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B. dracunculifolia is popularly used to treat skin diseases. This work aimed to evaluate the topical anti-inflammatory properties of B. dracunculifolia root extract (BdR) and its major compound baccharis oxide (BOx) on mice ear edema models. BdR was analyzed by GC-MS, and BOx was isolated by chromatographic fractionation. Topical anti-inflammatory activities were determined by using the croton oil, capsaicin, histamine, and phenol-induced mouse ear edema models. N-acetyl-β-D- glucosaminidase (NAG) and myeloperoxidase (MPO) activities, as well as NO dosage and histopathological analyses, were also evaluated. Phytochemical analysis of BdR showed BOx as one of the major constituents. BdR and BOx (both at 0.1, 0.5, and 1.0 mg/ear) significantly reduced croton oil, histamine, and phenol-induced ear edema, while only BOx was effective in reducing capsaicin-induced edema. MPO and NAG activities, as well as NO production, were significantly inhibited by BdR and BOx. Histopathological analysis confirmed the topical anti-inflammatory properties of BdR and BOx. Our findings showed that BdR and BOx demonstrated significant topical anti-inflammatory effects in mouse ear edema induced by different agents, suggesting their possible application on skin inflammatory diseases.

To investigate the efficacy and safety of preoperative arterial embolization for neurogenic heterotopic ossification of the hip.This single-center retrospective study reviewed outcomes in 16 consecutive patients who had surgical resection of neurogenic heterotopic ossification of the hip, 8 of whom underwent preoperative arterial embolization and 8 of whom did not. Both patient cohorts had similar baseline characteristics. A mean of 2.62+/-1.9 arteries per patient including gluteal, lateral circumflex femoral and deep circumflex iliac branches were embolized using a NBCA - Lipiodol mixture. Data from both cohorts regarding intraoperative blood loss, volume of blood transfused, complications and duration of hospitalization, were compared.A mean of 2.6±1.9 arteries was embolized with NBCA-Lipiodol, mainly gluteal arteries, lateral circumflex femoral artery and deep circumflex iliac artery. In the embolization group, mean intraoperative blood loss was 875±320ml, mean number of units of blood used was 0.5±0.7, and number of days of hospitalization was on average 6.4±1.6 days. In the control group, mean intraoperative blood loss was 1350±120 ml, mean number of units of blood used was 2±1.1, and number of days of hospitalization was on average 11.5±1.4. The embolization group had an average reduction in blood loss of 35.2% (p0.05), reduction of units of blood administered of 75% (p0.05), and reduction of days of hospitalization of 44.3% (p0.05). No procedural complications were recorded.Preoperative arterial embolization is effective and safe in reducing intraoperative blood loss, number of hospitalization days, and need for blood transfusions in surgical resection of neurogenic heterotopic ossification of the hip.

Introduction Staging of the mediastinum lymph nodes involvement in patients with non-small cell lung cancer (NSCLC) is an important prognostic factor determining the most appropriate multimodality treatment plan. The objective of this study is to assess ultrasound characteristics of mediastinal lymph nodes metastasis and effectiveness of intraoperative ultrasound-guided mediastinal nodal dissection in patients with resected NSCLC. Materials and Methods All patients undergoing video-assisted thoracoscopic surgery lobectomy and pulmonary lymphadenectomy from November 2020 to March 2022 at the thoracic surgery department of the Vanvitelli University of Naples underwent intraoperative ultrasound-guided mediastinal lymph nodal dissection. Results This study evaluates whether individual B-mode features and a compounding thereof can be used to accurately and reproducibly predict lymph node malignancy. Discussion Intraoperative ultrasound, during systematic mediastinal lymph node dissection, is helpful in preventing lesion to mediastinal structures. Pathological nodal sonographic characteristics are round shape, short-axis diameter, echogenicity, margin, the absence or presence of coagulation necrosis sign, and the absence or presence of central hilar structure, increased color Doppler flow, the absence or presence of calcification, and nodal conglomeration. Operating time was not substantially prolonged. The procedure is simple, safe and highly accurate. Conclusions Ultrasonic techniques allow surgeons to detect the relationship between lymph nodes and surrounding large blood vessels during biopsy, improving the safety and simplicity of the operation, increasing the number of harvested lymph nodes, and reducing the risk of intraoperative injury; it is a fast, easily reproducible, and inexpensive method.

Background Allogeneic hematopoietic stem-cell transplantation is the standard of care for Hurler syndrome (mucopolysaccharidosis type I, Hurler variant [MPSIH]). However, this treatment is only partially curative and is associated with complications. Methods We are conducting an ongoing study involving eight children with MPSIH. At enrollment, the children lacked a suitable allogeneic donor and had a Developmental Quotient or Intelligence Quotient score above 70 (i.e., none had moderate or severe cognitive impairment). The children received autologous hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with an alpha-L-iduronidase (IDUA)-encoding lentiviral vector after myeloablative conditioning. Safety and correction of blood IDUA activity up to supraphysiologic levels were the primary end points. Clearance of lysosomal storage material as well as skeletal and neurophysiological development were assessed as secondary and exploratory end points. The planned duration of the study is 5 years. Results We now report interim results. The children's mean (+/- SD) age at the time of HSPC gene therapy was 1.9 +/- 0.5 years. At a median follow-up of 2.10 years, the procedure had a safety profile similar to that known for autologous hematopoietic stem-cell transplantation. All the patients showed prompt and sustained engraftment of gene-corrected cells and had supraphysiologic blood IDUA activity within a month, which was maintained up to the latest follow-up. Urinary glycosaminoglycan (GAG) excretion decreased steeply, reaching normal levels at 12 months in four of five patients who could be evaluated. Previously undetectable levels of IDUA activity in the cerebrospinal fluid became detectable after gene therapy and were associated with local clearance of GAGs. Patients showed stable cognitive performance, stable motor skills corresponding to continued motor development, improved or stable findings on magnetic resonance imaging of the brain and spine, reduced joint stiffness, and normal growth in line with World Health Organization growth charts. Conclusions The delivery of HSPC gene therapy in patients with MPSIH resulted in extensive metabolic correction in peripheral tissues and the central nervous system. (Funded by Fondazione Telethon and others; ClinicalTrials.gov number, ; EudraCT number, .)Hematopoietic Gene Therapy for Hurler Syndrome Eight patients with Hurler syndrome who lacked suitable allogeneic donors received autologous hematopoietic stem and progenitor cells transduced ex vivo with an alpha-L-iduronidase-encoding lentiviral vector. This therapy resulted in extensive metabolic correction in peripheral tissues and the central nervous system.

Glioblastoma, the most common and heterogeneous tumor affecting brain parenchyma, is dismally characterized by a very poor prognosis. Thus, the search of new, more effective treatments is a vital need. Here, we will review the druggable epigenetic features of glioblastomas that are, indeed, currently explored in preclinical studies and in clinical trials for the development of more effective, personalized treatments. In detail, we will review the studies that have led to the identification of epigenetic signatures, IDH mutations, MGMT gene methylation, histone modification alterations, H3K27 mutations, and epitranscriptome landscapes of glioblastomas, in each case discussing the corresponding targeted therapies and their potential efficacy. Finally, we will emphasize how recent technological improvements permit to routinely investigate many glioblastoma epigenetic biomarkers in clinical practice, further enforcing the hope that personalized drugs, targeting specific epigenetic features, could be in future a therapeutic option for selected patients.

12 p.-7 fig.-1 schem.-1 graph. abst., Modern adjuvants for vaccine formulations are immunostimulating agents whose action is based on the activation of pattern recognition receptors (PRRs) by well-defined ligands to boost innate and adaptive immune responses. Monophosphoryl lipid A (MPLA), a detoxified analogue of lipid A, is a clinically approved adjuvant that stimulates toll-like receptor 4 (TLR4). The synthesis of MPLA poses manufacturing and quality assessment challenges. Bridging this gap, we report here the development and preclinical testing of chemically simplified TLR4 agonists that could sustainably be produced in high purity and on a large scale. Underpinned by computational and biological experiments, we show that synthetic monosaccharide-based molecules (FP compounds) bind to the TLR4/MD-2 dimer with submicromolar affinities stabilizing the active receptor conformation. This results in the activation of MyD88- and TRIF-dependent TLR4 signaling and the NLRP3 inflammasome. FP compounds lack in vivo toxicity and exhibit adjuvant activity by stimulating antibody responses with a potency comparable to MPLA., The support from European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 860325 (www.BactiVax.eu), Italian Ministry grant PRIN 2017, no. 2017E44A9P (BacHounds:Supramolecular nanostructures for bacteria detection), and the Spanish Ministry for Science and Innovation (grants CTQ2017-88353-R and PRE2018-086249) is acknowledged.

Resumo O objetivo do artigo é identificar a prevalência de não recebimento de visita domiciliar por Agente Comunitário de Saúde (ACS) e os fatores associados. Trata-se de um estudo transversal realizado com 38.865 equipes e 140.444 usuários em todo o território nacional, que participaram da avaliação externa do Programa de Melhoria do Acesso e da Qualidade da Atenção Básica em 2017/2018. A associação de não recebimento de visita domiciliar por ACS e características dos municípios, equipes e indivíduos foi estimada pela razão de prevalência e intervalos de confiança de 95%. A prevalência de não recebimento de visita domiciliar pelo ACS foi de 18,6% e os principais motivos foram: ACS não realiza visita na casa, desconhecimento da existência de ACS no bairro ou unidade, e não tem ninguém em casa para atendê-lo. A probabilidade de receber visita domiciliar foi maior em regiões mais pobres como o Nordeste, em municípios com menor porte populacional, entre usuários com maior idade e menor renda, com condições crônicas de saúde ou que possuem alguém com dificuldade de locomoção no domicílio. Os resultados evidenciam a necessidade de aumento da cobertura de ACS no país, considerando que sua visita domiciliar promove equidade em saúde. Abstract This article aimed to identify the prevalence of not receiving a home visit by a community health agent (CHA) and the factors associated with it. This was a cross-sectional study, conducted with 38,865 health teams and 140,444 users in the entire country, who participated in the external evaluation of the Program of Access and Quality Improvement in Primary Health (PMAQ-AB, in Portuguese) in 2017/2018. The association between not receiving a home visit by a CHA and the characteristics of the towns, teams, and individuals were estimated by the prevalence ratio (PR) with 95% confidence intervals. The prevalence of not receiving a home visit by a CHA was 18.6% and the main causes were: CHA did not visit the home, lack of knowledge of the existence of CHAs in the neighborhood or unit, and no one present at the home when the CHA visited. The probability of receiving a home visit was higher in poorer regions like the Northeast Region of the country; in towns with a smaller population; among older age users with a lower income, users with chronic health conditions, or users who have someone with a physical disability at home. The results showed that there is a need to increase the coverage of CHA visits in the country, considering that their home visits improve equity in health care.

This essay explores the relationship between diversity and public health by addressing tensions related to classifications and recognition in the field of HIV and AIDS policy. The objective is to reflect on how classificatory and operative categories are articulated within the scope of programmatic responses towards the social production of differences and inequalities. To do so it draws from the theoretical framework of studies on vulnerability and recognition and from a methodology that includes a critical review of the literature on the category men who have sex with men (MSM) and ethnographic material, derived from the authors' research and a literature review related to social movements, and research and policies focused on lesbians, gays, bisexuals, transvestites and transsexuals (LGBT). It reviews how the MSM category was constructed in the field of HIV and AIDS prevention policies at an international level, situating political actors and tensions. It problematizes these tensions by analyzing processes of production of political subjects as well as changes in socio-state relations that involve LGBT. It emphasizes the importance of considering how differences and inequalities emerge in socio-political processes and of dedicating studies to improve policies, ensuring an effectively more respectful care.Este ensaio explora a relação entre diversidade e saúde pública ao abordar tensões que envolvem classificações e reconhecimento no campo das políticas de HIV e Aids. Objetiva refletir sobre como se articulam categorias classificatórias e operativas no âmbito das respostas programáticas em relação à produção social de diferenças e desigualdades. Para tanto, parte do referencial teórico dos estudos sobre vulnerabilidade e reconhecimento e de metodologia que inclui revisão crítica da literatura sobre a categoria HSH e material etnográfico oriundo de pesquisas das autoras e de revisão de literatura, relativo ao movimento social, pesquisas e políticas com foco em lésbicas, gays, bissexuais, travestis e transexuais (LGBT). Recupera o processo de construção da categoria HSH no campo das políticas de prevenção de HIV e Aids em âmbito internacional, situando atores políticos e tensões. Problematiza essas tensões ao analisar processos de produção de sujeitos políticos e mudanças nas relações socioestatais que envolvem LGBT. Enfatiza a importância de considerar como diferenças e desigualdades emergem nos processos sociopolíticos e de destinar estudos para aprimorar políticas, assegurando um cuidado efetivamente mais respeitoso.

The large variety of observed planetary systems is rooted in the complex physical and chemical processes that lead to their formation. In the last few years, great observational and theoretical developments have dramatically improved our understanding of how forming planets are affected by and interact with their birth environments, the protoplanetary disks. In this talk, I will focus on recent studies exploiting the outstanding ALMA sensitivity and spectral resolution to 1) unveil embedded cold Jupiters by their dynamical interaction with the gaseous formation environment; 2) characterize the main physical processes promoting planet formation; 3) constrain the chemical inventory of fundamental molecules in the terrestrial planet forming regions. I will finally show how in synergy with IR observations (JWST, VLT, upcoming ELT) these new ALMA data and analysis techniques have the potential to calibrate the mass-luminosity relationship of new-born planets.

This study was aimed to produce pear cider (Perry), using small caliber pears cv Abate Fètel, fermented by Starmerella bacillaris and Saccharomyces cerevisiae in co-inoculated (COF) and sequential (SEF) mixed cultures in comparison with S. cerevisiae monoculture fermentation (AXF), evaluating the influence of yeast starter cultures on Perry characteristics. The perries were re-fermented in bottle by S. cerevisiae strain EC1118. During primary fermentation, growth and fermentation kinetics were different in the co-inoculated and sequential fermentations in comparison with pure S. cerevisiae fermentation; however, sugars were depleted, and 6% (v/v) ethanol was produced in all the trials. Glycerol content was significantly higher in mixed fermentations due to Starm. bacillaris metabolism (+ 20% in COF, and + 42% in SEF conditions). After re-fermentation in bottle, higher levels of 3-Methyl-1-butanol, 1-propanol, acetaldehyde and esters were detected in Perry from the mixed fermentations. All the Perries were accepted by the consumers (general liking values from 6.01 to 6.26). Perries’ appearance from mixed fermentations was described as less intense and more clear. The use of small caliber pears cv Abate Fètel and Starm. bacillaris in combination with S. cerevisiae in Perry production might be a suitable tool to obtain novel beverages with distinctive organoleptic features.

The increasing population of resident space objects is currently fostering many Space Surveillance and Tracking (SST) initiatives, which are based on the use of ground sensors. Italy contributes to the European SST Support Framework with the BIstatic RAdar for LEo Survey (BIRALES). Orbit determination from BIRALES observations relies on the estimation of the angular profiles of the object crossing the sensor field of view by processing the receiver raw data. Based on the receiver array configuration, its field of view is currently populated with many independent beams. However, the results of the currently adopted orbit determination process are negatively affected by the simultaneous presence of multiple grating lobes in the receiver gain pattern and by the signal quality. Within this context, this work proposes a paradigm shift in BIRALES data processing by introducing a multiple signal classification (MUSIC) approach. First, in the track estimation phase, multiple signal directions of arrival are determined, at any time instant, from the data correlation matrix. The multiplicity of the solutions is due to the array geometry and yields ambiguity in track reconstruction. For the catalogued objects, this ambiguity can be solved by exploiting the availability of their orbital estimates. For the uncatalogued ones, it is solved by clustering the candidate signal directions of arrival and identifying the correct track using slant range, Doppler shift and signal to noise ratio measurements. Although introduced for BIRALES, the applicability of the method extends to any SST survey radar with an array receiver and with the ability to correlate the signals detected by each receiver element. Finally, algorithm performances and robustness are assessed on a large set of synthetic passes as well as on real measurements.

O objetivo deste trabalho é avaliar a trajetória de carreira de profissionais com nível de formação pós-graduação stricto sensu e com vínculo empregatício na indústria farmacêutica. A pesquisa adotou uma orientação qualitativa, baseada na técnica de análise de conteúdo, sendo os dados obtidos via preenchimento de questionários eletrônicos. Como resultado, foi observada uma tendência de mudança na visão sobre profissionais com titulação nível de pós-graduação stricto sensu, valorizando e incentivando sua formação continuada. Constatou-se que a busca pela pós-graduação é motivada majoritariamente por uma decisão individual, e não de uma decisão conjunta entre discente, organização de ensino e iniciativa privada.

The present study aims to investigate cross-cultural differences and similarities in maternal and children's adjustment to COVID-19 restrictions in Spain and Italy, with reference to determinants of maternal stress. A total of 950 mothers (45.4% from Spain

Purpose Among thoracic malformations, pectus deformities have the highest incidence and can result in a wide range of severe and mild clinical manifestations. Recently, the treatment of pectus deformities is shifting from traditional approaches toward customized solutions. This occurs by leveraging innovative rapid prototyping tools that allow for the design and fabrication of patient-specific treatments and medical devices. This paper aims to provide a comprehensive view of the growing literature in this area to analyze the progress made in this direction. Design/methodology/approach The search was performed on major search engines through keywords inherent to reverse engineering (RE) and additive manufacturing (AM) technologies applied to pectus deformities and related treatments, selecting 54 papers. These were analyzed according to the addressed pathology, the hardware and software tools used and/or implemented and their integration within the clinical pathway. Findings First, the analysis led to analyze and divide the papers according to how RE and AM technologies are applied for surgical and non-surgical treatments, pathological assessment and preoperative simulation and planning. Second, all papers were considered within the typical rapid prototyping framework consisting of the three phases of three-dimensional (3D) scanning, 3D modelling and 3D printing. Originality/value To the best of the authors’ knowledge, to date, no survey has provided a comprehensive view of innovative and personalized treatment strategies for thoracic malformations; the present work fills this gap, allowing researchers in this field to have access to the most promising findings on the treatment and evaluation of pathology.

The objective of the current research was to explore the potential prognostic value of readily available clinical and pathologic variables in bladder cancer. The novel association found between cholesterol levels and prognosis may provide the rationale for exploring novel treatments. Patients included had histologically confirmed urothelial bladder cancer and were treated with at least 3 cycles of cisplatin-based neoadjuvant chemotherapy before radical cystectomy with lymphadenectomy. A total of 245 patients at low, intermediate and high risk, presenting with 0-1, 2 or 3-4 risk factors, including positive lymph nodes, Hb 12.8, NLR ≥2.7 and cholesterol levels ≥199, were included. Five-year cancer-specific survival rate was 0.67, 0.78 and 0.94 at high, intermediate and low risk, respectively. Total cholesterol levels at the time of cystectomy may represent a commonly assessable prognostic factor and may be incorporated in a clinically meaningful risk-group classification model.Lay abstract This present study assessed a large group of patients with urothelial bladder cancer treated with chemotherapy followed by radical cystectomy, to capture the predictive power of commonly collected clinical, pathological and biochemical factors. The design of the study highlighted that higher cholesterol levels at the time of cystectomy were associated with shorter cancer-specific survival. This finding suggests that high blood-cholesterol levels truly have a negative influence on surviving cancer. In conclusion, total cholesterol levels at the time of cystectomy may represent a commonly assessable prognostic factor and could be incorporated into a clinically meaningful and valuable risk-group classification model.

Introduction Bone metastases are frequent in patients with cancer. Electrochemotherapy (ECT) is a minimally invasive treatment. Preclinical and clinical studies supported the use of ECT in patients with metastatic bone disease (MBD). The purposes of this multicentre study are to confirm the safety and efficacy of ECT, and to identify appropriate operating procedures in different MBD conditions. Materials and methods 102 patients were treated in 11 Centres and recorded in the REINBONE registry (a shared database protected by security passwords): clinical and radiological information, ECT session, adverse events, response, quality of life indicators and duration of follow-up were registered. Results 105 ECT sessions were performed (one ECT session in 99 patients, two ECT sessions in 3 patients). 24 patients (23.5%) received a programmed intramedullary nail after ECT, during the same surgical procedure. Mean follow-up was 5.9 ± 5.1 months (range 1.5–52). The response to treatment by RECIST criteria was 40.4% objective responses, 50.6% stable disease and 9% progressive disease. According to PERCIST criteria the response was: 31.4% OR; 51.7% SD, 16.9% PD with no significant differences between the 2 criteria. Diagnosis of breast cancer and ECOG values 0–1 were significantly associated to objective response. A significant decrease in pain intensity and significant better quality of life was observed after ECT session at follow-up. Conclusion The results are encouraging on pain and tumour local control. ECT proved to be an effective and safe treatment for MBD and it should be considered as an alternative treatment as well as in combination with radiation therapy.

BackgroundPenile cancer (PC) is an extremely rare malignancy, and the patients at advanced stages have currently limited treatment options with disappointing results. Immune checkpoint inhibitors anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) are currently changing the treatment of several tumors. Furthermore, the microsatellite instability (MSI) and the deficient mismatch repair system (dMMR) proteins represent predictive biomarkers for response to immune checkpoint therapy. Until present, few data have been reported related to PD-L1 expression and MSI in PC. The main aim of our study was the evaluation of PD-L1 expression in tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) in immune cells and the analysis of dMMR/MSI status in a large series of PCs.MethodsA series of 72 PC, including 65 usual squamous cell carcinoma (USCC), 1 verrucous, 4 basaloid, 1 warty, and 1 mixed (warty-basaloid), was collected. Immunohistochemistry (IHC) was performed to assess PD-L1 expression using two different anti-PD-L1 antibodies (clone SP263 and SP142 Ventana) and MMR proteins expression using anti-MLH1, anti-PMS2, anti-MSH2, and anti-MSH6 antibodies. PCR analysis was performed for the detection of MSI status.ResultsOf the 72 PC cases analyzed by IHC, 45 (62.5%) cases were TC positive and 57 (79%) cases were combined positive score (CPS) using PDL1 SP263. In our cohort, TILs were present in 62 out of 72 cases (86.1%), 47 (75.8%) out of 62 cases showed positivity to PDL1 clone SP142. In our series, 59 cases (82%) had pMMR, 12 cases (16.7%) had lo-paMMR, and only 1 case (1.3%) had MMR. PCR results showed that only one case lo-paMMR was MSI-H, and the case dMMR by IHC not confirmed MSI status.ConclusionOur findings showed that PD-L1 expression and MSI status represent frequent biological events in this tumor suggesting a rationale for a new frontier in the treatment of patients with PC based on the immune checkpoint inhibitors.

The psychedelic compound psilocybin has shown therapeutic benefit in the treatment of numerous psychiatric diseases. A recent randomized clinical trial conducted at Johns Hopkins Bayview Medical Center demonstrated the efficacy of psilocybin-assisted therapy in the treatment of Major Depressive Disorder (MDD). Similarly, a phase IIb study evaluating psilocybin-assisted therapy for treatment-resistant depression (TRD) presented statistically meaningful and long-term reduction in depressive symptoms. Also, many studies have reported the successful treatment of severe anxiety after a single oral dose of psilocybin, especially in patients struggling with cancer-related distress (CRD). Despite these compelling clinical results, concerns regarding the duration of the psychedelic experience produced by psilocybin pose a significant barrier to its widespread therapeutic application. Psilocybin, derived from magic mushrooms is the naturally occurring prodrug of the neuroactive compound psilocin. When orally administered, exposure to the acidic gastrointestinal (GI) environment together with enzymatic processing by intestinal and hepatic alkaline phosphatase lead to the dephosphorylation of psilocybin producing elevated levels of systemic psilocin. These plasma levels are detectable up to 24 h and produce a psychoactive episode lasting as long as 6 h post-ingestion. In order to positively modify the kinetics of the acute psychedelic response, we have engineered a library of novel prodrug derivatives (NPDs) of psilocin, introducing a diversity of alternative metabolically cleavable moieties modified at the 4-carbon position of the core indole ring. This library consists of twenty-eight unique compounds represented by nine distinct prodrug classes. Each molecule was screenedin vitrofor metabolic stability using isolated human serum, and human cellular fractions derived from liver and intestinal tissues. This screen revealed fifteen prodrugs that produced measurable levels of psilocinin vitro, with ester and thiocarbonate-based prodrug derivatives significantly represented. These fifteen NPDs were further evaluated for pharmacokinetic (PK) profiles in mice, assessing plasma levels of both residual prodrug and resultant psilocin. PK results confirmed the efficiency of ester and thiocarbonate-based prodrug metabolism upon oral and intravenous administration, achieving levels reduced, albeit comparable to levels of psilocybin-derived psilocin. Of note, almost all NPDs tested maintained reduced overall exposure of psilocin relative to psilocybin, with no measurable levels detected at 24 h post-dose. Finally, all NPDs were screened for CNS bioavailability in healthy mice using the Head Twitch Response (HTR), a behavioural biomarker of 5-HT2Areceptor stimulation and an established proxy for psychoactive potential. Interestingly, five NPDs produced peak HTR that approached or exceeded levels induced by an equivalent dose of psilocybin. Among these bioactive prodrugs, an ester-based and thiocarbonate-based molecule produced long-term anxiolytic benefit in chronically stressed mice evaluated in the marble burying psychiatric model. Overall, this screening campaign identified novel candidate prodrugs of psilocin with altered metabolic profiles and reduced pharmacological exposure, potentially attenuating the duration of the psychedelic response. These molecules still maintained the long-term psychiatric and physiological benefits characteristic of psilocybin therapy. Additionally, these modified parameters also offer the opportunity for altered routes of administration bypassing conventional oral dosing.

Termites build complex nests which are an impressive example of self-organization. We know that the coordinated actions involved in the construction of these nests by multiple individuals are primarily mediated by signals and cues embedded in the structure of the nest itself. However, to date there is still no scientific consensus about the nature of the stimuli that guide termite construction, and how they are sensed by termites. In order to address these questions, we studied the early building behavior ofCoptotermes formosanustermites in artificial arenas, decorated with topographic cues to stimulate construction. Pellet collections were evenly distributed across the experimental setup, compatible with a collection mechanism that is not affected by local topography, but only by the distribution of termite occupancy (termites pick pellets at the positions where they are). Conversely, pellet depositions were concentrated at locations of high surface curvature and at the boundaries between different types of substrate. The single feature shared by all pellet deposition regions was that they correspond to local maxima in the evaporation flux. We can show analytically and we confirm experimentally that evaporation flux is directly proportional to the local curvature of nest surfaces. Taken together, our results indicate that surface curvature is sufficient to organize termite building activity, and that termites likely sense curvature indirectly through substrate evaporation. Our findings reconcile the apparently discordant results of previous studies.

The immune checkpoint inhibitors (ICIs) revolutionized cancer therapeutic landscape and substantially improved the survival of patients (pts) with advanced malignancies. Several predictive biomarkers are under evaluation, in order to identify patients who can benefit from ICI. Recently, elevated NLR, calculated from absolute neutrophil count and white cell count, were found to be independent predictors of reduced survival and increased risk of progression in melanoma patients receiving ICI. The purpose of this study is to retrospectively investigate relationship of NLR with inflammation-immune mediators.The immune checkpoint inhibitors (ICIs) revolutionized cancer therapeutic landscape and substantially improved the survival of patients (pts) with advanced malignancies. Several predictive biomarkers are under evaluation, in order to identify patients who can benefit from ICI. Recently, elevated NLR, calculated from absolute neutrophil count and white cell count, were found to be independent predictors of reduced survival and increased risk of progression in melanoma patients receiving ICI. The purpose of this study is to retrospectively investigate relationship of NLR with inflammation-immune mediators.

Breast cancer (BC) represents the most frequent cancer worldwide, with almost 2.26 million new diagnoses recorded in 2020, and is the most common malignant neoplasia diagnosed during pregnancy. Pregnancy-related Breast Cancer (PrBC), indeed, is diagnosed in 1 in 2000–4000 pregnant women every year in Europe. PrBC is frequently characterized by unfavorable biological marks that, along with the late diagnosis, the limited imaging applicable, and the often-suboptimal treatments necessary to protect the fetus, could possibly lead to a worse prognosis in this population of patients. Babies born from mothers treated for cancer during pregnancy have been followed during a long-term follow-up and have showed cognitive and physical functions not different from the general population, but more studies are needed. Taking into consideration the complexity of the disease, a multidisciplinary approach is crucial to define the best therapeutical path.

The glycocalyx lines systemic capillaries and influences the distribution of osmotic forces across the capillary between the intravascular and interstitial compartments. By creating a pericapillary space between the capillary and the interstitium with a low osmotic pressure, the predicted and measured water flux at the distal end of systemic capillaries is outward under physiological conditions – contrary to the prediction of the traditional Starling model of capillary fluid transport. This has led to a ‘revised’ Starling model in which the predicted the movement of water from the capillary into the interstitium is consistently outward, and the return of water from the interstitial compartment necessary to maintain intravascular volume occurs nearly exclusively through the lymphatic system. We developed a methematicl model of the revised Starling Hypothesis that is applicable to the whole body in the special circumstance of hemodialysis, where the contributions of renal function to blood volume regulation may be ignored, and the total input and output of water and solutes are controlled and measured as part of the process of hemodialysis. We created a revised, two compartment (vascular+interstitial space), Starling model using the quantitative model of Facchini et al. (Microvasc. Res. 94:52-63, 2014) that describes capillary transport through the glycocalyx (albeit as normalized dimensionless values). We modelled the return of interstitial water to the vascular space through lymphatic flow based on the interstitial pressure (Possenti et al., Micro. Vasc. Res. 122:101-110, 2019), and we estimated the interstitial pressure based upon the formulation of Chapple et al. (Comp. Meth, and Prog. In Biomed. 41: 33-54,1993). We used the two-compartment model (intravascular and extravascular spaces) developed by de los Reyes et al. (J. Theoret. Biol. 390:146-155, 2016) to analyze transcapillary fluxes based on the traditional Starling model, and we embedded the description of fluxes across glycocalyx developed by Facchini et al. to decribe the fluxes of solutes and water across the glycocalyx and peri-glycocalyx/sub-capillary space and added control of lymphatic function within this two-compartment model to create a revised Starling model. The traditional and revised models were evaluated using data from periods of ultrafiltration in which the hematocrit (Crit-line), body weight and measured fluid input or ultrafiltrate removed were measured, and we compared the predicted fluxes of solvent and solutes across the capillary and through the lymphatic system between the traditional and revised Starling models. The two models lead to dramatically different predictions—all of the fluid transported out of the capillary must come back via the lymphatics according to the revised Starling model. This places vital importance upon the lymphatic flow during vascular refilling when blood volume is reduced and must be repleted to maintain stable cardiac function. Partially funded by the Renal Research Institute This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Understanding the chemical link between protoplanetary disks and planetary atmospheres is complicated by the fact that the popular targets in the study of disks and planets are widely separated both in space and time. The 5 Myr PDS 70 systems offers a unique opportunity to directly compare the chemistry of a giant planet's atmosphere to the chemistry of its natal disk. To that end, we derive our current best physical and chemical model for the PDS 70 disk through forward modelling of the $^{12}$CO, C$^{18}$O, and C$_2$H emission radial profiles with the thermochemical code DALI and find a volatile C/O ratio above unity in the outer disk. Using what we know of the PDS 70 disk today, we analytically estimate the properties of the disk as it was 4 Myr in the past when we assume that the giant planets started their formation, and compute a chemical model of the disk at that time. We compute the formation of PDS 70b and PDS 70c using the standard core accretion paradigm and account for the accretion of volatile and refractory sources of carbon and oxygen to estimate the resulting atmospheric carbon-to-oxygen number ratio (C/O) for these planets. Our inferred C/O ratio of the gas in the PDS 70 disk indicates that it is marginally carbon rich relative to the stellar C/O = 0.44 which we derive from an empirical relation between stellar metallicity and C/O. Under the assumption that the disk has been carbon rich for most of its lifetime, we find that the planets acquire a super-stellar C/O in their atmospheres. If the carbon-rich disk is a relatively recent phenomenon (i.e. developed after the formation of the planets at $\sim 1$ Myr) then the planets should have close to the stellar C/O in their atmospheres. This work lays the groundwork to better understand the disk in the PDS 70 system as well as the planet formation scenario that produce its planets., Comment: 18 pages, 14 figures, 5 tables, accepted for publication in A&A

In recent years, the advanced knowledge of clinical, biological and molecular features of prostate cancer have led to the introduction of new drugs and have allowed the relocation of old drugs in different settings. In this way, the new concepts of systemic disease arise: high risk or high volume vs. low risk and low volume disease castration sensitive prostate cancer (CSPC), diversifying the use of previously approved drugs (CRPC) and opening new scenarios for sequence therapy. The aim of this review is to integrate new developments into the medical management of systemic prostate cancer.

O objetivo deste ensaio é realizar estudo comparado dos conflitos de jurisdição decorrentes de litígios havidos no ambiente da internet, tendo por paradigmas (1) o caso do Tribunal de Justiça Europeu de 6 de outubro de 2015, processo C‑362/14; (2) o Recurso Especial n. 1.168.547, julgado em fevereiro de 2011, pelo Superior Tribunal de Justiça brasileiro e (3) a Ação Direta de Constitucionalidade n. 51, em tramitação perante o Supremo Tribunal Federal do Brasil. Ademais, estuda a adequação, prevista no catálogo principiológico da Lei 13.709/2018 como pressuposto de validade para a transferência internacional de dados. A anacronia da aderência ao território como critério definição da jurisdição, em tais casos, é a hipótese do trabalho. Este ensaio utiliza, na abordagem, o método hipotético-dedutivo; na investigação, o procedimento tipológico e estruturalista; interpretação tópico-sistemática valendo-se das técnicas de pesquisa exploratória e explicativa, instrumentalmente documental (bibliográfica e jurisprudencial).

Metastases are the main type of malignancy involving bone, which is the third most frequent site of metastatic carcinoma, after lung and liver. Skeletal-related events such as intractable pain, spinal cord compression, and pathologic fractures pose a serious burden on patients’ quality of life. For this reason, mini-invasive treatments for the management of bone metastases were developed with the goal of pain relief and functional status improvement. These techniques include embolization, thermal ablation, electrochemotherapy, cementoplasty, and MRI-guided high-intensity focused ultrasound. In order to achieve durable pain palliation and disease control, mini-invasive procedures are combined with chemotherapy, radiation therapy, surgery, or analgesics. The purpose of this review is to summarize the recently published literature regarding interventional radiology procedures in the treatment of cancer patients with bone metastases, focusing on the efficacy, complications, local disease control and recurrence rate.

Resumo Objetivou-se medir a prevalência de autopercepção negativa da saúde e sintomas depressivos em idosos segundo a presença de incontinência urinária, após nove anos de acompanhamento. Trata-se de um estudo de coorte prospectivo de base populacional intitulado Saúde do Idoso Gaúcho de Bagé, no Rio Grande do Sul. Foram entrevistados 1.593 idosos no estudo de linha de base (2008) e 735 entre setembro de 2016 e agosto de 2017. A exposição “incontinência urinária (IU)” foi avaliada no estudo de linha de base e os desfechos “autopercepção negativa da saúde” e “sintomas depressivos” em 2016/17. A razão de odds e o intervalo de confiança de 95% foram calculados com regressão logística bruta e ajustada para variáveis demográficas, sociais, comportamentais e de condições de saúde. A prevalência de IU foi 20,7% em 2008 e 24,5% em 2016/17; a incidência foi de 19,8%, sendo 23,8% entre as mulheres e 14,6% entre os homens (p = 0,009). Idosos com IU no estudo de linha de base apresentaram chances 4,0 (IC95%:1,8-8,8) e 3,4 (IC95%:1,8-6,2) vezes maior de desenvolver autopercepção negativa da saúde e sintomas depressivos, respectivamente, após nove anos de acompanhamento, comparados àqueles sem IU. Os resultados evidenciam maior chance de problemas mentais entre idosos com IU.

Objetivo: analisar as evidências científicas sobre o prognóstico de pacientes tabagistas que foram hospitalizados por COVID-19. Método: revisão integrativa baseada na estratégia PICO, realizada com 21 artigos indexados nas bases de dados Pubmed, Web of Science, Lilacs e SCOPUS, em maio de 2021. Resultados: foram identificados 798 estudos, e destes 21 compuseram a amostra. Os principais prognósticos identificados foram: risco aumentado de hospitalização, risco de gravidade da COVID-19 aumentado, maiores ocorrências de hospitalização e longa permanência em Unidade de Terapia Intensiva, maiores chances de uso de ventilação contínua e maiores índices de mortalidade. Conclusões: evidenciou-se relação do tabagismo com maiores índices de hospitalização, agravamento da doença, maiores chances de admissão em Unidades de Terapia Intensiva, necessidade de ventilação mecânica e elevados índices de mortalidade. Ainda, fomenta a produção de estudos que visem estudar características desfavoráveis na evolução da COVID-19.

Simple Summary The liver can be considered an immune organ, given its role as a hub for gut-derived antigens and liver-resident immune cells and the tolerance status of its environment. However, chronic inflammation represents a disruption to this balance and, pathogenetically, represents the beginning of a multistep process leading to cancer. The present study aimed to describe the key points of liver cancer pathogenesis, which may help in understanding the limits and perspectives of investigations concerning immunotherapy. Abstract In contrast to several tumors whose prognoses are radically affected by novel immunotherapeutic approaches and/or targeted therapies, the outcomes of advanced hepatocellular carcinoma (HCC) remain poor. The underlying cirrhosis that is frequently associated with it complicates medical treatment and often determines survival. The landscape of HCC treatment had included sorafenib as the only drug available for ten years, until 2018, when lenvatinib was approved for treatment. The second-line systemic treatments available for hepatocellular carcinoma include regorafenib, cabozantinib, ramucirumab, and, more recently, immune checkpoint inhibitors. However, the median survival remains below 15 months. The results obtained in clinics should be interpreted whilst considering the peculiar role of the liver as an immune organ. A healthy liver microenvironment ordinarily experiences stimulation by gut-derived antigens. This setup elucidates the response to chronic inflammation and the altered balance between tolerance and immune response in HCC development. This paper provides an overview of the mechanisms involved in HCC pathogenesis, with a special focus on the immune implications, along with current and future clinical perspectives.