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In this study, a simple green synthesis of vanadium pentoxide nanoparticles (VNPs) was prepared by the extract of Kaffir lime fruit (Citrus hystrix) as a green reducing and stabilizing agent, along with the investigation of calcination temperature was carried out at 450 and 550 °C. It was affirmed that, at higher temperature (550 °C), the VNPs possessed a high degree crystalline following the construction of (001) lattice diffraction within an increase in crystalline size from 47.12 to 53.51 nm, although the band gap of the materials at 450 °C was lower than that of the VNPs-550 (2.53 versus 2.66 eV, respectively). Besides, the materials were assessed for the potential bioactivities toward antibacterial, antifungal, DNA cleavage, anti-inflammatory, and hemolytic performances. As a result, the antibacterial activity, with minimal inhalation concentration (MIC) < 6.25 µg/mL for both strains, and fungicidal one of the materials depicted the dose-dependent effects. Once, both VNPs exhibited the noticeable efficacy of the DNA microbial damage, meanwhile, the outstanding anti-inflammatory agent was involved with the IC50 of 123.636 and 227.706 µg/mL, accounting for VNPs-450 and VNPs-550, respectively. Furthermore, this study also demonstrated the hemolytic potential of the VNPs materials. These consequences declare the prospects of the VNPs as the smart and alternative material from the green procedure in biomedicine.
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Antibacterianos , Citrus , Frutas , Extratos Vegetais , Compostos de Vanádio , Citrus/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Compostos de Vanádio/química , Compostos de Vanádio/farmacologia , Frutas/química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Nanopartículas/química , Testes de Sensibilidade Microbiana , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Antifúngicos/farmacologia , Antifúngicos/química , Antifúngicos/síntese química , Temperatura , Hemólise/efeitos dos fármacos , Química Verde , HumanosRESUMO
Background In the United States, homelessness is an issue that may affect a significant portion of the adolescent population. There is no consensus on the extent to which this population has been impacted by poor mental health and lack of resources. This study aimed to characterize trends among those who struggle with housing insecurity and mental illness to provide a clearer picture of mental health needs among this population. Methods Data from 641 adolescents who presented to a local adolescent homeless shelter between 2015 and 2021 were utilized to determine if there were significant associations between specific mental illness diagnoses and biopsychosocial characteristics. A chi-square test of independence was performed on demographic and psychosocial variables for categories with a frequency greater than five. For continuous variables, an unpaired t-test was utilized to assess significance (p<0.05). Results Among the study population, 61.3% (369) had at least one psychiatric diagnosis, which is higher than even the most conservative estimates of mental illness among the general public. Having one or more psychiatric diagnoses was significantly associated with suicide attempts, documented aggressive behavior, and tobacco use. Contrary to our initial hypothesis, there were no significant correlations between psychiatric diagnoses and demographic characteristics or drug use other than tobacco. Conclusions Our findings indicate that though the particular reasons for homelessness among adolescents may vary, the prevalence of mental illness among these young individuals was roughly uniformly distributed and vastly above normal levels. Future research must focus on developing interventions to mitigate the effects of mental illness among homeless adolescents, as they are at a vulnerable point in their formative years.
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Coffee pulp is an abundant residue from the coffee industry, but it still contains large amounts of valuable compounds such as polyphenols. The extraction of polyphenols from coffee pulp by the conventional method is accompanied by contaminated compounds. This study, therefore, applied an aqueous two-phase system consisting of different ratios of ethanol/ammonium sulfate to eliminate impurities from coffee-pulp crude extract. The purification efficiency was evaluated via total polyphenol content, antioxidant activity and two major polyphenols in coffee pulps including chlorogenic acid and caffeic acid. Results showed that phenolic compounds mostly predominated in the alcohol-rich phase in which the antioxidant activity was greatly increased after the purification process. Compared to un-purified crude-coffee extract, the antioxidant activity of the purified samples increased approximately 34%, which was assumed to occur due to the slight increase of chlorogenic acid and caffeic acid. Fourier-transform infrared spectroscopy supported the effectiveness of the purification process by eliminating some impurities.
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Ácido Clorogênico , Polifenóis , Antioxidantes/farmacologia , Ácidos Cafeicos , Extratos Vegetais/química , EtanolRESUMO
This paper presents an RGB-NIR (Near Infrared) dual-modality technique to analyze the remote photoplethysmogram (rPPG) signal and hence estimate the heart rate (in beats per minute), from a facial image sequence. Our main innovative contribution is the introduction of several denoising techniques such as Modified Amplitude Selective Filtering (MASF), Wavelet Decomposition (WD), and Robust Principal Component Analysis (RPCA), which take advantage of RGB and NIR band characteristics to uncover the rPPG signals effectively through this Independent Component Analysis (ICA)-based algorithm. Two datasets, of which one is the public PURE dataset and the other is the CCUHR dataset built with a popular Intel RealSense D435 RGB-D camera, are adopted in our experiments. Facial video sequences in the two datasets are diverse in nature with normal brightness, under-illumination (i.e., dark), and facial motion. Experimental results show that the proposed method has reached competitive accuracies among the state-of-the-art methods even at a shorter video length. For example, our method achieves MAE = 4.45 bpm (beats per minute) and RMSE = 6.18 bpm for RGB-NIR videos of 10 and 20 s in the CCUHR dataset and MAE = 3.24 bpm and RMSE = 4.1 bpm for RGB videos of 60-s in the PURE dataset. Our system has the advantages of accessible and affordable hardware, simple and fast computations, and wide realistic applications.
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Algoritmos , Face , Frequência Cardíaca/fisiologia , Movimento (Física) , Iluminação , Fotopletismografia/métodos , Processamento de Sinais Assistido por ComputadorRESUMO
Radical ring-opening polymerization (rROP) has received renewed attention to incorporate cleavable linkages into the backbones of vinyl polymers, especially from cyclic ketene acetals (CKAs). Among the monomers that hardly copolymerize with CKAs are (1,3)-dienes such as isoprene (I). This is unfortunate since synthetic polyisoprene (PI) and its derivatives are the materials of choice for many applications, in particular as elastomers in the automotive, sport, footwear, and medical industries, but also in nanomedicine. Thionolactones have been recently proposed as a new class of rROP-compatible monomers for insertion of thioester units in the main chain. Herein, we report the synthesis of degradable PI by rROP via the copolymerization of I and dibenzo[c,e]oxepane-5-thione (DOT). Free-radical polymerization as well as two reversible deactivation radical polymerization techniques were successfully used for the synthesis of (well-defined) P(I-co-DOT) copolymers with adjustable molecular weights and DOT contents (2.7-9.7 mol%). Reactivity ratios of r DOT = 4.29 and r I = 0.14 were determined, suggesting preferential incorporation of DOT in comparison to I. The resulting P(I-co-DOT) copolymers were successfully degraded (from -47% to -84% decrease in M n) under basic conditions. As a proof of concept, the P(I-co-DOT) copolymers were formulated into stable and narrowly dispersed nanoparticles, showing similar cytocompatibility on J774.A1 and HUVEC cells compared to their PI counterparts. Furthermore, Gem-P(I-co-DOT) prodrug nanoparticles were synthesized by the "drug-initiated" method and exhibited significant cytotoxicity on A549 cancer cells. P(I-co-DOT) and Gem-P(I-co-DOT) nanoparticles were degraded under basic/oxidative conditions by bleach and under physiological conditions in the presence of cysteine or glutathione.
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The distinctive morphology characteristics of microfold cells (M cells) allow the vaccine antigen not only to interact with immune cells directly, but also to effectively stimulate mucosal immune responses via receptors on its apical surface. Human prion protein, a transmembrane receptor for Brucella abortus Hsp60, is highly expressed on the M cell surface. Nonetheless, this protein tends to express in inclusion body in prokaryotic hosts. In this study, the shorter interacting regions of human prion protein were identified via computational methods such as docking and molecular dynamics simulations to minimize its aggregation tendency. The computational calculations revealed three novel human prion protein-interacting regions, namely PrP125, PrP174, and PrP180. In accordance with in silico prediction, the biologically synthesized peptides fusing with GST tag demonstrated their specific binding to Hsp60 protein via pull-down assay. Hence, this finding laid the groundwork for M-cell targeting candidate validation through these newly identified interacting regions.
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Objective: Enteral feeding after intestinal atresia has always been a concern for clinicians. But the present studies mainly focused on single factors. This research aimed to comprehensively analyze the multiple factors on complete enteral nutrition after primary anastomosis, and establish the convenient prediction model. Methods: We retrospectively collected reliable information in neonates with intestinal atresia form January 2010 to June 2022. The cox regression analysis was performed to select independent risk factors and develop nomogram. Subsequently, ROC curve, calibration curve and decision curve were drawn to thoroughly evaluate the accuracy and applicability of the model. Results: The predictors finally included in the model were gestational age, meconium peritonitis, distance from the anastomosis to the ileocecal region, diameter ratio of proximal to distal bowels, and time of initial feeding. The nomogram of predicting the probability of week 2, week 3 and week 4 was drawn and their area under the curve were 0.765, 0.785 and 0.747, respectively. Similarly, calibration and decision curve indicated that the prediction model had a great prediction performance. Conclusion: The clinical value of predictive models can be recognized. The hope is that the predictive model can help pediatricians reduce hospital costs and parental anxiety.
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The simultaneous occurrence of the COVID-19 pandemic and the transition to adulthood have posed particular obstacles to university students' mental health. However, it remains unclear whether hope promotes mental health in the relationship between self-compassion, psychological well-being, and life satisfaction. Therefore, this study investigated the role of hope as a mediator in the relationship between self-compassion, psychological well-being, and life satisfaction among Vietnamese undergraduate students in the context of the COVID-19 pandemic. Participants consisted of 484 students (aged 18-24) from several universities in Vietnam. To measure the four variables in the research model, we opted for the Self-Compassion Scale, the State Hope Scale, the World Health Organization 5-item Well-Being Index, and the Satisfaction With Life Scale. The results showed that (1) self-compassion was significantly positively correlated with psychological well-being, (2) self-compassion was not correlated with life satisfaction, (3) hope was a mediator of the relationship between self-compassion and psychological well-being, and (4) hope was a mediator of the relationship between self-compassion and life satisfaction. These findings suggest interventions on self-compassion to enhance hope and subsequently increase students' mental health, which offers colleges, psychologists, and psychiatrists a guideline to cope with harmful psychological implications during the COVID-19 pandemic.
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Objective: The purpose of this study was to establish a predictive model of postoperative fever in children with acute appendicitis through retrospective analysis, and the prediction ability of the model is demonstrated by model evaluation and external validation. Methods: Medical records information on children undergoing surgery for acute appendicitis within 2 years were retrospectively collected, prospective collection was performed for external validation in the next 3 months. The patients were divided into two groups according to whether the postoperative body temperature exceeded 38.5°C. Multivariate logistic regression analysis was used to determine independent risk factors and develop regression equations and nomogram. ROC curve, calibration curve and decision curve were made for model evaluation. Finally, the clinical implication of the prediction model was clarified by associating postoperative fever with prognosis. Results: High risk factors of postoperative fever included in the prediction model were onset time (X1), preoperative temperature (X2), leukocyte count (X3), C-reactive protein (X4) and operation time (X5). The regression equation is logit (P) = 0.005X1+0.166X2+0.056X3+0.004X4+0.005X5-9.042. ROC curve showed that the area under the curve (AUC) of the training set was 0.660 (0.621, 0.699), and the AUC of the verification set was 0.712 (0.639, 0.784). The calibration curve suggested that the prediction probability was close to the actual probability. Decision curve analysis (DCA) showed that patients could benefit from clinician's judgment. Furthermore, prognostic analysis showed children presenting with postoperative fever had the more duration of postoperative fever, hospitalization stays and cost, except for rehospitalization. Conclusion: All the results revealed that the model had good predictive ability. Pediatricians can calculate the probability of postoperative fever and make timely interventions to reduce pain for children and parents.
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In this study, supercritical CO2 (scCO2 ) was used to impregnate polymers with paramagnetic polarizing agents to prepare samples for dynamic nuclear polarization (DNP) solid-state NMR (ssNMR) experiments. As a proof of concept, we impregnated polystyrene samples with bTbK, which stands for bis-TEMPO-bisketal where TEMPO is 2,2,6,6-tetra-methylpiperindin-1-oxyl. Substantial DNP signal enhancements could be measured on DNP-enhanced 1 H â 13 C cross-polarization (CP) magic-angle spinning (MAS) spectra recorded at 9.4 T and ~100 K, reaching a maximum value of 8 in the most favorable case, which appeared comparable or even higher than what is typically obtained on similar systems for former sample preparation methods. These results highlight the potential of scCO2 impregnation as an efficient and possibly versatile methodology to prepare polymer samples for DNP ssNMR investigations.
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Dióxido de Carbono , Polímeros , Espectroscopia de Ressonância Magnética/métodos , Imageamento por Ressonância MagnéticaRESUMO
Administering medicines to 0- to 5-year-old children in a resource-limited environment requires dosage forms that circumvent swallowing solids, avoid on-field reconstitution, and are thermostable, cheap, versatile, and taste masking. We present a strategy that stands to solve this multifaceted problem. As many drugs lack adequate water solubility, our formulations used oils, whose textures could be modified with gelling agents to form "oleogels." In a clinical study, we showed that the oleogels can be formulated to be as fluid as thickened beverages and as stiff as yogurt puddings. In swine, oleogels could deliver four drugs ranging three orders of magnitude in their water solubilities and two orders of magnitude in their partition coefficients. Oleogels could be stabilized at 40°C for prolonged durations and used without redispersion. Last, we developed a macrofluidic system enabling fixed and metered dosing. We anticipate that this platform could be adopted for pediatric dosing, palliative care, and gastrointestinal disease applications.
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Alimentos , Óleos , Animais , Criança , Pré-Escolar , Sistemas de Liberação de Medicamentos , Géis , Humanos , Suínos , ÁguaRESUMO
Superior mesenteric artery (SMA) syndrome is a potentially fatal condition that can be difficult to diagnose for emergency medicine physicians due to its rarity and vague gastrointestinal symptom presentation. Patients arriving at the emergency department (ED) with this condition may encounter delays in proper supportive care and treatment. We present the case of a 21-year-old female who was seen in the ED for nausea, non-bloody vomiting, and rapid weight loss. Through point-of-care ultrasound (POCUS) findings, she was diagnosed with SMA syndrome and received appropriate, supportive care for her condition before catastrophic complications could occur. This case demonstrates the utility of POCUS in SMA syndrome and the importance of considering this diagnosis despite its rarity.
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Artéria Mesentérica Superior , Síndrome da Artéria Mesentérica Superior , Adulto , Feminino , Humanos , Artéria Mesentérica Superior/diagnóstico por imagem , Sistemas Automatizados de Assistência Junto ao Leito , Testes Imediatos , Síndrome da Artéria Mesentérica Superior/diagnóstico por imagem , Síndrome da Artéria Mesentérica Superior/terapia , Ultrassonografia , Adulto JovemRESUMO
Continual innovation to address emerging population needs necessitates health service ongoing redesign and transformation worldwide. Recent examples include service transformations in response to Covid-19, many of which were led and managed by nurses. Ensuring change readiness is central to delivering these transformative changes yet has been identified as a central challenge impacting nurse leaders and managers. Recent evidence indicates that affective commitment to change among healthcare staff may be an important contributor to gaining support for change implementation but understudied in healthcare. A cross-sectional survey study was used to examine the association between affective commitment to change and change readiness among 30 healthcare staff across four projects in one state-wide health system in Australia. Our findings indicate that affective commitment to change; healthcare worker's emotional and personal perception of the value of the proposed change is independently associated with individual and collective change readiness. Given that achieving change readiness is a central goal of change management strategies, this pilot work provides valuable insight to inform the change management practices of nurse leaders and managers.
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COVID-19 , Estudos Transversais , Atenção à Saúde , Serviços de Saúde , Humanos , Inovação OrganizacionalRESUMO
OBJECTIVE: To analyze a case of heavy uterine bleeding in adolescence caused by an arteriovenous malformation (AVM) in Hanoi Obstetrics and Gynecology Hospital, Vietnam. METHODS: We observed a case of a 14-year-old girl, without vaginal sexual intercourse experience, having heavy uterine bleeding caused by AVM. She underwent a laparoscopic operation at the hospital for vascular lesions in the uterine anterior wall, which caused an internal hemorrhage of 1500 ml blood loss into the peritoneal cavity. Three years later, this patient was hospitalized twice for massive vaginal bleeding. RESULTS: Results of ultrasound and magnetic resonance imaging indicated a uterine intramural mass with enlarged vessels connecting to the endometrial cavity. A pelvic digital subtraction angiography was performed and showed profuse bleeding from a ruptured branch of the left uterine artery. This artery was embolized at Bach Mai hospital and the bleeding was stopped. The patient had stable health and normal menstrual periods after 4 months of follow up. CONCLUSION: Abnormal mass with dilated vessels in the myometrium in a patient experiencing heavy uterine bleeding is an exclusive sign of uterine vascular malformation and can be treated by angioembolization.
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Malformações Arteriovenosas , Útero , Adolescente , Malformações Arteriovenosas/complicações , Malformações Arteriovenosas/diagnóstico por imagem , Malformações Arteriovenosas/terapia , Feminino , Humanos , Gravidez , Anormalidades Urogenitais , Artéria Uterina/diagnóstico por imagem , Hemorragia Uterina/cirurgia , Útero/anormalidadesRESUMO
The concept of personalized medicine has been steadily growing for the past decades. Monoclonal antibodies (mAbs) are undoubtedly playing an important role in the transition away from conventional medical practice to a more tailored approach to deliver the best therapy with the highest safety margin to a specific patient. In certain instances, mAbs and antibody drug conjugates (ADCs) may represent the preferred therapeutic option for several types of cancers due to their high specificity and affinity to the antigen. Monoclonal antibodies can be labeled with specific radionuclides well-suited for PET (Positron Emission Tomography) or gamma camera scintigraphy. The use of radiolabeled mAbs allows the interrogation of specific biomarkers and assessment of tumor heterogeneity in vivo by a single diagnostic imaging scan that includes the whole-body in the field-of-view. Moreover, the same mAb can then be radiolabeled with an analogous radionuclide for the delivery of beta-minus radiation or alpha-particles as part of a radioimmunotherapy (RIT) approach. However, the path to develop, validate, and implement mAb-based radiopharmaceuticals from bench-to-bedside is complex due to the extensive pre-clinical experiments and toxicological studies required, and the necessity of labor-intensive clinical trials that often require multi-time-point imaging and blood draws for internal radiation dosimetry and pharmacokinetics. As more mAb-based radiopharmaceuticals have been developed and evaluated, the opportunities and limitations offered by mAbs have become better defined. Our aim with this manuscript is therefore to provide an overview of the recent advances in the development of mAb-based radiopharmaceuticals and their clinical applications in Oncology.
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Anticorpos Monoclonais/farmacologia , Neoplasias/diagnóstico por imagem , Neoplasias/radioterapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Radioimunoterapia/métodos , Compostos Radiofarmacêuticos/farmacologia , Humanos , Medicina de Precisão/métodosRESUMO
BACKGROUND: The increasing prioritisation of healthcare quality across the six domains of efficiency, safety, patient-centredness, effectiveness, timeliness and accessibility has given rise to accelerated change both in the uptake of initiatives and the realisation of their outcomes to meet external targets. Whilst a multitude of change management methodologies exist, their application in complex healthcare contexts remains unclear. Our review sought to establish the methodologies applied, and the nature and effectiveness of their application in the context of healthcare. METHODS: A systematic review and narrative synthesis was undertaken. Two reviewers independently screened the titles and abstracts followed by the full-text articles that were potentially relevant against the inclusion criteria. An appraisal of methodological and reporting quality of the included studies was also conducted by two further reviewers. RESULTS: Thirty-eight studies were included that reported the use of 12 change management methodologies in healthcare contexts across 10 countries. The most commonly applied methodologies were Kotter's Model (19 studies) and Lewin's Model (11 studies). Change management methodologies were applied in projects at local ward or unit level (14), institutional level (12) and system or multi-system (6) levels. The remainder of the studies provided commentary on the success of change efforts that had not utilised a change methodology with reference to change management approaches. CONCLUSION: Change management methodologies were often used as guiding principle to underpin a change in complex healthcare contexts. The lack of prescription application of the change management methodologies was identified. Change management methodologies were valued for providing guiding principles for change that are well suited to enable methodologies to be applied in the context of complex and unique healthcare contexts, and to be used in synergy with implementation and improvement methodologies.
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Negro ou Afro-Americano , Taxa de Filtração Glomerular , Insuficiência Renal Crônica/etnologia , Veteranos , Adulto , Idoso , Biomarcadores/sangue , Creatinina/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Prevalência , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Uncircumcised males are at higher risk of urinary tract infection (UTI) in the first year of life and circumcision is recommended as an option for males with vesicoureteral reflux (VUR). Uncircumcised males treated successfully with topical corticosteroid cream have decreased risk of UTI but the role of preputial management has not been explored previously in males with VUR. OBJECTIVE: We hypothesized that among uncircumcised boys with VUR, those with retractable foreskin would be at reduced risk of UTI compared to those with non-retractable foreskin. STUDY DESIGN: Males less than one year of age with primary VUR were prospectively enrolled. Patients with concomitant urologic diagnoses or less than one month of follow-up were excluded. Phimosis severity was graded on a 0-5 scale. Primary outcome was UTI during follow-up. Patients were divided into three groups for analysis: circumcised, low grade phimosis (grades 0-3) and high grade phimosis (grades 4-5). Multivariable Cox proportional hazards regression was used to estimate UTI risk adjusting for risk factors. RESULTS: One-hundred and five boys (24 circumcised and 81 uncircumcised) with VUR were included. Median age at enrollment was 4.4 months (IQR 2.2-6.6) and median follow-up was 1.1 years (IQR 0.53-2.9). Males with phimosis grades 4-5 had a higher UTI rate (29%) compared to phimosis grade 0-3 (4%). Based on Kaplan-Meier curves, boys with initial phimosis grades 4-5 were significantly more likely to develop a UTI than boys who were circumcised or had phimosis grades 0-3 (p = 0.005). On multivariable analysis, boys with phimosis grades 4-5 were significantly more likely to develop UTI when compared to boys with grades 0-3 phimosis (HR = 8.4, 95% CI: 1.1-64, p = 0.04). DISCUSSION: Males with a retractable prepuce had a lower UTI risk compared to males with non-retractable prepuce (high grade phimosis) and this remained significant on multivariable analysis. This is concordant with prior studies demonstrating that a retractable prepuce is associated with decreased UTI risk. Limitations of our study include using phimosis grade at time of study enrollment and heterogenous prophylactic antibiotic use in our population. CONCLUSIONS: Retractable foreskin reduces UTI risk in uncircumcised boys less than one year of age with VUR. Medical phimosis treatment to achieve a retractable prepuce offers an alternative and less invasive modality to reduce UTI risk in males with VUR.
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Circuncisão Masculina , Fimose , Infecções Urinárias , Refluxo Vesicoureteral , Prepúcio do Pênis/cirurgia , Humanos , Lactente , Masculino , Fimose/tratamento farmacológico , Fimose/epidemiologia , Infecções Urinárias/epidemiologia , Infecções Urinárias/prevenção & controle , Refluxo Vesicoureteral/epidemiologiaRESUMO
Prostate cancer is the most common cancer to affect men in the United States and the second most common cancer in men worldwide. Prostate-specific membrane antigen (PSMA)-based positron emission tomography (PET) imaging has become increasingly popular as a novel molecular imaging technique capable of improving the clinical management of patients with prostate cancer. To date, several 68Ga and 18F-labeled PSMA-targeted molecules have shown promising results in imaging patients with recurrent prostate cancer using PET/computed tomography (PET/CT). Studies of involving PSMA-targeted radiopharmaceuticals also suggest a higher sensitivity and specificity, along with an improved detection rate over conventional imaging (CT scan and methylene diphosphonate bone scintigraphy) and 11C/18F-choline PET/CT. In addition, PSMA-617 and PSMA I&T ligands can be labeled with α- and ß-emitters (e.g., 225Ac, 90Y, and 177Lu) and serve as a theranostic tool for patients with metastatic prostate cancer. While the clinical impact of such concept remains to be verified, the preliminary results of PSMA molecular radiotherapy are very encouraging. Herein, we highlighted the current status of development and future perspectives of PSMA-targeted radiopharmaceuticals and their clinical applications.