RESUMO
BACKGROUND: In high-resource settings, the survival of children with immunocompromise (IC) has increased and immunosuppressive therapies are increasingly being used. This study aimed to determine the clinical characteristics, performance of diagnostic tools, and outcome of IC children with tuberculosis (TB) in Europe. METHODS: Multicenter, matched case-control study within the Pediatric Tuberculosis Network European Trials Group, capturing TB cases <18 years diagnosed 2000-2020. RESULTS: A total of 417 TB cases were included, comprising 139 children who are IC (human immunodeficiency virus, inborn errors of immunity, drug-induced immunosuppression, and other immunocompromising conditions) and 278 non-IC children as controls. Nonrespiratory TB was more frequent among cases than controls (32.4% vs 21.2%; P = .013). Patients with IC had an increased likelihood of presenting with severe disease (57.6% vs 38.5%; P < .001; odds ratio [95% confidence interval], 2.073 [1.37-3.13]). Children with IC had higher rates of false-negative tuberculin skin test (31.9% vs 6.0%; P < .001) and QuantiFERON-TB Gold assay (30.0% vs 7.3%; P < .001) results at diagnosis. Overall, the microbiological confirmation rate was similar in IC and non-IC cases (58.3% vs 49.3%; P = .083). Although the mortality in children with IC was <1%, the rate of long-term sequelae was significantly higher than in non-IC cases (14.8% vs 6.1%; P = .004). CONCLUSIONS: Children with IC and TB in Europe have increased rates of nonrespiratory TB, severe disease, and long-term sequelae. Immune-based TB tests have poor sensitivity in those children. Future research should focus on developing improved immunological TB tests that perform better in patients with IC, and determining the reasons for the increased risk of long-term sequelae, with the aim to design preventive management strategies.
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Hospedeiro Imunocomprometido , Tuberculose , Humanos , Estudos de Casos e Controles , Criança , Masculino , Feminino , Adolescente , Europa (Continente)/epidemiologia , Tuberculose/epidemiologia , Tuberculose/diagnóstico , Pré-Escolar , Lactente , Teste Tuberculínico , Antituberculosos/uso terapêuticoRESUMO
By employing a variation of the polyamidation method using in situ silylated diamines and acid chlorides, it was possible to obtain a rod-type polyamide: poly(p-phenylene terephthalamide) (PPTA, a polymer used in the high-value-added material Kevlar), with a molecular weight much higher than that obtained with the classical and industrial polyamidation method. The optimization of the method has consisted of using, together with the silylating agent, a mixture of pyridine and a high-pKa tertiary amine. The research was complemented by a combination of nuclear magnetic resonance and molecular simulation studies, which determined that the improvements in molecular weight derive mainly from the formation of silylamide groups in the growing polymer.
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Nylons , Polímeros , Peso Molecular , Espectroscopia de Ressonância Magnética , DiaminasRESUMO
BACKGROUND: Antiviral prophylaxis is recommended in cytomegalovirus (CMV)-seropositive kidney transplant (KT) recipients receiving antithymocyte globulin (ATG) as induction. An alternative strategy of premature discontinuation of prophylaxis after CMV-specific cell-mediated immunity (CMV-CMI) recovery (immunoguided prevention) has not been studied. Our aim was to determine whether it is effective and safe to discontinue prophylaxis when CMV-CMI is detected and to continue with preemptive therapy. METHODS: In this open-label, noninferiority clinical trial, patients were randomized 1:1 to follow an immunoguided strategy, receiving prophylaxis until CMV-CMI recovery or to receive fixed-duration prophylaxis until day 90. After prophylaxis, preemptive therapy (valganciclovir 900 mg twice daily) was indicated in both arms until month 6. The primary and secondary outcomes were incidence of CMV disease and replication, respectively, within the first 12 months. Desirability of outcome ranking (DOOR) assessed 2 deleterious events (CMV disease/replication and neutropenia). RESULTS: A total of 150 CMV-seropositive KT recipients were randomly assigned. There was no difference in the incidence of CMV disease (0% vs 2.7%; P = .149) and replication (17.1% vs 13.5%; log-rank test, P = .422) between both arms. Incidence of neutropenia was lower in the immunoguided arm (9.2% vs 37.8%; odds ratio, 6.0; P < .001). A total of 66.1% of patients in the immunoguided arm showed a better DOOR, indicating a greater likelihood of a better outcome. CONCLUSIONS: Prophylaxis can be prematurely discontinued in CMV-seropositive KT patients receiving ATG when CMV-CMI is recovered since no significant increase in the incidence of CMV replication or disease is observed. CLINICAL TRIALS REGISTRATION: NCT03123627.
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Infecções por Citomegalovirus , Transplante de Rim , Soro Antilinfocitário/uso terapêutico , Antivirais/uso terapêutico , Citomegalovirus , Ganciclovir/uso terapêutico , Humanos , Transplante de Rim/efeitos adversos , TransplantadosRESUMO
BACKGROUND: The "diagnose-and-leave-in" policy has been established to reduce the risks and costs related to unnecessary polypectomies in the average-risk population. In individuals with Lynch syndrome, owing to accelerated carcinogenesis, the general recommendation is to remove all polyps, irrespective of size, location, and appearance. We evaluated the feasibility and safety of the diagnose-and-leave-in strategy in individuals with Lynch syndrome. METHODS : We performed a post hoc analysis based on per-polyp data from a randomized, clinical trial conducted by 24 dedicated colonoscopists at 14 academic centers, in which 256 patients with confirmed Lynch syndrome underwent surveillance colonoscopy from July 2016 to January 2018. In vivo optical diagnosis with confidence level for all detected lesions was obtained before polypectomy using virtual chromoendoscopy alone or with dye-based chromoendoscopy. Primary outcome was the negative predictive value (NPV) for neoplasia of high-confidence optical diagnosis among diminutive (≤â5âmm) rectosigmoid lesions. Histology was the reference standard. RESULTS: Of 147 rectosigmoid lesions, 128 were diminutive. In 103 of the 128 lesions (81â%), the optical diagnostic confidence was high and showed an NPV of 96.0â% (95â% confidence interval [CI] 88.9â%-98.6â%) and accuracy of 89.3â% (95â%CI 81.9â%-93.9â%). By following the diagnose-and-leave-in policy, we would have avoided 59â% (75/128) of polypectomies at the expense of two diminutive low grade dysplastic adenomas and one diminutive sessile serrated lesion that would have been left in situ. CONCLUSION: In patients with Lynch syndrome, the diagnose-and-leave-in strategy for diminutive rectosigmoid polyps would be feasible and safe.
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Pólipos do Colo , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Pólipos do Colo/diagnóstico por imagem , Pólipos do Colo/cirurgia , Colonoscopia , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Humanos , Imagem de Banda EstreitaRESUMO
Plexiform fibromyxoma (PF) is an uncommon primary tumor of the gastrointestinal tract, with a mesenchymal origin and a benign behavior. Herein, we report a case and provide a literature review. A 41-year-old male patient underwent surgery in our unit for a PF at the gastric antrum, after being admitted due to vomiting and weight loss. As illustrated by our case, the mean age at presentation is around 40 years, the antrum is the most common location and abdominal pain the most widely reported manifestation. None of the reviewed cases involved regional or distant spread.
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Neoplasias do Sistema Digestório , Fibroma , Tumores do Estroma Gastrointestinal , Neoplasias Gástricas , Adulto , Fibroma/diagnóstico por imagem , Fibroma/cirurgia , Humanos , Masculino , Antro Pilórico , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/cirurgiaRESUMO
In the kidney, the accumulation of heavy metals such as Cd2+ produces mitochondrial dysfunctions, i.e., uncoupling of the oxidative phosphorylation, inhibition of the electron transport through the respiratory chain, and collapse of the transmembrane electrical gradient. This derangement may be due to the fact that Cd2+ induces the transition of membrane permeability from selective to nonselective via the opening of a transmembrane pore. In fact, Cd2+ produces this injury through the stimulation of oxygen-derived radical generation, inducing oxidative stress. Several molecules have been used to avoid or even reverse Cd2+-induced mitochondrial injury, for instance, cyclosporin A, resveratrol, dithiocarbamates, and even EDTA. The aim of this study was to explore the possibility that the antioxidant tamoxifen could protect mitochondria from the deleterious effects of Cd2+. Our results indicate that the addition of 1 µmol/L Cd2+ to mitochondria collapsed the transmembrane electrical gradient, induced the release of cytochrome c, and increased both the generation of H2O2 and the oxidative damage to mitochondrial DNA (among other measured parameters). Of interest, these mitochondrial dysfunctions were ameliorated after the addition of tamoxifen.
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Cádmio/toxicidade , Peróxido de Hidrogênio/metabolismo , Rim/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Rim/patologia , Mitocôndrias/patologia , Oxirredução/efeitos dos fármacosRESUMO
Sperm quality in donkeys (Equus asinus) after freezing thawing is still considered lower than that from other animals, including horses. The aim of this study was to test a new freezing extender supplemented with jenny colostrum on donkey sperm. After thawing, we evaluated sperm motility by means of computer-assisted analysis, viability by SYBR-14 and propidium iodide (PI), membrane functional integrity by HOS-test and acrosome integrity by isothiocyanate conjugated with peanut agglutinin (FITC-PNA) and PI. Ejaculates were collected from five fertile Donkeys. Sperm samples were pooled, diluted and cryopreserved into three experimental extender groups: BotuCrio®, lactose-extender supplemented with egg yolk (20%) and lactose-extender supplemented with jenny colostrum (20%). The results demonstrated that lactose-jenny colostrum samples displayed significantly higher values in almost all parameters evaluated (pâ¯<â¯0.05) compared with the other two extenders after thawing (BotuCrio® and lactose-egg yolk based extender, respectively) -Total Motility, Viability, HOS test, VCL, VSL and VAP. Acrosome status, LIN, STR and WOB despite showing lower values, none of them were statistically significant (pâ¯>â¯0.05). In conclusion, the extender containing jenny colostrum can be successfully used for donkey semen crypreservation and could effectively improve donkey sperm qualities after freezing -thawing.
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Colostro/metabolismo , Criopreservação/métodos , Crioprotetores/farmacologia , Preservação do Sêmen/métodos , Motilidade dos Espermatozoides/efeitos dos fármacos , Acrossomo/fisiologia , Animais , Membrana Celular/fisiologia , Gema de Ovo/metabolismo , Equidae , Feminino , Fluoresceínas , Congelamento , Cavalos , Lactose , Masculino , Aglutinina de Amendoim , Gravidez , Sêmen/fisiologiaRESUMO
The aim of this study was to test and compare two new components in extenders for freezing donkey semen: mare colostrum and jenny colostrum. Colostrum was obtained from four mares and four jennies right after the foal's birth. Ejaculates were collected from five fertile donkeys. Sperm samples were pooled, diluted and cryopreserved in three different experimental extender groups: lactose supplemented with egg yolk extender (20%) as the control group, lactose supplemented with jenny colostrum extender (20%), and lactose supplemented with mare colostrum extender (20%). After thawing, we evaluated the sperm motility by means of computer-assisted analysis, viability by SYBR-14 and propidium iodide (PI), membrane functional by HOS test and acrosome integrity by isothiocyanate conjugated with peanut agglutinin (FITC-PNA) and PI. The results demonstrated that lactose-jenny colostrum extender displayed significantly higher values (p < .05) in nearly all parameters evaluated - Total Motility, Viability, HOS test, VCL, VSL, VAP, LIN, STR and WOB -, compared with mare colostrum and egg yolk extenders after thawing. In conclusion, the extender containing jenny colostrum used for donkey semen cryopreservation improved the donkey sperm quality after the freezing-thawing process.
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Colostro , Criopreservação/veterinária , Crioprotetores/farmacologia , Preservação do Sêmen/veterinária , Animais , Criopreservação/métodos , Equidae , Feminino , Cavalos , Masculino , Análise do Sêmen/veterinária , Preservação do Sêmen/métodos , Motilidade dos Espermatozoides/efeitos dos fármacosRESUMO
Chitosan is a stressing molecule that affects the cells walls and plasma membrane of fungi. For chitosan derivatives, the action mode is not clear. In this work, we used the yeast Ustilago maydis to study the effects of these molecules on the plasma membrane, focusing on physiologic and stress responses to chitosan (CH), oligochitosan (OCH), and glycol-chitosan (GCH). Yeasts were cultured with each of these molecules at 1 mg·mL-1 in minimal medium. To compare plasma membrane damage, cells were cultivated in isosmolar medium. Membrane potential (Δψ) as well as oxidative stress were measured. Changes in the total plasma membrane phospholipid and protein profiles were analyzed using standard methods, and fluorescence-stained mitochondria were observed. High osmolarity did not protect against CH inhibition and neither affected membrane potential. The OCH did produce higher oxidative stress. The effects of these molecules were evidenced by modifications in the plasma membrane protein profile. Also, mitochondrial damage was evident for CH and OCH, while GCH resulted in thicker cells with fewer mitochondria and higher glycogen accumulation.
Assuntos
Membrana Celular/efeitos dos fármacos , Parede Celular/efeitos dos fármacos , Quitina/análogos & derivados , Quitosana/farmacologia , Ustilago/efeitos dos fármacos , Membrana Celular/ultraestrutura , Permeabilidade da Membrana Celular , Parede Celular/ultraestrutura , Quitina/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Oligossacarídeos , Concentração Osmolar , Fosfolipídeos/metabolismo , Poliaminas/farmacologia , Polieletrólitos , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Ustilago/metabolismo , Ustilago/ultraestruturaRESUMO
Organophosphate esters (OPEs) are widely used as flame retardants and plasticizers and have been detected ubiquitously in the remote atmosphere. Fourteen OPEs were analyzed in 115 aerosol phase samples collected from the tropical and subtropical Atlantic, Pacific, and Indian Oceans during the MALASPINA circumnavigation campaign. OPEs were detected in all samples with concentrations ranging from 360 to 4400 pg m-3 for the sum of compounds. No clear concentration trends were found between the Northern and Southern hemispheres. The pattern was generally dominated by tris(1-chloro-2-propyl) phosphate (TCPP), although tri-n-butyl phosphate (TnBP) had a predominant role in samples close to continents and in those influenced by air masses originating in continents. The dry deposition fluxes of aerosol phase ∑14OPE ranged from 4 to 140 ng m-2 d-1. An estimation of the OPE gas phase concentration and gross absorption fluxes by using three different sets of physical chemical properties suggested that the atmosphere-ocean diffusive exchange of OPEs could be 2-3 orders of magnitude larger than dry deposition. The associated organic phosphorus inputs coming from diffusive OPE fluxes were estimated to potentially trigger up to 1.0% of the reported primary production in the most oligotrophic oceanic regions. However, the uncertainty associated with these calculations is high and mostly driven by the uncertainty of the physical chemical properties of OPEs. Further constraints of the physical chemical properties and fluxes of OPEs are urgently needed, in order to estimate their environmental fate and relevance as a diffusive source of new organic phosphorus to the ocean.
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Retardadores de Chama , Plastificantes , Atmosfera/química , Monitoramento Ambiental , OrganofosfatosRESUMO
Many studies have been carried out on the environmental impact of the research stations on the Antarctic continent. However, the assessment of indoor air quality in these confined environments has been neglected. The main objectives of this study are to investigate the granulometric distribution of the indoor particles in the different compartments of the Brazilian Antarctic Station, to examine the number and mass concentration of the indoor particles, to conduct chemical and morphological analyses of the indoor PM2.5, and to identify the possible sources of the PM. The results showed that Na, K, Cl, Fe, Zn, S and Si were the main elements detected. High levels of black carbon were recorded in the workshop, which may be associated with the use of diesel vehicles. To identify the human activities related to the indoor particle emission in the station, the size distribution of the particles in the living room was monitored for seven consecutive days, during normal station operation. It was possible to identify the influence of individual processes, such as incineration, cooking and the movement of people, upon the particle size number concentration. The indoor/outdoor (I/O) ratio for the total suspended particles (TSP), PM10, PM2.5 and PM1 measured was significantly larger than those reported for urban buildings. In general, the I/O ratio distribution for all the compartments shows peak values between 2.5 and 10 µm, which is often related to human activity, such as cleaning, personnel circulation or clothing surfaces. The maximum I/O ratio at this range varied from 12 to 60. In addition, the compartments affected by combustion processes tend to present a significant number of submicron particles.
Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar em Ambientes Fechados/análise , Monitoramento Ambiental , Regiões Antárticas , Tamanho da Partícula , PesquisaRESUMO
BACKGROUND & AIMS: We compared the ability of biennial fecal immunochemical testing (FIT) and one-time sigmoidoscopy to detect colon side-specific advanced neoplasms in a population-based, multicenter, nationwide, randomized controlled trial. METHODS: We identified asymptomatic men and women, 50-69 years old, through community health registries and randomly assigned them to groups that received a single colonoscopy examination or biennial FIT. Sigmoidoscopy yield was simulated from results obtained from the colonoscopy group, according to the criteria proposed in the UK Flexible Sigmoidoscopy Trial for colonoscopy referral. Patients who underwent FIT and were found to have ≥75 ng hemoglobin/mL were referred for colonoscopy. Data were analyzed from 5059 subjects in the colonoscopy group and 10,507 in the FIT group. The main outcome was rate of detection of any advanced neoplasm proximal to the splenic flexure. RESULTS: Advanced neoplasms were detected in 317 subjects (6.3%) in the sigmoidoscopy simulation group compared with 288 (2.7%) in the FIT group (odds ratio for sigmoidoscopy, 2.29; 95% confidence interval, 1.93-2.70; P = .0001). Sigmoidoscopy also detected advanced distal neoplasia in a higher percentage of patients than FIT (odds ratio, 2.61; 95% confidence interval, 2.20-3.10; P = .0001). The methods did not differ significantly in identifying patients with advanced proximal neoplasms (odds ratio, 1.17; 95% confidence interval, 0.78-1.76; P = .44). This was probably due to the lower performance of both strategies in detecting patients with proximal lesions (sigmoidoscopy detected these in 19.1% of patients and FIT in 14.9% of patients) vs distal ones (sigmoidoscopy detected these in 86.8% of patients and FIT in 33.5% of patients). Sigmoidoscopy, but not FIT, detected proximal lesions in lower percentages of women (especially those 50-59 years old) than men. CONCLUSIONS: Sigmoidoscopy and FIT have similar limitations in detecting advanced proximal neoplasms, which depend on patients' characteristics; sigmoidoscopy underperforms for women 50-59 years old. Screening strategies should be designed on the basis of target population to increase effectiveness and cost-effectiveness. ClinicalTrials.gov number: NCT00906997.
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Colo/patologia , Neoplasias do Colo/diagnóstico , Fezes/química , Imuno-Histoquímica/métodos , Sigmoidoscopia/métodos , Idoso , Análise Custo-Benefício , Feminino , Humanos , Imuno-Histoquímica/economia , Masculino , Programas de Rastreamento/economia , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Sigmoidoscopia/economia , Reino UnidoRESUMO
Ubiquinone derivatives modulate the mammalian mitochondrial Permeability Transition Pore (PTP). Yeast mitochondria harbor a similar structure: the respiration- and ATP-induced Saccharomyces cerevisiae Mitochondrial Unselective Channel ( Sc MUC). Here we show that decylubiquinone, a well-characterized inhibitor of the PTP, suppresses Sc MUC opening in diverse strains and independently of respiratory chain modulation or redox-state. We also found that naturally occurring derivatives such as hexaprenyl and decaprenyl ubiquinones lacked effects on the Sc MUC. The PTP-inactive ubiquinone 5 (Ub5) promoted the Sc MUC-independent activation of the respiratory chain in most strains tested. In an industrial strain however, Ub5 blocked the protection elicited by dUb. The results indicate the presence of a ubiquinone-binding site in the Sc MUC.
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Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Saccharomyces cerevisiae/metabolismo , Ubiquinona/genética , Ubiquinona/metabolismo , Animais , Poro de Transição de Permeabilidade Mitocondrial , Espécies Reativas de Oxigênio , LevedurasRESUMO
In Saccharomyces cerevisiae addition of glucose inhibits oxygen consumption, i.e. S. cerevisiae is Crabtree-positive. During active glycolysis hexoses-phosphate accumulate, and probably interact with mitochondria. In an effort to understand the mechanism underlying the Crabtree effect, the effect of two glycolysis-derived hexoses-phosphate was tested on the S. cerevisiae mitochondrial unspecific channel (ScMUC). Glucose-6-phosphate (G6P) promoted partial opening of ScMUC, which led to proton leakage and uncoupling which in turn resulted in, accelerated oxygen consumption. In contrast, fructose-1,6-bisphosphate (F1,6BP) closed ScMUC and thus inhibited the rate of oxygen consumption. When added together, F1,6BP reverted the mild G6P-induced effects. F1,6BP is proposed to be an important modulator of ScMUC, whose closure contributes to the "Crabtree effect".
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Frutosedifosfatos/metabolismo , Glucose/metabolismo , Consumo de Oxigênio , Canais de Potássio/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Glucose-6-Fosfato/metabolismo , Glicólise , Ativação do Canal Iônico , Potencial da Membrana Mitocondrial , Dilatação MitocondrialRESUMO
Introduction: Extensive research has explored the incorporation of humor in therapy, revealing its potential positive effects on clients' mental well-being and personal growth. However, limited research exists on how coaching could benefit from humor as an intervention and how its utilization impacts the interaction processes and outcomes for both the coachee and coach. Therefore, our research focuses on the use and effects of spontaneous humor within professional dialogues. This paper aims to extract insights from academic literature on humor in adjacent fields and apply these insights to the context of coaching. Methods: This paper offers implications for coaching theory and practice, alongside a proposed research agenda. The initial phase involves analyzing reviews on humor in professional contexts, and coaching. Secondly, following the PRISMA guidelines for review, we identified 13 empirical studies, which address the role of humor in counseling, psychotherapy, and mentoring. Results and discussion: Our findings suggest that humor serves as a valuable tool for establishing and deepening the working alliance, fostering adaptive coping mechanisms in clients, and enhancing the cognitive and behavioral process. Moreover, humor is shown to be advantageous for professionals in navigating challenging client relationships. These findings hold significance for the realm of coaching practice as well. In light of these insights, we propose the integration of humor use in education toolkits for coaching professionals.
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OBJECTIVE: To investigate the overall effect of whey protein supplementation on skeletal muscle mass in adults with type 2 diabetes mellitus (T2DM). METHODS: Systematic review of reports on corporal muscle mass from clinical trials that assessed the use of whey protein supplementation by means of validated techniques in patients with T2DM. PubMed, SCOPUS, Web of Science, LILACS, and SciELO databases were searched up to April 2022. Risk of bias was assessed by the Cochrane Collaboration Risk of Bias tool. We conducted a qualitative synthesis of information. RESULTS: Four studies (424 participants) that met the selection criteria were identified out of 1,787 records. Of these, 3 studies assessed the total muscle mass using dual-energy X-ray absorptiometry (DXA), and 1 reported changes to the transverse diameter of the vastus lateralis muscle with ultrasound imaging. In the intervention groups, DXA assessments demonstrated an increase in total muscle mass in 3 studies and in the appendicular muscle mass in 2. Changes to the proportion of muscle mass were not seen in the DXA studies and only a discrete difference was seen in the comparative groups studied by ultrasound imaging. CONCLUSION: Following the administration of whey protein supplementation in patients with T2DM, a partially positive effect was seen in skeletal muscle mass gain with a moderate certainty of evidence.
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Diabetes Mellitus Tipo 2 , Suplementos Nutricionais , Músculo Esquelético , Proteínas do Soro do Leite , Adulto , Humanos , Absorciometria de Fóton , Administração Oral , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Músculo Esquelético/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas do Soro do Leite/administração & dosagemRESUMO
Transplantation (KTx) is considered to be the best renal replacement therapy, and improving its outcomes remains a primary challenge. KTx ureteral stenting has been used to prevent urological complications, but there is no consensus on the timing of stent removal, and literature regarding routine ultrasonography after ureteric stent removal (RUSUS) to detect complications is lacking. Point-of-care ultrasound has been gaining drive in the medical community in recent years, including nephrologists. We aimed to define the incidence of urological complications diagnosed with RUSUS, if those findings changed patient's management and ultrasound utility. Contrary to previously published data, in our cohort RUSUS allowed a timely diagnosis and early treatment of urological complications, a key factor for successful transplantation. KTx point-of-care ultrasound is a cost-effective and reproducible test that provides relevant information to guide clinical decisions, seeming most efficient when performed approximately 2 weeks post ureteral stent removal. Interventional nephrologists can promptly perform these examinations, reducing waiting times and improving graft and patient's survival.
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Complicações Pós-Operatórias , Ureter , Humanos , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia , Ureter/diagnóstico por imagem , Ureter/cirurgia , Stents , Rim , UltrassonografiaRESUMO
Genetic studies indicate that breast cancer can be divided into several basic molecular groups. One of these groups, termed IntClust-2, is characterized by amplification of a small portion of chromosome 11 and has a median survival of only five years. Several cancer-relevant genes occupy this portion of chromosome 11, and it is thought that overexpression of a combination of driver genes in this region is responsible for the poor outcome of women in this group. In this study we used a gene editing method to knock out, one by one, each of 198 genes that are located within the amplified region of chromosome 11 and determined how much each of these genes contributed to the survival of breast cancer cells. In addition to well-known drivers such as CCND1 and PAK1 , we identified two different genes ( SERPINH1 and P4HA3 ), that encode proteins involved in collagen synthesis and organization. Using both in vitro and in vivo functional analyses, we determined that P4HA3 and/or SERPINH1 provide a critical driver function on IntClust-2 basic processes, such as viability, proliferation, and migration. Inhibiting these enzymes via genetic or pharmacologic means reduced collagen synthesis and impeded oncogenic signaling transduction in cell culture models, and a small-molecule inhibitor of P4HA3 was effective in treating 11q13 tumor growth in an animal model. As collagen has a well-known association with tissue stiffness and aggressive forms of breast cancer, we believe that the two genes we identified provide an opportunity for a new therapeutic strategy in IntClust-2 breast cancers.
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Background and objectives: Dimensional response is an unmet need in second lines of advanced soft tissue sarcomas (STS). Indeed, the three approved drugs, pazopanib, trabectedin, and eribulin, achieved an overall response rate (ORR) of less than 10%. This fact potentially hinders the options for fast symptomatic relief or surgical rescue. The combination of trabectedin plus low-dose radiation therapy (T-XRT) demonstrated a response rate of 60% in phase I/II trial, while real-life data achieved 32.5% ORR, probably due to a more relaxed timing between treatments. These results were obtained in progressing and advanced STS. In this study, the merged databases (trial plus real life) have been analyzed, with a special focus on leiomyosarcoma patients. Design and methods: As responses were seen in a wide range of sarcoma histologies (11), this study planned to analyze whether leiomyosarcoma, the largest subtype with 26 cases (30.6%) in this series, exhibited a better clinical outcome with this therapeutic strategy. In addition, four advanced and progressing leiomyosarcoma patients, all with extraordinarily long progression-free survival of over 18 months, were collected. Results: A total of 847 cycles of trabectedin were administered to 85 patients, with the median number of cycles per patient being 7 (1-45+). A trend toward a longer progression-free survival (PFS) was observed in leiomyosarcoma patients with median PFS (mPFS) of 9.9 months [95% confidence interval (CI): 1.1-18.7] versus 5.6 months (95% CI: 3.2-7.9) for the remaining histologies, p = 0.25. When leiomyosarcoma and liposarcoma were grouped, this difference reached statistical significance, probably due to the special sensitivity of myxoid liposarcoma. The mPFS for L-sarcomas was 12.7 months (95% CI: 7-18.5) versus 4.3 months (95% CI: 3.3-5.3) for the remaining histologies, p = 0.001. Cases with long-lasting disease control are detected among leiomyosarcoma patients. Conclusion: Even when extraordinarily long-lasting responses do exist among leiomyosarcoma patients treated with T-XR, we were unable to demonstrate a significant difference favoring leiomyosarcoma patients in clinical outcomes.
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RAC1P29S is the third most prevalent hotspot mutation in sun-exposed melanoma. RAC1 alterations in cancer are correlated with poor prognosis, resistance to standard chemotherapy, and insensitivity to targeted inhibitors. Although RAC1P29S mutations in melanoma and RAC1 alterations in several other cancers are increasingly evident, the RAC1-driven biological mechanisms contributing to tumorigenesis remain unclear. Lack of rigorous signaling analysis has prevented identification of alternative therapeutic targets for RAC1P29S-harboring melanomas. To investigate the RAC1P29S-driven effect on downstream molecular signaling pathways, we generated an inducible RAC1P29S expression melanocytic cell line and performed RNA-sequencing (RNA-seq) coupled with multiplexed kinase inhibitor beads and mass spectrometry (MIBs/MS) to establish enriched pathways from the genomic to proteomic level. Our proteogenomic analysis identified CDK9 as a potential new and specific target in RAC1P29S-mutant melanoma cells. In vitro, CDK9 inhibition impeded the proliferation of in RAC1P29S-mutant melanoma cells and increased surface expression of PD-L1 and MHC Class I proteins. In vivo, combining CDK9 inhibition with anti-PD-1 immune checkpoint blockade significantly inhibited tumor growth only in melanomas that expressed the RAC1P29S mutation. Collectively, these results establish CDK9 as a novel target in RAC1-driven melanoma that can further sensitize the tumor to anti-PD-1 immunotherapy.