other relevant receptors  is randomly distributed among the different genetic groups.DRD2 (rs1799732) and the development of MetS in women with schizophrenia taking long-term antipsychotics. The inclusion of other risk factors for the development of MetS in the analysis, as well as an increase in the sample size, will reveal new data on the involvement of dopamine receptor genes in the pathogenesis of drug-induced metabolic dysfunctions.In our study, no statistically significant associations with metabolic disorders were found in the general group of patients. However, we identified a link between the functional polymorphism