Kaposi’s sarcoma, a rare opportunistic tumor, is observed in four epidemiological conditions . Although in most cases KS is an indolent disease, it can be locally aggressive and/or it can invade other organs than the skin, resulting in more severe presentations, especially in patients with severe immunosuppression. There is no consensus on the imaging workup that is necessary for either the initial staging of the disease or the follow-up. Future perspectives include the use of certain non-invasive imaging tools that may help to evaluate the clinical response to treatment, as well as certain new histological markers that may help in guiding the treatment planning for this atypical neoplasm.18F-fluoro-deoxy-glucose positron emission tomography, thermography and laser Doppler imaging for the diagnosis of KS and for the follow-up of therapeutic response in patients requiring systemic treatment.Kaposi’s sarcoma (KS) is a rare, atypical malignancy associated with immunosuppression and can be qualified as an opportunistic tumor, which responds to immune modulation or restoration. Four different epidemiological forms have been individualized . Although clinical examination is sufficient to diagnose cutaneous lesions of KS, additional explorations are necessary in order to detect lesions involving other organs. New histological markers have been developed in recent years concerning the detection of HHV-8 latent or lytic proteins in the lesions, helping to confirm the diagnosis when it is clinically doubtful. More recently, the evaluation of the local immune response has also been shown to provide some guidance in choosing the appropriate therapeutic option when necessary. We also review the indication and the results of conventional radiological imaging and of non-invasive imaging tools such as  Kaposi’ sarcoma (KS) is an atypical tumor that is associated with immunosuppression. KS can be qualified as an opportunistic tumor, and it is well demonstrated that in patients with immunodeficiency, the restoration of immunity can be sufficient to cure KS. For example, in patients with acquired immunodeficiency syndrome (AIDS)-KS, antiretroviral treatment alone has been shown to cure KS , and sinThere are four major epidemiological forms of KS: classic (or Mediterranean) KS (CKS), which mostly affects elderly men of Mediterranean, east European, or Jewish heritage with a peak incidence after the sixth decade of life; endemic African KS, which occurs in sub-Saharan Africa among children and adults; iatrogenic immunosuppressive KS, which affects patients who are receiving chronic immunosuppressive therapy, mostly organ-transplant recipients; and Epidemic KS or AIDS-KS, which affects people living with HIV (PLHIV), which is the most common AIDS-associated malignancy . AmongstCutaneous and mucosal manifestations, which are largely predominant in all types of KS, allow a generally obvious clinical diagnosis, since the lesions are characteristic, although they may vary in aspect. The diagnosis is based on the combination of different clinical elements: purple to brown macules A, a dist18F-fluoro-deoxy-glucose (FDG) positron emission tomography (PET), or FDG-PET, is also a promising examination, both for the diagnosis and follow-up of patients with KS. Tools that were developed for monitoring the treatment response of KS are also essential. Indeed, KS is a very polymorphic disease, for which the treatment response is very difficult to quantify. As such, it is complex to assess the effectiveness of therapies in clinical trials. New non-invasive imaging methods that are based on thermography and laser Doppler imaging (LDI) could revolutionize the initial staging of KS and the evaluation of the treatment response.The detection of lesions in certain anatomical localizations, whether symptomatic or not, requires further explorations. A histological analysis, from bronchial or digestive endoscopy-guided biopsies, or from biopsies of lymph nodes, bone, or skin, allow for a definite diagnosis. Conventional imaging, including CT and MRI, can identify visceral and bone lesions that may go unnoticed upon clinical examination. Exhaustive screening for KS lesions is crucial to establish the correct staging of the disease, which guides therapeutic choices, and allows for a prognosis assessment. Depending on the KS lesion localization, additional examinations are very variable, and it is generally necessary to combine several tools. Another challenging aspect is the assessment of the therapeutic response under cART in HIV+ patients and/or under specific treatment . For skin lesions, this response is often difficult to determine, and there are now non-invasive imaging options that could help distinguish scarring from lesions that are still active.That is why in this review we aim to describe the current and future tools for the diagnosis of KS.As KS cannot be considered a true neoplasm, to date, the staging of KS has not been unified or incorporated into the tumor, node and metastasis (TNM) staging system developed by the American Joint Committee on Cancer (AJCC). Instead, the modified AIDS Clinical Trials Group (ACTG) staging classification, which is based on the tumor, immune status and systemic illness (TIS), is used for AIDS-related KS. In the era of cART, mostly the T and S stages (and not I) seem useful for the identification of patients with poor prognoses  7,8].,8.7,8].Outside the context of AIDS-KS, there is no consensual classification for the staging of classic KS, and there is no accepted classification for iatrogenic or endemic KS.For a long time, the classification of classic KS relied on Krigel’s classification, which describes four stages: stage (I) is limited to the skin, localized, and without aggressive histological features; stage (II) is characterized by locally aggressive skin involvement with or without locoregional lymphadenopathy; stage (III) consists of generalized skin lesions and/or lymph nodes; and stage (IV) is visceral involvement . In KrigHowever, most recent reviews admit that the classification described by Brambilla et al. is probably more appropriate . Based oAlthough histopathological features are identical in different epidemiological forms of KS, prognosis varies largely between them. As such, it is also important to appreciate certain prognostic parameters which are not perfectly translated in the currently recommended staging classifications.First, the overall tumor volume should be assessed, as well as the risk of visceral involvement. However, apart from AIDS-KS and some cases of iatrogenic KS, visceral involvement is very rare. KS is primarily a skin tumor, and the extension of the disease onto the skin in itself may constitute the best parameter for assessing disease severity. The degree of skin extension can vary from one lesion of less than 1 cm up to more than 100 plaques all over the skin surface. Evidently, the severity of KS is associated with the degree of skin extension. Yet, some forms of KS have a limited skin surface extension but are locally aggressive. This is not so rare in patients with endemic KS, in which there may be only one skin lesion that progresses to an ulcerative stage with exuberant proliferation and soft tissue invasion, or even invasion of the adjacent bone. In such cases, the amount of skin surface involved can be very limited and will not reflect the severity of the disease, and systemic treatment such as chemotherapy or immunotherapy is required.Due to the absence of a consensual staging system for non-AIDS-KS, European consensus-based interdisciplinary guidelines were established, which state that patient management should distinguish three situations: localized non-aggressive, locally aggressive and disseminated KS . These gFor the screening of bronchial and digestive mucosal KS, an endoscopy is the best way to visualize and biopsy the macroscopic lesions in order to obtain a histopathological diagnosis.Finally, if in most cases there are no histopathological traits that distinguish different forms of KS, there are yet some very rare cases of particularly aggressive tumors which are histopathologically qualified as anaplastic C, the prIn order to definitely establish the diagnosis of KS, a histopathological analysis of a biopsy sample is required. Conventional hematoxylin and eosin staining show several features that are shared by the different epidemiological forms of KS  with aspects depending on the nature of the clinical lesion as it progresses from the patch to the plaque and nodular phases ,14. MultImmunomodulatory pathways could play an important role in KS pathogenesis. Over the past few years, several studies have therefore been carried out to investigate the prognostic value of programmed death-1 (PD-1)/PD-ligand-1 (PD-L1) expression in KS with controversial results and a lack of standardized protocols for PD-L1 detection ,17,18,19No current guidelines recommend the use of virological diagnosis tools to detect the HHV-8 genome or antibodies for the screening, monitoring or diagnosis of any epidemiological form of KS ,23. As sHowever, several studies have suggested that PCR-based methods, and mainly real-time polymerase chain reaction (PCR), may help to monitor KS. First of all, HHV-8 nucleic acid can be detected in several specimens including various biopsies, blood, broncho-alveolar lavage, ascites and pleural liquid with high sensitivity and specificity. Also, the HHV-8 genome has been detected in the specific HHV-8-infected “spindle cells” of all forms of KS . Its det6 cells compared to patients with regressing KS [Studies performed on whole blood or plasma samples reported variations in the HHV-8-DNA viral load in different subtypes of KS. In epidemic forms, the HHV-8-DNA viral load is undetectable in 7 to 21% of cases ,30,31,32ssing KS . In HIV-ssing KS ,30. Furtssing KS .Various serology tests have been developed to detect lytic and/or latent HHV-8 antigens, and are based on immunofluorescence ,40 , as well as important signal enhancement after gadolinium injection, particularly in lesions with a peribronchovascular distribution. Those MR characteristics are highly suggestive of a KS diagnosis .Hepato-splenic involvement is reported in approximately one-third of KS patients in autopsy case series .Abdominal ultrasound imaging of the liver can demonstrate mild hepatomegaly with inhomogeneous cystic nodules along the peripheral branches of portal veins with hyper-echoic parenchymal bands. An abdominal CT may show inhomogeneous hepatomegaly with multiple small hypo-dense periportal nodules which may exhibit iso- or hyper-attenuation on delayed images, similar to that of hemangiomas . MRI shoVisceral involvement is often asymptomatic and can present as an enhanced mass with enhanced regional lymph nodes. Lymphadenopathies are common, especially in the retroperitoneum. The most frequently reported visceral complications are appendicitis, bowel obstruction , hemorrhage, and perforation  Figure .Musculo-skeletal KS is rare. Lytic bone lesions and soft-tissue masses with cutaneous and subcutaneous involvement may be seen on conventional imaging ,54. The FDG-PET is a nuclear medicine imaging modality that uses FDG, which is a radio-labelled glucose analogue that is used for the exploration of cellular glucose metabolism. It is now systematically coupled with anatomical imaging (most often CT), for the anatomical localization of FDG uptake. FDG-PET is a well-recognized modality for the workup of various inflammatory and neoplastic diseases in which glucose metabolism is increased.In KS, there is a known increase in cellular glucose metabolism which affects cells latently infected with HHV-8 , partly In the literature, several FDG-PET studies have reported KS patients with FDG-avid lesions, even though most of these are case reports. These studies have mostly concerned AIDS-related KS ,61,62,63FDG-avid KS lesions have been reported in the skin ,67,68,69max value greater than 10 excluded KS, but that the exact diagnosis of the lymphadenopathy could not be established based on PET alone (which is expected due to the non-specific nature of FDG uptake). However, this study outlined the value of FDG-PET for the localization of FDG-avid lymph nodes as targets for biopsy, which remains an important factor of obtaining diagnoses.Only two patient series have reported FDG-PET results in KS. The first retrospectively evaluated the utility of FDG-PET for differentiating the diagnoses in 120 HIV patients with lymphadenopathy, only 13 of which had KS, and showed that FDG uptake in lymphadenopathy due to KS was of similar intensity to that of HIV-reactive lymphadenopathy, and lower than those due to lymphoma or mycobacterial and fungal infections . The autThe second patient series is the only one to have reported the sensitivity and specificity of FDG-PET in a sizeable sample of KS patients . This retrospective study, which included 75 patients with KS of all four subtypes, showed an excellent diagnostic performance of FDG-PET with sensitivity and specificity above 85% for the evaluation of KS involvement in the skin, lymph nodes, bone, muscle and lung. For the other localizations , the specificity remained excellent (above 95%) but the sensitivity was lower, which was hypothesized to be due to small lesion size, as well as the physiological excretion of FDG in these sites, which may hinder lesion detection. Interestingly, the authors mention that in 24% of patients, FDG-PET revealed unknown lesions based on usual imaging workup, suggesting that FDG-PET may perform better than conventional imaging.Some of the previously mentioned case reports included follow-up FDG-PET studies performed for treatment response assessment. In one case of gastric and mouth KS (without skin lesions), FDG uptake decreased almost completely in the gastric lesion following treatment with paclitaxel . AnotherOverall, FDG-PET constitutes a promising non-invasive whole-body evaluation for detecting KS lesions. This modality seems effective for the identification of appropriate biopsy targets and may also be useful for staging, and possibly for the assessment of treatment response. However, available data mostly concerns case reports, and more studies are warranted to evaluate sensitivity and specificity and to determine the role of FDG-PET in relation to conventional imaging.Three non-invasive, non-contact imaging methods have either been investigated separately or in a multi-modality setting in order to assess the response to therapy of KS lesions.p < 0.001). In ten patients, measurements were obtained prior to therapy and after receiving a regimen of liposomal doxorubicin and interleukin-12. After 18 weeks of therapy, the temperature and blood flow of the lesions were significantly reduced compared to the baseline .The first study concerns the evaluation of two non-invasive methods, thermography and LDI, for their ability to quantitatively assess the parameters of vascularity in lesions of HIV-associated KS . ThermogThe third extensively evaluated technique is multi-spectral imaging, which collects images at several near-infrared wavelengths which are then inputted into a mathematical, optical skin model that considers the contributions from different analytes in the epidermis and dermis skin layers. Through a reconstruction algorithm, the percentage of blood in a given area of tissue and the fraction of that blood that is oxygenated are quantified, and can be compared to values that were previously measured in normal skin tissue either in the usual state or in a state of induced ischemia. . This meKS is an opportunistic tumoral process which in most cases is an indolent disease and does not need specific treatment. However, in some instances, KS may be locally aggressive or disseminated, requiring a reliable assessment of the disease stage before choosing the appropriate therapeutic option. Among the non-invasive imaging methods, FDG-PET, thermography and LDI constitute promising tools for assessing the extension, disease activity as well as treatment response of KS lesions. In the future, the development of new histological parameters such as PD-L1 expression may also help to define the place of immune modulators in the treatment of KS.


Beat the Blues (BTB) is a culturally tailored depression program for older African Americans. Tested in an NIA Stage 3 efficacy trial, findings showed statistically and clinically significant benefits, including decreased depressive symptoms, improved depression knowledge and symptom recognition, and behavioral activation. The multi-component intervention was co-constructed in partnership with a large senior center. Drawn from previously tested depression programs and tailored to preferences/needs of the targeted population, its five components included care management, depression education and symptom recognition, resources/referrals, and stress reduction and behavioral activation techniques. Despite significant findings, strong effect sizes and high acceptability, moving BTB to NIA Stage 4 (effectiveness) or 5 (dissemination) has been challenging. Challenges that will be discussed include lack of senior center funding to support training and delivery and infrastructure to embed BTB in community-based programs, and reluctance of health systems to adopt BTB because of its focus on one racial group.


Caustic wash is one of many industrial processes that are used to produce jet fuel. In this study, an analysis of the key parameters of the kerosene caustic wash process was conducted to improve the total performance of the treatment process. The investigated parameters are caustic concentration (from 0.03 to 3.0 wt%), caustic volume , number of treatment stages (one and two stages), wash water type , and wash water volume (10% and 30% of kerosene feed volume). Results revealed that the reaction between sodium hydroxide and naphthenic acids is a diffusion-controlled chemical reaction. The diluted caustic solutions (0.5 wt%) are better than the concentrated ones (3 wt%). Higher excess caustic volume has a slight effect on kerosene acidity. Performing the caustic treatment process in one stage is sufficient, and the two-stage process has no effect on acidity. Washing caustic-treated kerosene with demineralized water (pH=7) has a slight adverse effect on kerosene acidity. Increasing the demineralized water volume results in a slight increase in the acidity of the treated kerosene. Wash water should be slightly alkaline (pH 7.5–8) to prevent the reverse reaction of sodium naphthenates back into naphthenic acid. Increasing wash water volume (more than 10 vol% of kerosene feed) has no noticeable effect on the water content of treated kerosene. The aviation sector is a fast-growing transportation sector, although it faces big challenges today due to COVID-19. The worldwide airline operations consume annually around 1500–1700 million barrels of Jet A-1 fuel. Forecasts indicate that the aviation sector will grow at 4.8% per year until 2036. Airlines from all over the world must purchase quality and safe fuels, and hence, jet fuel must meet very restricted international specifications [Many industrial processes are used to produce jet fuels with those specifications, based on the impurities in the kerosene. Among these processes are the caustic wash process, UOP caustic-free Merox process, Merichem Napfining and MERICAT processes, hydrotreating, and alternative renewable jet fuels –12.The caustic wash process is limited to refineries that produce kerosene fractions which already meet the international jet fuel specifications except for the total acidity. The process consists of withdrawing a side-stream kerosene from the atmospheric crude distillation unit followed by stripping, cooling, caustic washing, water washing, salt drying, clay filtration, and final water separation. Total acidity is the only specification that is caustic-extractable. Other specifications such as aromatics, smoke point, sulfur content, and freezing point are not caustic-extractable and hence not affected by the caustic wash process , 6.Water content is an important parameter that reflects the fuel purity. Water content, in the dissolved phase alone, does not affect fuel performance. However, water in any other phase could participate in aircraft incidents and accidents. The excess water content affects directly the fuel quality and the normal operation of the flight equipment, even severely endangering the flight safety. Free water can affect the aircraft’s fuel system reliability and lead to operational delays and increased maintenance costs –17.Many improvements have been done to enhance the caustic wash performance. The Fiber-Film Contactor employs non-dispersive contacting of the caustic and hydrocarbon phases. This prevents emulsion formation and minimizes caustic and water carryover. The contactor provides a large interfacial surface area which increases the mass transfer rate , 10. TheIn this study, an analysis of the key parameters of the kerosene caustic wash process was conducted to improve the total performance of the treatment process . The investigated parameters are caustic concentration, caustic volume, number of treatment stages, wash water type, and wash water volume. Focus is placed on reducing the total acidity of petroleum kerosene to meet Jet A-1 specifications.In this study, the main target is to analyze the caustic wash process of petroleum kerosene fractions to produce jet fuel matching the international standard specifications of Jet A-1 (ASTM D-1655 and DEF STAN 91-91) , 5.A sample of straight-run kerosene was taken from the atmospheric distillation unit. Table TM Plus FEB30.All chemicals used were of analytical higher grades. The total acidity test was carried out using the ASTM method D-3242 standard. The water content of kerosene was measured by Coulometric Karl Fischer Titration . The water content of the sample was measured by three parallel experiments, and the maximum value was reported . Wash waOne liter of kerosene feed Table  is mixedDifferent caustic concentrations were used: 0.03 wt%, 0.05 wt%, 0.125 wt%, 0.25 wt%, 0.5 wt%, 1 wt%, and 3 wt%. The volume of the caustic solution depends on the caustic concentration. Table Kerosene sample was treated using the caustic solution with concentration 0.5 wt% and different excess volumes of caustic: 10%, 100%, 150%, 200%, and 250%. The total acidity of treated kerosene was then measured.Kerosene sample was treated with caustic solution 1 wt% in two stages (using 10% excess caustic) to study the effect of the number of treatment stages on the effectiveness of the treatment process. The total acidity of the treated kerosene was measured and compared with the results of the one-stage process.In the industrial plants, the caustic wash is normally followed by water wash to remove any entrained droplets of caustic solution that escapes with the treated kerosene and impairs the downstream systems. Here, caustic wash followed by water wash will be studied. Two types of wash water were used, demineralized water and alkaline soft water. Table Caustic-washed kerosene (from step 1) is washed with water by stirring together with a 300 RPM laboratory mixer for 5 min. The mixture is left for 30 min for separation of the aqueous phase (by gravity) from the “treated” kerosene. Total acidity and water content of treated kerosene were measured and recorded.The volume of wash water has increased from 10 to 30%. The treatment process as per section 2.7 was performed. Total acidity and water content of treated kerosene are measured and compared with section 2.7.Sodium hydroxide readily reacts with naphthenic acids to form sodium naphthenate and water according to the following reaction , 18:1\d2S (if any) contained in the kerosene fraction in accordance with the following Eq.  to the surface of droplets of the aqueous phase of sodium hydroxide (dispersed phase).Reaction of acids with alkali in the droplets of the aqueous phase and removal of reaction products with the aqueous phase.The process of acids removal from kerosene in flow contactor or stirred tank mixer can be divided into two steps:The diffusion step is controlled mainly by the surface area of droplets. The chemical reaction step in the droplets is mainly affected by the concentration of sodium hydroxide in the aqueous phase.In industrial practice, a small volume of high concentration of NaOH aqueous solution is used (1–2 volumes of the aqueous solution to 100 volumes of kerosene). In this case, the surface area of droplets is very small, the diffusion rate is small (resistance is high), and the chemical reaction rate is high . Thus, the overall process is controlled by diffusion.If the volume of the aqueous phase is increased by adding water only, the surface area of the dispersed phase increases, while the concentration of sodium hydroxide is decreased. This means the resistance of the diffusion step is decreased, while the resistance of reaction increases but the diffusion step is still controlling. This behavior continues with the dilution of NaOH solution, and the overall process of acid removal from kerosene is improved. At some point (optimum point of operation), the effect of the chemical reaction step becomes appreciable.In our study, the point of maximum efficiency is at 5.5 volumes of the aqueous solution to 100 volumes of kerosene  and the efficiency is 91.8%. In actual refinery operations, using less volume of aqueous solution with a high concentration of NaOH (3 wt%), the efficiency is 63.6%.For the given kerosene sample, the optimum caustic concentration is 0.5 wt% and using caustic solutions less than 0.5 wt% have a negligible effect on product acidity. From Table The conventional caustic wash process is an economically attractive process, since no catalyst or any special chemicals. From Table Process efficiency with caustic solution of 3 wt% concentrationProcess efficiency with caustic solution of 0.5 wt% concentrationRequired amount of NaOH to attain the same efficiency with caustic solution of 3 wt% concentration = 27.5 × 91.8/63.6 = 39.7 mg (including 10% excess).Saving in caustic consumption with diluted caustic solutions of 0.5 wt% concentrationFigure Figure Figure On the other hand, using alkaline soft water (with pH=9.44) has a slightly positive effect on kerosene acidity. Increasing the alkaline soft water volume results in a slight decrease in the acidity of the treated kerosene.The abovementioned behavior can be interpreted by the effect of wash water pH. Demineralized water has pH =7 which is lower than the pH of soft water (soft water pH=9.44). As more demineralized water is added, some sodium naphthenates convert to naphthenic acid by the reverse reaction (Eq. 1).On the other hand, alkaline soft water contains some alkalinity  of kerosene feed.For the given kerosene sample, saving in caustic consumption with diluted caustic solutions of 0.5 wt% concentration is 30.7% compared with caustic solutions of 3 wt%.Using more excess caustic solution has a slight effect on kerosene acidity. For the given kerosene sample, 10% excess caustic  is sufficient.Performing the caustic treatment process in one stage is sufficient and the two-stage process has no effect on acidity.Washing caustic-treated kerosene with demineralized water (pH=7) has a slight adverse effect on kerosene acidity. Increasing the demineralized water volume results in a slight increase in the acidity of the treated kerosene. Wash water should be slightly alkaline (pH 7.5–8) to prevent the reverse reaction of sodium naphthenates back into naphthenic acid.Increasing wash water volume has no noticeable effect on the water content of treated kerosene. For the given kerosene sample, washing the caustic-treated kerosene with alkaline soft water (10% of kerosene feed) is sufficient for the treatment. Both types of wash water have the same effect on water content.


Background: Some previous studies have shown reduced levels of plasma B-type natriuretic peptide (BNP) in individuals with obesity. We aimed to estimate the relationship between BNP and abdominal fat distribution, adjusted for confounding factors. Methods: This cross-sectional study included 1806 Japanese individuals (981 men and 825 women) who underwent a medical health check-up. Analyzed data included age, sex, visceral fat area (VFA), and subcutaneous fat area (SFA) as obtained from computed tomography, blood pressure, and blood test results including BNP. Multiple linear regression analysis was used to examine the association between BNP, VFA, and SFA after adjusting for age, sex, comorbidities, and body mass index. Results: In the models analyzed separately for VFA and SFA, BNP correlated independently with VFA in multiple linear regression analysis among all subjects and in both men and women, while SFA correlated inversely with BNP in all subjects and women but not in men. In the model that included both VFA and SFA, BNP correlated independently with VFA, but SFA and BNP were not correlated in any models. Conclusion: Higher VFA showed an independent, significant association with lower BNP. In addition, the inverse correlation with BNP was stronger for VFA than for SFA. B-type natriuretic peptide (BNP) is a peptide hormone secreted primarily by the ventricles, exerting diuretic effects, vasorelaxation, inhibitory effects on renin-aldosterone secretion, reduction of circulating plasma volume , and supA negative association has been reported between obesity and BNP levels ,5,6,7,8.Visceral obesity as measured by waist circumference reportedly correlates negatively with BNP level ,16. AbdoTo the best of our knowledge, only two large cross-sectional studies conducted in the United States ,18 and aBecause of the difference in abdominal fat distribution between Americans and Asians, the correlation of VAT and SAT with BNP in Americans may not be applicable to Asians. Only one small study has been reported in Asians with Japanese subjects with diabetes, and there are no large studies in Asians.We therefore aimed to determine the correlation between BNP and VFA or SFA as estimated by CT among a Japanese population.This cross-sectional study screened 2885 Japanese adults who participated in health check-up at Juntendo University Hospital in Tokyo, Japan between January 2017 and December 2018. Among these, 978 participants were excluded because of duplicated visits; 73 due to a history of heart disease such as arrhythmia, heart failure, or ischemic heart disease; 21 because of the presence of atrial fibrillation on electrocardiography (ECG); and 7 due to missing data. Only the initial visit was included in this analysis. A total of 1806 patients thus participated in the present study .Height and weight were measured in the standing position, and body mass index (BMI) was calculated as the weight in kilograms divided by the square of the height in meters. After the subject rested in a sitting position for at least 10 minutes, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured using an automatic sphygmomanometer.We collected venous blood samples after overnight fasting to measure blood glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), high-sensitivity C-reactive peptide (hs-CRP), serum creatinine (Cre), serum insulin, and BNP levels. For the measurement of BNP, blood samples were collected in tubes containing ethylenediaminetetraacetic acid and measured using an immunoenzymometric assay kit (E-Test TOSOH II (BNP); Tosoh Corp., Tokyo, Japan). Homeostasis model assessment ratio (HOMA-IR) was calculated as (fasting insulin (μIU/mL) × fasting blood glucose (mmol/L))/22.5 . Twelve-Images were manually traced on the inner aspect of the entire trunk, muscle layers, and abdominal wall. VFA and SFA were quantified using commercially available software  that defined fat as any tissue with a threshold of −150 to −70 Hounsfield units. We defined VFA as any fat surrounded by the inner aspect of the abdominal wall and SFA as any fat surrounded by the lateral aspect of the abdominal wall .We used a self-administered questionnaire to gather data on a history of heart disease ; presence of lifestyle-related diseases ; and lifestyle-related factors . The completed answers to questionnaires were confirmed in an interview by well-trained nursing staff.Data regarding subject lifestyle were collected based on Breslow’s health habits and stratified as follows: alcohol consumption , smoking status , exercise frequency per week , sleeping hours , eat breakfast every morning (yes/no), and snack between meals ≥2 times/week (yes/no) ,25.The presence of a metabolic disorder was defined according to the Japan Society for the Study of Obesity criteria . Lipid-rResults are expressed as mean ± standard deviation (SD) for continuous variables and as prevalence (%) for categorical variables. Since data on BNP, SFA, and VFA showed skewed distributions, these values were log-transformed before analysis. Pearson’s correlation coefficient was used to examine the relationship between SFA, VFA, and BNP.Multiple regression analysis was performed in the total sample to examine independent contributions of BNP, VFA, and SFA. The independent variables were evaluated using three models. Model 1 was adjusted for age and sex. In Model 2, we adjusted hs-CRP, left ventricular hypertrophy (LVH) on ECG, pulse rate, Cre, hypertension, metabolic glucose disorder, smoking, and BMI, with reference to previous reports and known confounding factors ,17,18. Ap < 0.05 were considered statistically significant. All statistical analyses were performed using EZR software , a graphical user interface for R . More precisely, EZR is a modified version of R Commander designed to add statistical functions frequently used in biostatistics [Values of atistics .The study protocol was reviewed and approved by the ethics committee at Juntendo University . We obtained written informed consent from all participants at the time of undergoing health check-up.2, 134.1 ± 69.5 cm2, and 23.3 ± 3.6 kg/m2, respectively. Men were with higher BMI, WC, and VFA than women. Women had higher BNP and SFA than men.A total of 1806 patients  were included . Table 1r = −0.13, p < 0.05) and log VFA  showed significant negative correlations with log BNP.p = 0.002, VFA: p < 0.001). However, BNP was significantly correlated with VFA but not with SFA in a model including both SFA and VFA . Results were unchanged after the replacement of metabolic glucose disorder with HOMA-IR in Model 2  even after adjusting SFA . SFA correlated inversely with BNP only in women (p = 0.003) but not when adjusted for VFA (p = 0.24). These results were unchanged in which the metabolic glucose disorder was replaced with HOMA-IR ( HOMA-IR .p > 0.05 for both). In all models, all variance inflation factor values were less than 10. This means that no collinearity was present in any models.There was no evidence for an interaction of sex with SFA and VFA  is abundant in adipose tissue  and invoBecause expression of NPR-A and NPR-C is higher in VFA than in SFA , VFA couTaking this study into consideration, we need to be careful in our analysis of BNP values because BNP values could be underestimated in the presence of VFA or SFA accumulation. Our data also suggest that BNP might have both pathophysiological and therapeutic implications in abdominal obesity and Mets.This study has the following limitations. First, our study may have included some selection bias, as all participants were selected from a single facility. Collaborative research with other facilities that include people who have not undergone health check-up is needed. Second, since this study was cross-sectional in design, the causal relationship between BNP and VFA remains unknown. Prospective studies are thus needed. Third, we evaluated the use of medications but did not know the type of medicine. Since the kind of drug may affect BNP level, further studies with more detailed investigation of concomitant medications are needed. We also examined cardiac hypertrophy on ECG and should evaluate cardiac function more closely by echocardiography. Fourth, in SFA, the entire abdominal subcutaneous fat was measured, so investigation of independent associations between superficial and deep segments and BNP was not possible. Despite the above limitations, this study is the first to confirm an inverse correlation of VFA with BNP in a multivariate analysis of a sufficient sample size from Japan.Our study suggests that higher VFA shows a significant independent correlation with lower BNP in Japanese people even after adjusting for confounding factors. In addition, the inverse correlation between SFA and BNP appears weaker than the inverse correlation between VFA and BNP. This finding supports the hypothesis that VFA is involved in the inverse association of BNP with Mets and obesity.


In terms of mode of action, these antipsychotics are either antagonist or partial agonist at the above-mentioned receptors. Although D2Rs and D3Rs possess high degree of homology in their molecular structure, have common signaling pathways and similar in vitro pharmacology, they have different in vivo pharmacology and therefore behavioral roles. The aim of this review, with summarizing preclinical and clinical evidence is to demonstrate that while currently used antipsychotics display substantial in vitro affinity for both D3Rs and D2Rs, only very few can significantly occupy D3Rs in vivo. The relative importance of the level of endogenous extracellular dopamine in the brain and the degree of in vitro D3Rs receptor affinity and selectivity as determinant factors for in vivo D3Rs occupancy by antipsychotics, are also discussed.Dysfunctions of the dopaminergic system are believed to play a major role in the core symptoms of schizophrenia such as positive, negative, and cognitive symptoms. The first line of treatment of schizophrenia are antipsychotics, a class of medications that targets several neurotransmitter receptors in the brain, including dopaminergic, serotonergic, adrenergic and/or muscarinic receptors, depending on the given agent. Although the currently used antipsychotics display  Currently used antipsychotics display medium-to-high in vitro affinity for D2R as well as D3R, and high correlation can be demonstrated between their affinities for these receptors. This is not surprising considering the high structural homology, and the in vitro functional and pharmacological similarities of the two receptors. On the other hand, significant differences have been demonstrated in their in vivo pharmacology and behavioral roles. All currently used antipsychotics, in agreement with their in vitro D2R affinity, show significant in vivo brain D2R occupancy at their antipsychotic effective doses. However, despite their substantial in vitro D3R affinity, not all antipsychotics demonstrated in vivo D3R occupancy in animals or in humans. Here, a review is given on the data available for the in vitro affinity for D2Rs and D3Rs and a hypothesis is provided as to why a group of antipsychotics do not show significant in vivo brain D3R occupancy despite their notable in vitro D3R affinity.It is widely accepted that dysfunction of the dopaminergic neurotransmitter system plays a major role in the pathophysiology of schizophrenia. The primary pharmacotherapy of schizophrenia involves the use of antipsychotics, a group of drugs representing great heterogeneity in their chemical structure, pharmacological and functional profile, as well as clinical efficacy. At present, all available antipsychotics display affinity for DSchizophrenia is one of the most serious and debilitating psychiatric disorder affecting about 1% of the population disregarding economic, social, or cultural background of the society –4.The early, so called “dopamine hypothesis” stated that low prefrontal dopamine activity would cause “deficit symptoms” whereas enhanced activity in mesolimbic dopamine system would be in the background of the positive symptoms . In factRecognition of the neuroleptic action of chlorpromazine in 1952 represented a breakthrough in the drug treatment of schizophrenia . ChlorprAt the time of their discovery, the main mechanism of action of the first-generation antipsychotics was believed to be mediated by their actions on the monoaminergic system. Carlsson and Lindquist demonstrated that haloperidol and chlorpromazine increased monoamine turnover in the rat brain and these changes were attributed to the monoamine receptor antagonism action of these compounds . Van Ros1 receptors (D1Rs), D2R and serotonin 5-HT2 receptors (5-HT2R). They found that the 5-HT2R/D2R affinity ratio was the most useful means of differentiation from the typical antipsychotics. They demonstrated that compounds displaying 5-HT2R/D2R affinity ratio of 1.12 or higher were the ones showing the atypical characteristics (2A receptor (5-HT2AR) affinity that would be similar or higher than that for the D2R. The quest for compounds with D2R/5-HT2AR affinity led to discovery of risperidone, asenapine, olanzapine, quetiapine, ziprasidone, blonanserin and lurasidone, collectively classified as atypical or second-generation antipsychotics.Some antipsychotics, such as clozapine, fluperlapine and melperone were found to produce weak catalepsy in rodents, with minimal extrapyramidal symptoms and serum prolactin elevation in humans, compared to the earlier typical antipsychotic drugs, such as haloperidol. Meltzer and Matsubara explored the basis of these differences by testing the affinity of 38 antipsychotics for the rat striatal dopamine Deristics . These fAtypical antipsychotics, like to the typical antipsychotics, are efficacious in the treatment of positive symptoms of schizophrenia but display relatively lower propensity to cause extrapyramidal side effects. However, it was claimed that the label of “atypical” is not fully justified as they are different from first-generation antipsychotics only in their side effect profile  –19. In f2R, D3R and serotonin 5-HT1A receptors (5-HT1AR) as well as antagonism at serotonin 5-HT2AR and 5-HT2B receptors (5-HT2BRs) is represented by aripiprazole, cariprazine and brexpiprazole. Amongst these three partial agonist antipsychotics, aripiprazole and brexpiprazole display preferential binding affinity for dopamine D2R  family: D1 and D5 receptors (D1-receptor family) stimulate cAMP signaling pathway through a Gsα G-proteins, whereas D2-, D3- and D4-receptors (D2-receptor family) inhibit cAMP signaling through a Gi/oα G-proteins  is the highest in basal ganglia , accumbens nuclei, substantia nigra, amygdala and the frontal cortex. The cortex, substantia nigra, hypothalamus and the hippocampus express low level of dopamine D5 receptors (D5Rs). High levels of D2Rs are found in the basal ganglia, while cortical regions express low level of these receptors. D2Rs are the primary drug targets in schizophrenia, Parkinson’s disease, restless leg syndrome and neuroendocrine tumors. Highest expression of dopamine D3Rs are found mainly in the limbic system , with minor/low levels of expression in cortical regions. Dopamine D4 receptors (D4Rs) are found with relatively low level of expression in the amygdala, hippocampus, hypothalamus, cortex and, in the substantia nigra  and behavioral effects and side-effect profiles. However, their common property is that all display medium-to-high affinity for dopamine receptors of D2R-subtype  under in vitro conditions  and their degree of D3R selectivity are summarized in First and second-generation antipsychotics possess diverse structural, pharmacological  and the free plasma levels of antipsychotics were also demonstrated  helices embedded in the cell membrane connected by three extracellular (EL) and three intracellular (IL) loops (The DL) loops . The C-t2R and D3R exhibits a high level of general sequence identity which is increased in the transmembrane helices forming a highly conserved orthosteric binding site (OBS)  see . The mos ligands , 58. Mor ligands , 60. The D3R see . The SBSmbering; ] is leucentation .2R and D3R  stimulate cAMP signaling pathway through Gsα G-proteins whereas D2R, D3R, and D4R (D2R family) inhibit this pathway through Gi/oα G-proteins. There exists cAMP- independent pathways such as the recently recognized ß-arrestin pathway which is thought to be involved in several physiological functions and drugs’ effects  and D3R inhibit the enzyme adenylyl cyclase (AC) through Gi/oα subtype of G-protein leading to inhibition of cAMP-PKA-pDARPP32-PPI pathway. However, differences may exist in the coupling efficiency of the two receptors and AC (or its subtypes).Upon activation, both isoforms of D2R and D3R can activate ERK/MAPK signaling albeit with different mechanisms: D2Rs are coupled to and activate through α-subunit of Gi/o protein following agonist stimulation whereas, D3R functions through Go or Gß subunit depending on the signaling machinery of the given cell line. Both D2Rs and D3Rs are positively coupled to ß-arrestin-Akt-GSK3 pathway. GSK3ß is expressed in several brain regions and plays important role in neuronal development, neurovegetative and psychiatric diseases such as schizophrenia or bipolar disorder  for D2Rs and D3Rs . Similarly, high level of correlation was found between the affinity of antipsychotics for the rat D2R and D3Rs using [3H](+)-PHNO radioligand , the region is involved in schizophrenia pathology, and that significant correlation existed between the affinity of antipsychotics for D2Rs and D3Rs, it was thought that D3R affinity may play a role in the therapeutic efficacy of antipsychotics and led to propose development of selective D3R antagonists as novel antipsychotics , which form a lipophilic cavity. Hydrogen bond interaction with the serines in the 5.42 and 5.46 positions is typical for agonist binding state in D3R  (Non-selective ligands most probably bind to both the Dum ions) . These rum ions) .3R can be predicted at a reliable manner. In order to illustrate this, we docked several selected ligands into the D3R structures available in the Protein Data Bank  elicit catalepsy at higher doses  (3R-preferring D3R/D2R (such as S33138) antagonists  , 102 or agonists , 103 exeagonists .3R receptors in humans although their involvement is assumed in central nervous system (CNS) diseases such as schizophrenia, Parkinson’s disease, addiction, anxiety, and depression or in the clinical effects of antipsychotics  began soon after the discovery of D3R. Several antagonists fulfilling the selectivity requirements such as SB-277011A -4-propyl-9-hydroxynaphthoxazine . (+)-PHNO was originally described as an orally acting, potent dopamine receptor full agonist (3R (Ki: 0.16 nM) vs. D2R (Ki: 8.5 nM) -PHN 8.5 nM) .11C]-(+)-PHNO was synthesized by Wilson et al. -PHNO highly binds to regions rich in D3Rs. Using selective compounds such as the D3R antagonists SB-277011A, GSK598809 or the D2R antagonist SV-156, [11C]-PHNO proved to be useful for the separation of D3R and D2R binding signal and quantification of D3Rs in the brain, thus becoming an important tool for the investigation of the in vivo D3R occupancy by antipsychotics -PHNO, D3Rs are labeled in the rat cerebellum L9,10 and D2R in the striatum. This is based on the finding that the selective D3R antagonist, SB-277011 inhibited [3H](+)-PHNO binding in CB L9,10 membranes but not in the striatum whereas, the opposite profile was obtained with the D2R selective antagonist, SV-156  with significantly lower level or no occupancy in VP, ICj and substantia nigra (SN) (D3R rich regions). In contrast, in the in vitro autoradiography experiments all these antipsychotics inhibited [3H]-(+)-PHNO binding in the above regions except CB L9,10. It was concluded that under in vivo conditions the above-mentioned antipsychotics occupy dopamine D2R but not D3Rs despite their significant affinity for D3Rs in vitro  and cerebellar L9,10 region (D3R rich) to determine their in vivo D3R and D2R occupancy. The affinity data are given in Kiss et al. (in vivo binding/uptake of intravenously given [3H](+)-PHNO binding/uptake in the rat striatum and cerebellar L,910 regions. The results are summarized in 3R, full agonists pramipexole and PHNO potently inhibited [3H](+)-PHNO binding of CB L,910 membranes with marked preference toward CB L9,10 D3Rs. Cariprazine, didesmethyl-cariprazine (DDCAR), asenapine, raclopride and amisulpride, produced dose-dependent inhibition of [3H](+)-PHNO binding/uptake both in the striatal and CB L9,10 regions. Raclopride and asenapine, however demonstrated high striatal vs. cerebellar selectivity  produced inhibition of [3H](+)-PHNO binding/uptake in the striatum and little or modest level of inhibition in the CB L9,10.We extended this approach and compared the s et al. . We alsoectivity . The ant2R and serotonin 5-HT2R antagonist (in vitro for human D2R and D3Rs (Ki: 0.28 nM). Using the in vivo [3H](+)-PHNO method it caused dose-dependent, high occupancy of striatal D2R and D3R in the rat CB L9,10. In agreement with our data (see above) risperidone, olanzapine and aripiprazole demonstrated high occupancy only in the striatum and moderate or no occupancy was noted in the CB L9,10 region -PHNO PET. This study demonstrated that these antipsychotics caused high D2R occupancy in the D2R-rich dorsal striatum, using either [11C]raclopride or [11C](+)-PHNO. However, they failed to show binding signal in the D3R-rich globus pallidus using [11C](+)-PHNO (11C](+)-PHNO PET were reported by Mizrahi et al. demonstrating that in drug-naive, first episode schizophrenia patients, olanzapine and risperidone resulted in high occupancy in the D2R-rich regions but not in the globus pallidus where even “negative occupancy” was noted , in agreement with data obtained in rats, achieved significant D3R occupancy in healthy volunteers -PHNO . Similaras noted . On the lunteers .11C]raclopride -PHNO confirmed the D2R occupancy of aripiprazole however, minor levels of D3R occupancy was detected  (11C](+)-PHNO binding in brain regions with varying D2R and D3R expression. It showed significant occupancy of both D2R and D3R, albeit with approximately 3–6-fold selectivity for D3R   dose-dep for D3R , 143.2R preference   . Occupanse range .3Rs  demonstrated antipsychotic-like activity in animal experiments  compared with D2R 1 ; 1 ; . The in i values for D3Rs the picture is further complicated since like D2R, D3R may also exist in low and high affinity state. Sokoloff et al. did not find differences between affinity of dopamine for D3R in the absence or presence of Gpp(NH)p (24 vs. 27 nM)  , 80. How. 27 nM)  and Seem. 27 nM)  reportedeceptors . Affinitin vivo microdialysis in rodents, under physiological conditions the extracellular,  dopamine concentrations are in the low nanomolar range in various brain regions, including n. accumbens (∼1.5–4.5 nM), striatum (∼2–5 nM), hippocampus (∼1 nM) and in subnanomolar range in the prefrontal cortex (∼0.3–0.6 nM) (As determined by –0.6 nM) , 148–15411C]-(+)-PHNO PET Caravaggio et al. estimated that the Kd (dissociation constant) of dopamine is 22–24 nM and they reported that concentration of dopamine is between 8 and 9 nM in the ventral striatum, caudate and putamen and 2.8 nM in the globus pallidus  seem to be resistant to EEDQ-induced inactivation in vivo sites  concentration dependently reduced the vo sites .N- p-iso-thiocyanatophenethyl-spiperone) did not alkylate D3Rs receptors in n. accumbens and in the island of Calleja at doses that resulted in blockade of D2Rs receptors in caudate and n. accumbens. On the other hand, under in vitro conditions when slices from the above regions were incubated with EEDQ or NIPS, both inhibited dopamine D2Rs as well as D3Rs and inhibition at D3R sites were prevented by dopamine in nanomolar concentration range whereas only millimolar concentration of dopamine was able to protect D2Rs. The authors concluded that their results 3 receptors in vivo is prevented by its high affinity for even minor concentrations of endogenous dopamine“are consistent with the view that alkylation of D”  also did not significantly change extracellular dopamine concentration in the medial prefrontal cortex  elevated the extracellular dopamine concentrations in the rat prefrontal cortex, hippocampus, n. accumbens and in the striatum , 162. Iteceptors  which mal cortex , 161, whl cortex  blonansel cortex , and clol cortex  resultedl cortex , 163.2R antagonists can inhibit dopamine uptake via D2Rs  with D3R occupancy ED50 doses PHNO uptake/occupancy, We compared the effects of selected antipsychotics, D3R) occupancy ED50 doses, the agonists (+)-PHNO and (-)-pramipexole reduced the striatal dopamine turnover index by about 50%, whereas antipsychotics such as asenapine, haloperidol, olanzapine, risperidone, and ziprasidone and the D2R preferring antagonist SV-156 greatly enhanced (by about 3–4-fold) striatal dopamine turnover index -PHNO uptake) which were much lower than that of necessary for 50% occupancy of CB L9, 10 D3Rs, all antipsychotics  caused much less increase in dopamine turnover index -pramipexole and (+)-PHNO (which is probably due to the D2R agonist effects manifested under in vivo conditions). At pharmacological doses, neither cariprazine nor its one of the major metabolite, DD-CAR did not seem to alter significant alteration in dopamine metabolism in rat striatum.The results of dopamine turnover studies, in agreement with microdialysis results, indicate that D2R and D3R affinity and selectivity of some D3R selective antagonist, agonists, and antipsychotics along with their D3R occupancy determined in rats or in human.In in vitro affinity data one may expect compounds with low-or sub-nanomolar affinities for both receptor subtypes, would show D2R as well as D3R occupancy in vivo. However, the preclinical and human occupancy studies summarized above do not necessarily support such a correlation.Based solely on the 3R-preferring agonist, (+)-PHNO and pramipexole as well as the antagonists  all display low- or sub-nanomolar D3R affinity and high selectivity for D3Rs in vitro. These compounds produced D3R occupancy in rat or human studies. The same  is applicable for the partial agonists, cariprazine and its metabolite, DD-CAR. Although aripiprazole and brexpiprazole displayed low nanomolar in vitro D3R affinity, their D3R selectivity was below 1, which could explain their lack of D3R occupancy in vivo. Among the currently used antipsychotics, only the D2R/D3R antagonist blonanserin, which has low- or sub-nanomolar affinity for these receptors has been shown to have significant in vivo occupancy for both receptors in rats. Second generation antipsychotics  with low D3R affinity (Ki: >3–10 nM) and selectivity resulted in negligible D3R occupancy.Both D3Rs in the rat or human brain comes from the use of [3H](+)-PHNO or the [11C](+)-PHNO radiotracers. Their use represented a great advance in the in vivo imaging of D3Rs and determination of occupancy of brain D3Rs by antipsychotics.Our knowledge about the occupancy of D3H](+)-PHNO or the [11C](+)-PHNO however, are not ideal ligands/tracers for several reasons. They may not be sensitive enough for more detailed mapping of D3Rs in regions having low D3R expression e.g., cerebral cortex. Although both display higher affinity than dopamine for D3R, they are still sensitive to endogenous dopamine  continues  may greatly change the affinity of the two receptors toward the agonist tracer and the affinity of drugs to be examined and their occupancy. Thus, the quest for better ligands (agonist or antagonist?) for the demonstration of brain Dontinues , 181.2Rs  there is no reliable information on the optimal level of D3R occupancy for manifestation of therapeutic effect.Moreover, in contrast with the known therapeutically optimal occupancy of antipsychotics at D2R and D3Rs in vitro. In agreement with the in vitro D2R affinity they show significant D2R occupancy in the rat and human brain at their antipsychotic-effective doses. However, as revealed by animal and human occupancy studies, despite the considerable in vitro D3R affinity, not all antipsychotics demonstrated brain D3R occupancy in vivo.All currently used antipsychotics display high-to-medium affinity for both DThere may exist several possibilities for this dichotomy, as outlined in the following:3Rs than for D2Rs and thus endogenous dopamine might, at least partly, keeps D3Rs occupied even under basal conditions.First, dopamine displays much higher affinity for D2Rs, leads to several-fold increase of extracellular dopamine. Further, Amato et al. demonstrated that antipsychotics initially suppress dopamine transporter (DAT) activity leading to increase of dopamine in synaptic cleft, a mechanism which represents a further possible alternative way to modulate extracellular dopamine -pramipexole and (+)-PHNO reduced dopamine turnover, i.e., they decrease extracellular dopamine and increase D3R availability. Administration of antipsychotics , due to antagonism of presynaptic and biosynthesis and release regulating Ddopamine . Thus, t3R antagonists (D3R vs. D2R selectivity ≥100) such as ABT-925, GSK595809 and SB-277011 (with the in vitro low nanomolar D3R) affinity produced high D3R occupancy in animal or human studies, indicating primary importance of selectivity to achieve D3R occupancy in vivo.Third, beside the effects on the endogenous dopamine levels, the D3R affinity and selectivity appear to be further factors of importance. All three selective D3R/D2R partial agonist cariprazine and the D2R/D3R antagonist blonanserin shows that, in the presence of relatively high affinity for D2Rs, subnanomolar affinity for D3Rs appears to be necessary for D3R occupancy in vivo. Further, cariprazine and the F17464 (subnanomolar affinity for D3R with 75-fold D3R vs. D2R), do not increase extracellular dopamine and hence are able to compete for D3Rs vs. extracellular dopamine.Example of antipsychotics such as the D2R/D3R partial agonist antipsychotics, aripiprazole and brexpiprazole is somewhat controversial. Both demonstrated low nanomolar affinity for D2Rs and D3Rs (with D2R preference) in vitro, with negligible effects on extracellular dopamine in vivo. However, both produced no or very low occupancy of D3Rs for which the likely explanation is the D2R preference.The case of Din vitro D2R/D3R affinity vs. their brain D3R occupancy in vivo, indicate that levels of extracellular dopamine (or its change) in different brain regions is a key factor regarding D3R occupancy. On the other hand, the compounds’ high  D3R affinity and/or high D3R vs. D2R selectivity are also important determining factors to achieve significant D3R occupancy in the brain.In conclusion, data reviewed and discussed here regarding the current antipsychotics’ BKi and BKr drafted the manuscript with several inputs from IL. All authors were participating in the final editing and critical revision of the article and approved the final version to be published.BKi, BKr, and IL were employees of Gedeon Richter Plc.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.


The experimental STEM images along [001], [011] and [111] orientations suggest that the divalent Mg2+ cations occupy all A sites, and the trivalent Fe3+ cations occupy all B sites in MgFe2O4 ferrite prepared by electrospinning, which is consistent with the normal spinel structure. We further clarify that the preferred sites of dopant Zn2+ ions are Fe3+ crystallographic sites in the Zn-doped MgFe2O4 ferrite nanofibers. Magnetic measurements show that Zn doping affects the spin states of the Fe3+, and the Fe3+-O2−-Fe3+ super-exchange interaction leads to enhancements in the magnetization and reduction in the Curie temperature. Our work should contribute a significant step toward eventually realizing the practical application of doped spinel ferrites.Determining the exact occupation sites of the doping ions in spinel ferrites is vital for tailoring and improving their magnetic properties. In this study, the distribution and occupation sites of cations in MgFe Twenty-four metallic ions occupied two interstitial crystallographic sites, including tetrahedral and octahedral sites. They showed a distribution of parallel and antiparallel magnetic moments in two sub-lattices, which resulted in a net magnetic moment per formula unit and eventually determined the unique magnetic properties of the spinel ferrites. Their magnetic properties could be systematically varied by changing the identity of the divalent M2+ cation or by a partial substitution while maintaining the basic crystal structure.The direct imaging of atomic structures, especially in the site preference of substituted ions, is vital for magnetic materials to correctly explain their magnetic performance and provide guidance for potential commercial applications, including microwave devices, magnetic storage media, ferrofluids and biomedical devices ,4,5,6,7.2O4), an important functional soft magnetic  [3+ sub-lattices of the spinel structure, such as ZnxMg1−xFe2O4 [2+ ions are selected as doping ions to further improve the magnetic performance of the MgFe2O4 ferrite. However, the preferred site of the dopant Zn atoms is indistinct, so a satisfactory explanation of the magnetic properties of Zn-doped MgFe2O4 is still a matter of debate. Therefore, it is necessary to image their specific distributions in a sub-ångstrom resolution. Among the techniques for detecting the distributions and the preferred site of the doping ions [2O4 nanofibers and the influence of the substitution and occupancy of doped Zn2+ on their magnetic properties. Biocompatible magnesium ferrite (MgFe~ 713 K) ,18 and a~ 713 K) , is an i~ 713 K) ,21. Rece~ 713 K) . Many at~ 713 K) ,24. The 1−xFe2O4 ,26,27,28ing ions ,33,34,352O4 nanofibers were directly and precisely observed by Cs-STEM, which demonstrated that dopant Zn2+ cations preferred to randomly occupy Fe3+ crystallographic sites rather than Mg2+ sub-lattices to modify magnetic properties. The findings indicated that the Zn2+ substitution results in an increase in magnetization and a decrease in the Curie temperature. These results offer insights into interactions between dopant atoms and the magnetic properties in spinel structures and provide guidance for designing magnetoelectric multiferroics applications.In this study, the occupation sites and the occupancies of trace dopants in Zn-doped MgFe2O4 (MFO) and MgZn0.2Fe1.8O4 (MZFO) nanofibers were synthesized by electrospinning. A typical precursor solution was used , which contained 0.1 mmol of magnesium nitrate hexahydrate, 0.2 mmol of iron nitrite nonahydrate ; 5 mL of N, N-dimethyl formamide  was dissolved into a glass container marked as A solution. Next, 1 mL of A solution, 1 mL of ethanol alcohol and 0.1786 g of poly vinylpyrrolidone  were dissolved into a 5 mL vessel combined with sufficient stirring for 4~5 h. A typical precursor solution was successfully obtained. The electrospinning process was performed with 18 kV DC voltage with a 15 cm gap between the needle tip  and the collector; the feed rate was 0.4 mL⋅h−1. The electrospun polymer composite nanofibers were first heated at 200 °C for 2 h and then calcined at 900 °C for 3 h with a heating rate of 1 °C⋅min−1 in air. The samples were finally cooled to room temperature with the same rate of 1 °C⋅min−1.Synthesis of MFO and MZFO nanofibers. Single-particle-chain normal spinel MgFeCharacterization of MFO and MZFO nanofibers. The morphology and atomic-level crystal structures of the individual single-particle-chain MFO and MZFO nanofibers were systemically characterized with an aberration-corrected scanning transmission electron microscope , which operated at 300 kV and was equipped with a monochromator, Gatan image filter , EDX . And an X-ray diffraction instrument . Magnetic properties were investigated using a superconducting quantum interference magnetometer  and a magnetic property measurement system .2O4 nanofibers (MFO) and Zn-doped MFO nanofibers (MZFO) were prepared using the electrospinning method. All nanofibers had a continuous structure and uniform chemical composition  and the bright blue spheres represent Fe cations (the atomic radius is 1.27 Å). Single-particle-chain MgFetion ESI . The avetion ESI . MFO nantion ESI . Figure The atomic-scale cation occupations and distributions of individual MFO single-particle-chain nanofibers were then captured using Cs-STEM. As shown in Mg < ZMg–Fe < ZFe) and the number of atoms (the length of the column). The atomic number of iron (Z = 26) was significantly higher than magnesium (Z = 12) when the number of atoms on the atomic column was the same or similar, so the atomic columns of pure Fe and mixed Mg-Fe were much brighter than the pure Mg atomic columns. However, when the number of atoms on the atomic column greatly differed, the contrast of images of different atomic columns was sensitive to the number of atoms rather than the atomic number. It is noted that the contrast of the HAADF-STEM image is sensitive to the effective atomic number Z  and coercivity (Hc) of MZFO nanofibers at 300 K were 54.7 emu/g (2.30 μB/fu) and 82 Oe, respectively, and the saturation magnetization (Ms) and coercivity (Hc) at 5 K were 92.2 emu/g (3.87 μB/fu) and 145 Oe, respectively, compared to the pure MFO nanofibers with 42.3 emu/g (1.78 μB/fu) 102 Oe at 300 K and 60.8 emu/g (2.55 μB/fu) 167 Oe at 5 K. It was found that the saturation magnetization (μB/f.u.) of MZFO nanofibers increased by 0.52 μB/f.u. and 1.32 μB/f.u. at 300 K and 5 K, respectively, and the coercivity had a slight tendency to increase.In order to further verify the correlation between crystal structure and magnetic properties, SQUID and MPMS technologies were used to characterize the magnetic properties of the normal spinel MFO nanofibers and Zn-doped MFO nanofibers. The external magnetic field (3 T) dependence on the magnetization of the MZFO and MFO nanofibers at 300 K and 5 K is shown in Ms and coercivity Hc should relate to the substitution of Zn2+ cations for Fe3+ cations at the octahedral sites, including the occupied sites; canted spin structure; and the super-exchange interaction between the cations and the O2- anions [Mnet) is calculated by the following:MB and ∑MA represent the moment sum of cations located at octahedral sites and tetrahedral sites, respectively. The magnetization of the nanofibers depends on the distribution of the magnetic Fe3+ ions among the two sites because the Mg2+ and Zn2+ ions are non-magnetic.The increase in saturation magnetization - anions , of whic- anions , the cat2O4 ferrites, all non-magnetic Mg2+ ions occupy the tetrahedral A sites, and all magnetic Fe3+ ions occupy the octahedral B sites. In the present study, Zn-doped MgFe2O4 ferrites, non-magnetic Zn2+ ions preferred occupying the octahedral Fe3+ site. A small amount of Zn2+ ions substituting Fe3+ ions increased the valence of the surrounding trivalent Fe3+ ions to Fe3+x ions, which may have contributed to the increase in the saturation magnetization. The coercivity was related to magnetocrystalline anisotropy (K1 ~ −2.46 × 104 erg/cm3 for MgFe2O4) and crystallite size in spinel magnetic ferrites. Therefore, the slight increase in coercivity could be attributed to the enhancement in magnetocrystalline anisotropy of ferrites due to the substitutions of Zn2+ ions in MgFe2O4 ferrite. The minor change in coercivity means that Zn doping does not change the soft magnetic properties of MgFe2O4 ferrite.The exchange interactions between two sub-lattices have different intensities; the antiferromagnetic A-B interaction is stronger than the ferromagnetic B-B interaction and A-A interaction, and the ferromagnetic A-A interaction is the weakest. In the normal spinel MgFeTc. It was evident that the Tc of MFO nanofibers was 725 K, which was higher than the value reported for MFO (713 K) in the literature [2+ ions were doped, the Tc of MZFO ferrite dropped to 690 K. The substitution of Zn ions for magnetic Fe ions reduced the Fe3+-O2--Fe3+ super-exchange interaction, eventually lowering the Curie temperature. The paramagnetic Curie point Tp of the MFO and MZFO nanofibers were 904 K and 852 K, respectively, as shown in T > Tp, the nanofibers were in a completely pure paramagnetic state.The Curie temperature of MFO and MZFO nanofibers was further measured in the temperature range of 300–950 K at the applied external magnetic field of 3 T, as shown in terature . When th2+ cations only randomly substitute for the Fe3+ sites rather than non-magnetic Mg2+ sub-lattices sites. Furthermore, the magnetic characterization showed that the Zn doping affects the spin states of the Fe3+, and the Fe3+-O2−-Fe3+ super-exchange interaction leads to an enhancement in magnetization and a reduction in the Curie temperature. We demonstrated that the doping of cations in spinel ferrites is an effective method to improve magnetic properties through tailoring the spin states of the cations and the occupation sites of the trace dopants, which provides guidance to modify the magnetic properties for the development of the next generation of multi-functional magneto-electric devices. In summary, we proved that the MFO nanofibers synthesized by electrospinning have a normal spinel structure by directly observing the occupancy and distribution of cations using Cs-STEM. The atomic HAADF-STEM images, combined with the theoretical atomic model and line intensity distribution, revealed that the dopant Zn


The current SARS-CoV-2 pandemic has exacerbated the rapid diagnosis of infectious diseases outbreaks to take suitable epidemiological measures to minimize negative impacts , for instance , carried by high-risk clone ST277 isolated from urban rivers. The authors observed a common resistome and virulome between clinical and environmental SPM-1-producing P. aeruginosa strains endemic from Brazil. Additionally, the SNP-based phylogenomics showed a high similarity between clinical and environmental genomes, suggesting that these clones could be disseminated onto water bodies from hospital settings.Hospital wastewaters represent a broad reservoir of antibiotic-resistant bacteria (ARB) and ARGs, which include extended-spectrum β-lactamases (ESBLs) and carbapenemase-producing Perry et al. analyzed the influence of different hospital clinical activities on the abundance of ARGs in hospital wastewater in Scotland, highlighting the advantages of shotgun metagenomics to identify a full range of ARGs that could be used to guide environmental policies about AMR. Additionally, the article of Guo et al., using a high-throughput sequencing-based metagenomic approach, investigated the composition of bacteria and ARGs in wastewater from hospitals in China, suggesting a correlation between the abundance of ARGs and specific bacterial genera and remarking that it is necessary to complement their study including physicochemical analysis for the raw wastewater. Both articles show interesting results and note the necessity to develop an integrative framework that would include omics, physicochemical and epidemiological research to enhance the evaluation of ARGs pollution in environmental sources.One of the current outstanding questions about the analysis of AMR in the environment is the standardization of genomic and metagenomic assays that could minimize the spatiotemporal variability, the allochthonous ARG levels, the environmental resistome complexity, and the biases about genomic extraction, sequencing, and genomic analyses  E. coli isolated from influents of a WWTP. This study suggests that these isolates could be disseminated into the outgoing river from WWTP. The sewage could act as a potential spreader of ARGs, including emerging carbapenemase genes like blaNDM−5. In South Africa, Mbanga et al. characterized isolates of Enterococcus spp. from a WWTP and their receiving water bodies that serve as a water source for domestic, agricultural, and recreational purposes. Those isolates harbor a wide plethora of ARGs and virulence factors, showing that the effluents of the WWTP could act as a dissemination vector of multidrug-resistant (MDR) microorganisms. This Research Topic includes a review paper by Uluseker et al. that extensively reviews the current knowledge on sources, spread, and removal mechanisms of ARGs in microbial communities of wastewaters, WWTPs, and downstream recipients. This review includes the basis of antibiotic resistance, an explanation about the dynamics of AMR and antibiotics in WWTPs, and suggestions to be considered for the operation, regulation, and design of WWTPs. These studies suggest the urgent need for regular surveillance and management of water bodies to limit the spread of these isolates.Several papers of this special issue analyzed the influence of WWTPs and their discharges on AMR dissemination: In South Korea, Singh et al. analyzed Escherichia coli from the river Yamuna (India), a highly polluted river that receives an intense anthropogenic influence from urban and animal origin. Their results showed high AMR profiles, highlighting the presence of CTX-M-15 type ESBLs and the occurrence of class I integrons in their isolates. In Ireland, Sala-Comorera et al. demonstrated the strong impact of different watercourses discharges onto the levels of AMR in both bacterial and bacteriophage fractions in marine bathing waters, which may expose the users to fecal pollution and therefore could increase the probability to be exposed to ARGs. Another outstanding question about AMR in the environment is to demonstrate which levels of AMR are necessary to represent a real environmental danger. Finally, Pallares-Vega et al., shown by in vitro assays the role of ecological factors that could hamper conjugative plasmid transfer from gut bacteria once discharged into the environment. Their findings highlight the possibility that the fecal organisms may transfer plasmids in aquatic ecosystems, despite the variable conditions that could occur environmentally.Montero et al. analyzed ESBL producing E. coli isolated from irrigation waters, vegetables, and fruits in Ecuador. These authors detected that the allelic variants of the blaMCTX− gene found in irrigation channels and vegetables were the same as those observed in commensal E. coli from domestic animals, and commensal and pathogenic E. coli from humans, suggesting a connection between these different sources. In addition, the article of Cheng et al. analyzed sediments from aquaculture farms in China by constructing network plots based on 16S rRNA metagenomics, physicochemical analysis, and quantification of ARGs. Their results provide evidence for understanding the environmental risks associated with aquaculture practices. On the other hand, Ye et al. showed in Edwardsiella tarda, an important pathogen in aquaculture, that reactive oxygen species (ROS) play a role in bacterial resistance and sensitivity to ceftazidime. They saw a lower ROS production in ceftazidime-resistant E. tarda than in a sensitive strain related to the inactivation of the pyruvate cycle. Additionally, their study reveals a new mechanism that increases ROS production, the activation of the pyruvate cycle by Fe3+. These findings provide tools and knowledge for future new strategies to fight MDR pathogens.The food supply chain connects environmental sources of bacteria with humans and represents another outstanding field in the One Health perspective for understanding the dissemination and evolution of AMR. The article of Zeballos-Gross et al. comprehensively reviewed the potential role of gulls as reservoirs and vectors of AMR in the environment, highlighting the current knowledge about related research, the phenotypic and molecular characterization of AMR, limitations about the existing methodologies, and suggestions for improving the derived results.In summary, this Research Topic provides an excellent update of the role of aquatic ecosystems on the evolution and dissemination of AMR worldwide. Therefore, the editors encourage the scientific community to consider the results and challenges of this special issue.WC-C, JO-P, LR-R, and EM contributed to analyzing the reviewed articles and preparing the manuscript. All authors contributed to the article and approved the submitted version.LR-R is a Serra Húnter Lecturer.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.


N-dimethylformamide (DMF) and tetrahydrofuran (THF) as reducing solvents with 8% of poly-ε-caprolactone (PCL) polymer. The solutions were electrospun, and the nanofibers obtained in the process were characterized by infrared spectroscopy, Raman spectroscopy, dark field optical microscopy, scanning electron microscopy and X-ray scattering spectroscopy. The nanofibers had an average diameter of 400 ± 100 nm. Once the characterization of the material was done, three implants of each concentration of the nanofibers were formed and placed in the subcutaneous tissue of the rats. Three experimental subjects were used, leaving the material in them for a length of two, four and six weeks, respectively. The rats showed good healing, with the lesions completely healed at four weeks after implantation. After that time, biopsies were taken, and histopathological sections were made to evaluate the inflammatory infiltrate. The tissues of the rats presented chronic inflammatory infiltrate composed mainly of lymphocytes and giant multinucleated cells. The material was rejected by the rats when a layer of collagen and fibroblasts was produced, coating the material, a process characteristic of a foreign body reaction.Currently, nanotechnology is perceived as a promising science that produces materials with diverse unique properties at a nanometric scale. Biocompatibility tests of poly-ε-caprolactone nanofibers, embedded with silver nanoparticles manufactured by means of the electrospinning technique, were carried out in Wistar rats to be used as oral dressings for the eradication of bacteria. Solutions of 12.5, 25, 50 and 100 mM of silver nitrate were made using  Over the years, there has been a need to correct problems related to tissue loss due to trauma, disease or deterioration. This has oriented research to the development of materials that can be used to reproduce the function of living tissues in biological systems in a safe and physiologically acceptable way. These materials are known as biomaterials, products used to reproduce the function of living tissues in biological systems safely . When a To ensure the functioning and success of a new biomaterial, it is necessary for the material to pass a series of tests that are carried out before clinical tests. These tests are mechanical simulations, in vitro tests, toxicological tests and in vivo tests in experimental animals. The set of these tests will determine the biocompatibility of the materials . 3- were weighed, and the different masses were added to the 10 mL DMF/THF solutions, obtaining concentrations of 12.5, 25, 50 and 100 mM. 0.8 g of poly-ε-caprolactone (PCL) was added to the solutions and mixed for one hour at 50 °C. Once the solutions were prepared, the electrospinning process was continued [The composite was fabricated using a modified version of the methodology by Pazos-Ortiz et al. . A totalontinued . ParticlPCL/Ag solutions were placed in a 10 mL volume container using a 14.5 mm diameter glass syringe. A 0.80 mm diameter stainless steel needle was attached to the syringe. The syringe was placed in the injector pump , which was programmed with a flow in a range of 7 to 10 µL/min. An aluminum foil was placed in a rotating collector; the distance between the collector and the tip of the needle was 8 cm. Finally, the positive pole of a power source was placed on the needle and the negative pole on the rotary collector, and a voltage in the range of 10 to 14 kV was administered. The electrospinning process was carried out for an estimated time of 3–5 h to obtain the nanofibers. This process was done for each solution prepared . After the process, the nanofibers were stored in previously labeled plastic for storage.The PCL/Ag fibers obtained by the electrospinning technique were characterized by infrared spectroscopy (FTIR) using an Alpha platinum-ATR Bruker spectrometer ; a WITec’s Raman spectrophotometer Alpha-300 R  with a 532 nm laser was used for Raman spectroscopy. For scanning electron microscopy (SEM), a JEOL JSM-6400 device  operated at 20 kV equipped with an X-ray scattering spectrometer (EDX) was used. The magnifications used were 5000×, 10,000× and 20,000×. For each characterization technique, a sample of each fiber measuring 1 cm × 1 cm was used.Wistar rats , weighing approximately from 150 to 300 g, were used, divided into three groups, and one rat was used as a control. Each of the rats was housed individually in conditions established by the American Veterinary Medical Association’s (AVMA) and NOM-062-ZOO-1999 technical specifications for the production, care and use of laboratory animals during the entire process of the experimental phase.Each of the rats was housed individually in conditions established by the Institutional Animal Care and Use Committee (IACUC), Comite Institucional de Etica y Bioetica, Universidad Autonoma de Ciudad Juarez (CIEB-UACJ) and the NOM-062-ZOO-1999 technical specifications for the production, care and use of laboratory animals during the entire process of the experimental phase .It was carefully verified that the rats were fully anesthetized and that the personnel performing the procedure were fully trained. Three fractions were taken from each concentration of the nanofibers. The implants measured approximately 5 mm in length by 1.3 mm in internal diameter. Once the implants were made, they were UV-sterilized for a half-hour to avoid any type of contamination during the implantation process.For the anesthetic process, an intramuscular injection of ketamine/xylazine  was performed in one of the hind legs of the rats. After anesthetizing the rats, the dorsal area was shaved and then covered with iodine  to avoid any infection during the surgery. After applying anesthesia, the material was implanted. With the help of a previously sterilized veterinary surgical kit, 4 incisions were made in the dorsal part of the rats. Once the PCL/Ag was implanted, the wounds were sutured with 2 points per incision.Euthanasia was done at 2, 4 and 6 weeks after implantation (one rat every 2 weeks). Intravenous injection of sodium pentobarbital is the preferred method for euthanizing horses, dogs, cats and rodents. A quick and painless death is caused in the body . An overFor inclusion in paraffin, the biopsies were placed in cassettes to be subsequently dehydrated by ethanol  with a gradation increasing to 100%. After doing so, the samples were transferred to xylene , which was used as an intermediate reagent. The cassettes were taken and transferred to paraffin previously liquefied in an oven. Liquid paraffin was poured into various molds. Samples were introduced and refrigerated at 4 °C for hardening. The paraffin blocks with the tissues were cut and, once the cuts were obtained, they were placed in a 37 °C water bath to warm them up. Afterwards, the cuts were placed in an oven at 60 °C for the deparaffinization process. Tissues were rehydrated with decreasing ethanol until they reached water. Tissues were dipped in hematoxylin (Sigma Aldrich) for 3 minutes, washed with water, then dipped in eosin (Sigma Aldrich) for 30 sand washed with ethanol to remove traces of dyes. Tissues were dehydrated again with increasing ethanol. Once the coverslip was placed on the slide with the histopathological cut, the tissues were observed under a microscope. Finally, the plates were observed in an Oxion light microscope at 10× and 40× and photos were taken by a Cemex camera .+, compared to other organic solvents such as ethanol [The four polymer solutions were spun by the electrospinning technique to obtain the nanocomposite. The fibers were made under specific conditions of voltage, distance between the injection source and the collecting plate, humidity, and flow rate. In the synthesis process of the PCL/Ag nanofibers, a polymeric solution reduced by DMF was used. DMF is a compound of organic origin used as a solvent and reducing agent in various processes in which silver salts are involved, in this case silver nitrate. Reduction with DMF is one of the most used and one of the best techniques for the reduction of Ag ethanol . The sil−1; a band with great intensity can be observed around 1700 cm−1, and bands with less intensity can be observed between 2700 and 3000 cm−1. In the infrared spectrum, stretch bands of the carbonyl group (C=O), characteristic of the PCL, are observed between 1700 and 730 cm−1. The bands that appear in the region between 2800 and 3000 cm−1 are related to carbon/hydrogen (C–H) bonds. Bands do not appear between the 2500 and 2000 cm−1 region; this region is characterized by the absence of bands [−1 regions, making it difficult to assign an origin to particular bands. The band at 1294 cm−1 corresponds to the ether group (COC), and the band at 1190 cm−1 to the ester group (OCO). Between 1280 and 1295 cm−1 are the stretch bands for single bonds such as alkanes (CC) and carbonyls (CO) [The infrared spectra obtained for each of the nanofibers  identifyof bands . In the −1 is generally assigned to the silver–oxygen compound (Ag–O) or to the ionic species absorbed in the polymer. Several narrow peaks at 934 cm−1 correspond to the ester group (vC–COO) and others within the 1000–1150 cm−1 spectral range correspond to the stretching of the skeleton. The peaks at 1280–1350 cm−1 (ωCH2), 1400–1500 cm−1 (δCH2) and 2800–3000 cm−1 (vCH) refer to the crystalline fraction of the PCL. The wide peak at 825 cm−1 indicates that the amorphous phase is present in the PCL fibers [Raman spectroscopy is a versatile method that allows us to study the degree of amorphous and crystalline phases of nanocomposite membranes. The Raman spectrum of PCL/Ag nanofibers is shown in L fibers . AccordiThe PCL/Ag nanofibers presented a smooth, cylindrical surface, without the presence of pores, with random orientation, without the presence of fractures and branched, as can be seen in Applying silver to experimentally induced wounds in rats shows rapid and efficient healing. If silver has a beneficial effect on the healing process, it can serve as a collaborator in the treatment of surgical wounds. The agrees with the results obtained from healing since, 2 weeks after implantation, good healing was already observed, and at 4 weeks after implantation, the lesions were completely healed, and at 6 weeks, there were no traces of lesions, as can be seen in In Biodegradable polymers of natural origin are ideal for carrying out tissue engineering processes due to their low immunogenic potential and their ability to interact with tissue. On the other hand, PCL is a synthetic polymer with long degradation times depending on its molecular weight. PCL can be biodegraded by living organisms in the open air such as bacteria and fungi, but it cannot be biodegraded in animals or human bodies due to a lack of adequate enzymes to carry out the process. It is not ruled out that it cannot be degraded in the body, but rather that the process takes longer, spreading mainly by hydrolytic means . The morWhen lesions were made in the rat tissue, a natural inflammatory response was generated due to the loss of tissue continuity, caused by lesions in the vasculature found in the subcutaneous connective tissues . InflammThe foreign body reaction indicates that there was a rejection by the Wistar rats of PCL/Ag. The foreign body reactions may be caused by an excessive amount of implanted material, which, as previously discussed, was the case. At the time of implantation of the PCL/Ag, protein adsorption was carried out from different pathways activated by the initial injury. The main pathways involved to start the healing process are the coagulation pathway, the complement system, the fibrinolytic system and platelet aggregation . Once thWith the arrival of neutrophils at the implantation site, an attempt is made to phagocytose the PCL/Ag, a case that is impossible because the size of the implant is greater than the neutrophils, a process called “frustrated phagocytosis”. Since the event was not resolved, it gives way to chronic inflammation characterized by the presence of lymphocytes, monocytes, macrophages, plasma cells and giant cells. These cells cover the material, generating a fibrous layer with the intention of isolating the material from the organism as shown in PCL/Ag nanofibers were manufactured using the electrospinning technique with a nanometric size of 400 ± 100 nm. The diameter of the nanofibers decreased as silver was added to their conformation due to an increase in the conductivity of the solutions. Scanning electron microscopy showed that the nanofibers are smooth, cylindrical and randomly oriented. IR spectrum, Raman and EDX showed that the PCL composite is embedded with silver. The wounds made in the implantation area healed completely at four weeks. PCL/Ag nanofibers generated chronic inflammatory infiltrate in the subcutaneous tissues of Wistar rats at 2, 4 and 6 weeks after implantation. A foreign body reaction to the PCL/Ag nanofibers was generated by the Wistar rats. The composite was not biocompatible because it generated an inflammatory infiltrate in the subcutaneous tissue of the Wistar rats, accompanied by a foreign body reaction. In the same way, thanks to this study, it is recommended to carry out future studies by placing single-layer nanocomposite implants and in a smaller quantity. This is recommended so that the reaction to foreign bodies is not carried out.