A Synthetic Circuit Empowering Reprogrammed B Cells for Therapeutic Proteins Expression Regulated by Tumor Detection.

Cancer remains a leading cause of death worldwide, but immunotherapies hold promises to cure it by awaking the patient's immune system to provide long-term protection. Cell therapies, involving the infusion of immune cells, either directly or genetically modified, are being developed to recognize and destroy cancer cells. Here, we explored the potential of a new synthetic circuit to reprogram B cells to cure cancers. This circuit consists in a sensor (a membrane-anchored IgG1), a transducer (a fragment of the NR4A1 promoter) and an effector molecule. Upon recognition of its target, this sensor triggers signaling pathways leading to the activation of the transducer and to effector expression (here, a reporter molecule). We showed that this circuit could discriminate tumors expressing the target antigen from those that did not, in a dose dependent manner in vitro. Going further, we replaced the original membrane-anchored sensor by an immunoglobulin expression cassette that can not only be membrane-anchored but also be secreted depending on B-cell maturation status. This allowed concomitant activation of the circuit and secretion of transgenic antibodies directed against the targeted antigen. Of note, these antibodies could correctly bind their target and were recognized by FcR expressed at the surface of immune cells, which should synergically amplify the action of the effector. The potential of reprogrammed B cells remains to be assessed in vivo by implementing a therapeutic effector. In the future, B-cell reprogramming platforms should allow personalized cancer treatment by adapting both the sensor and the therapeutic effectors to patients.

Uterine transposition for fertility preservation in pelvic cancers.

OBJECTIVE: To review rates of uterine preservation and gonadal function, surgical outcomes, and pregnancy outcomes in patients undergoing surgical uterine transposition. METHODS: A structured search and analysis of the published literature on uterine transposition was conducted. Information on study type, sample size, patient characteristics, clinical indications, details of the surgical technique, trans-operative and post-operative results, success rates in preserving reproductive organ function and fertility were extracted. RESULTS: A total of 18 cases were reported to date. Patients' median age was 29 (range 3-38) years. Rectal cancers accounted for 9 (50%) cases of published cases of uterine transposition, followed by 6 (33%) cervical squamous cell carcinomas, 1 (6%) vaginal squamous cell carcinoma, 1 (6%) sacral yolk sac tumor, and 1 (6%) pelvic liposarcoma. The median time for uterine transposition to the upper abdomen was 150 (range 80-360) min, and 90 (range 80-310) min for organ reimplantation in the pelvis. Cervical ischemia occurred in 5 (27.8%) cases, being the most commonly reported complication. The median follow-up time was 25 months, and three patients achieved spontaneous pregnancies resulting in successful gestations, out of five patients who were reported as having tried. One patient experienced recurrence and succumbed to the tumor during treatment. CONCLUSIONS: Uterine transposition is a feasible and safe surgical approach that offers patients undergoing pelvic radiotherapy an option to preserve gonadal and uterine function, with the potential for spontaneous pregnancy.

An evaluation of techniques to diagnose Dioctophyme renale in dogs.

Dioctophyme renale is a nematode with zoonotic potential that affects the kidneys of carnivorous, wild, and domestic mammals. In this study, we sought to evaluate the indirect ELISA method against routine methods used to diagnose dioctophimosis. Hence, 38 dogs parasitized by D. renale, as confirmed by surgery, were selected. The dogs were evaluated by abdominal ultrasound and urinalysis, and their sera were tested by indirect ELISA using D. renale adult secretion and excretion antigen (DES). Five dogs were followed up with serum collections on day 0 (day of surgery) and 30, 60, and 90 days after surgery to evaluate antibody kinetics. Abdominal ultrasound and indirect ELISA successfully diagnosed 37 dogs parasitized by D. renale, while urinalysis diagnosed 29 animals. The positive animals were parasitized with 1-7 parasites; 17 dogs were infected by male and female parasites, 15 only by female parasites, and six were parasitized only by male parasites. When assessing specificity and sensitivity, all techniques showed 100% specificity and 81.6%, 97.4%, and 97.4% sensitivity for urinalysis, ultrasound, and ELISA, respectively (p < 0.001). The five positive dogs that were followed up after surgery showed a progressive decrease in mean absorbances in indirect ELISA (0.644, 0.516, 0.511, and 0.440, respectively). This study demonstrated that the indirect ELISA using the DE antigen could diagnose dioctophimosis regardless of the number, sex, and location of the parasites, with the potential to be used in epidemiological research and implementing immunological and molecular studies, opening new lines of research on D. renale.

Dioctophyme renale é um nematódeo que possui potencial zoonótico e acomete o rim de mamíferos carnívoros, silvestres e domésticos. Neste estudo busca-se avaliar a técnica de ELISA indireto frente metodologias de rotina utilizadas no diagnóstico da dioctofimose. Para isto, 38 cães participaram do estudo, sendo todos parasitados por D. renale, confirmados por cirurgia. Esses cães foram avaliados por ultrassom abdominal, urinálise e seus soros testado por ELISA indireto utilizando antígeno de excreção e secreção (DES) de adultos de D. renale. Destes, cinco cães foram acompanhados com coletas de soro, no dia zero (dia da cirurgia) e após 30, 60 e 90 dias da cirurgia para avaliar a cinética dos anticorpos. O ultrassom abdominal e ELISA indireto apresentaram sucesso no diagnóstico de 37 cães parasitados por D. renale, enquanto que a urinálise diagnosticou 29 animais. Os animais positivos possuíam de um a sete parasitos, 17 cães apresentaram infecções por macho e fêmeas, 15 somente por fêmeas e seis foram parasitados apenas por machos. Na avaliação da especificidade e sensibilidade, todas as técnicas apresentaram 100% de especificidade e 81,6%, 97,4%, 97,4% de sensibilidade para urinálise, ultrassom e ELISA, respectivamente (p < 0,001). Os cinco cães positivos que foram acompanhados após a cirurgia apresentaram diminuição progressiva nas médias de absorbâncias no ELISA indireto (0,644, 0,516, 0,511 e 0,440, respectivamente). O estudo demonstrou que o ELISA indireto utilizando o antígeno DES poderia diagnosticar dioctofimose, independentemente do número, sexo e localização dos parasitos, com potencial para ser utilizada em estudos epidemiológicos e na implementação de estudos imunológicos e moleculares, abrindo novas linhas de pesquisa sobre Dioctophyme renale.

Accuracy of prognostic serological biomarkers in predicting liver fibrosis severity in people with metabolic dysfunction-associated steatotic liver disease: a meta-analysis of over 40,000 participants.

Introduction: A prognostic model to predict liver severity in people with metabolic dysfunction-associated steatotic liver disease (MASLD) is very important, but the accuracy of the most commonly used tools is not yet well established. Objective: The meta-analysis aimed to assess the accuracy of different prognostic serological biomarkers in predicting liver fibrosis severity in people with MASLD. Methods: Adults ≥18 years of age with MASLD were included, with the following: liver biopsy and aspartate aminotransferase-to-platelet ratio (APRI), fibrosis index-4 (FIB-4), non-alcoholic fatty liver disease fibrosis score (NFS), body mass index, aspartate aminotransferase/alanine aminotransferase ratio, diabetes score (BARD score), FibroMeter, FibroTest, enhanced liver fibrosis (ELF), Forns score, and Hepascore. Meta-analyses were performed using a random effects model based on the DerSimonian and Laird methods. The study's risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2. Results: In total, 138 articles were included, of which 86 studies with 46,514 participants met the criteria for the meta-analysis. The results for the summary area under the receiver operating characteristic (sAUROC) curve, according to the prognostic models, were as follows: APRI: advanced fibrosis (AF): 0.78, any fibrosis (AnF): 0.76, significant fibrosis (SF): 0.76, cirrhosis: 0.72; FIB-4: cirrhosis: 0.83, AF: 0.81, AnF: 0.77, SF: 0.75; NFS: SF: 0.81, AF: 0.81, AnF: 0.71, cirrhosis: 0.69; BARD score: SF: 0.77, AF: 0.73; FibroMeter: SF: 0.88, AF: 0.84; FibroTest: SF: 0.86, AF: 0.78; and ELF: AF: 0.87. Conclusion: The results of this meta-analysis suggest that, when comparing the scores of serological biomarkers with liver biopsies, the following models showed better diagnostic accuracy in predicting liver fibrosis severity in people with MASLD: FIB-4 for any fibrosis, FibroMeter for significant fibrosis, ELF for advanced fibrosis, and FIB-4 for cirrhosis.Clinical trial registration: [https://clinicaltrials.gov/], identifier [CRD 42020180525].

Health inequalities in Brazilian adolescents: Measuring and mapping gaps in a cross-sectional school-based survey.

Background and Aims: This study aims to describe inequalities in health indicators according to gender, area of residence, and socioeconomic position among Brazilian adolescents. Methods: Cross-sectional study using data from a school-based survey carried out in Brazil in 2019. Twelve health outcomes were evaluated. Dimensions of inequality assessed were gender, area of residence, wealth and subnational region. Results: This study comprises a sample of 124,898 adolescents. The most prevalent outcome was physical inactivity (71.9%) followed by thinking life is worthless (52.6%) and bullying (51.8%). Gender inequalities were more marked for physical inactivity and thinking life is worthless with girls presenting a prevalence more than 20 p.p. higher than boys. In zero-dose HPV, however, the prevalence in girls was 17.7 p.p. lower than in boys. Area of residence and wealth inequalities were smaller than gender disparities. Context presented a relevant role in inequality with analysis stratified by states of the country, revealing high variability in estimates. Conclusions: We highlight the need for attention to disparities between subgroups of the adolescent population, especially for gender inequalities that were the most marked for this age group.

Uterine transposition for fertility and ovarian function preservation after radiotherapy.

OBJECTIVE: To evaluate the feasibility of uterine transposition as a method of preserving fertility and ovarian function after pelvic radiation. METHODS: This prospective multicenter observational study included patients with non-gynecologic pelvic cancers who underwent pelvic radiation as part of their cancer treatment between June 2017 and June 2019. For inclusion in the study, patients were required to have normal menstrual cycles and hormone levels (follicle-stimulating hormone, luteinizing hormone, and estrogen) before treatment. Uterine transposition to the upper abdomen was performed prior to irradiation. Clinical examinations and Doppler ultrasonography were used to evaluate the gonadal vasculature post-surgery. The uterus was repositioned into the pelvis 2-4 weeks after radiation therapy or at the time of rectosigmoid resection in patients with rectal cancer who had undergone neoadjuvant treatment. Cancer treatment and follow-up were performed according to standard guidelines. RESULTS: Eight patients (seven with rectal cancer and one with pelvic liposarcoma) underwent uterine transposition at a median age of 30.5 years (range 19-37). The uterus was successfully preserved in six patients, accompanied by normal menses, hormonal levels, and vaginal intercourse after treatment. One patient with rectal cancer died of carcinomatosis 4 months after uterine transposition. One patient presented with uterine necrosis 4 days after uterine transposition, and the uterus was removed; however, one ovary was preserved. Cervical ischemia was the most common post-surgical complication in three (37.5%) patients. Three patients attempted to conceive, and two (66%) were spontaneously successful and delivered healthy babies at 36 and 38 weeks by cesarean section without complications. CONCLUSIONS: Uterine transposition is a feasible procedure for preserving gonadal and uterine function in patients requiring pelvic radiotherapy for non-gynecological cancer, with the potential for achieving spontaneous pregnancy and successful delivery.

Variation of modulation and expression of biomarkers associated with inflammation in bariatric surgery patients: A systematic review and meta-analysis.

BACKGROUND: Bariatric surgery is an effective intervention that causes a series of metabolic changes related to inflammatory processes; however, the variation of biomarkers related to these processes is not entirely understood. Our objective was to investigate the variation of modulation and expression of biomarkers associated with inflammation in patients who underwent bariatric surgery. METHODS: We searched the MEDLINE (via PubMed), EMBASE (via Elsevier), Cochrane Central Register of Controlled Trials, Latin American and Caribbean Literature on Health Sciences (via virtual health library), Cumulative Index to Nursing and Allied Health Literature (via EBSCO), Web of Science core collection, and Scopus (via Elsevier) databases, and the gray literature was examined from inception to January 2022. Three pairs of reviewers performed data screening, extraction, and quality assessment independently. Meta-analysis with random effects models was used for general, subgroup, and sensitivity analyses. The I2 statistic was used to assess heterogeneity between studies. RESULTS: In total, 96 articles were included in this systematic review; of these, 87 studies met the criteria for the meta-analysis, involving 3,533 participants. Five biomarkers were included in the meta-analysis (tumor necrosis factor alpha; interleukin 6; leptin; interleukin 1 beta, and lipopolysaccharides). Only leptin showed a significant decrease in the first month after surgery (mean difference -20.71; [95% confidence interval: -28.10 to -13.32, P < .0001; I2 = 66.7%), with moderate heterogeneity. The 12 months after surgery showed a significant decrease in tumor necrosis factor alpha (mean difference -0.89; [95% confidence interval: -1.37 to -0.42], P = .0002; I2 = 94.7%), interleukin 6 (mean difference -1.62; [95% confidence interval: -1.95 to -1.29], P < .0001; I2 = 94.9%), leptin (mean difference -28.63; [95% confidence interval: -34.02 to -23.25], P < .0001; I2 = 92.7%), and interleukin 1 beta (mean difference -2.46; [95% confidence interval: -4.23 to -0.68], P = .006; I2 = 98.3%), all with high heterogeneity. The type of surgery did not show significant differences for the biomarkers at the first month and 12 months, and the results have not changed with high-quality studies. In the 12-month measurement, variations in tumor necrosis factor alpha and leptin were associated with body mass index. CONCLUSION: The findings of this meta-analysis suggest that Roux-en-Y gastric bypass and sleeve gastrectomy bariatric surgeries are associated with a significant reduction in leptin at 1 month after bariatric surgical intervention and tumor necrosis factor alpha, leptin, and interleukin 1 beta after 12 months.

Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues.

Targeted antitumour therapy has revolutionized the treatment of several types of tumours. Among the validated targets, phosphatidylinositol-3 kinase (PI3K) deserves to be highlighted. Several PI3K inhibitors have been developed for the treatment of cancer, including gedatolisib (4). This inhibitor was elected as a prototype and molecular modifications were planned to design a new series of simplified gedatolisib analogues (5a-f). The analogues were synthesised, and the comparative cytotoxic activity profile was studied in phenotypic models employing solid and nonadherent tumour cell lines. Compound 5f (LASSBio-2252) stood out as the most promising of the series, showing good aqueous solubility (42.38 µM (pH = 7.4); 39.33 µM (pH = 5.8)), good partition coefficient (cLogP = 2.96), cytotoxic activity on human leukemia cell lines (CCRF-CEM, K562 and MOLT-4) and an excellent metabolic stability profile in rat liver microsomes (t1/2 = 462 min; Clapp = 0.058 mL/min/g). The ability of 5f to exert its cytotoxic effect through modulation of the PI3K pathway was demonstrated by flow cytometry analysis in a comparative manner to gedatolisib.

Time evolution of advice on healthy habits in Brazilians with hypertension and diabetes: National Health Survey / Evolução temporal de orientações sobre hábitos saudáveis em brasileiros com hipertensão e diabetes: Pesquisa Nacional de Saúde

Abstract To evaluate time evolution of receiving advice on healthy habits among Brazilians with hypertension and diabetes mellitus. Cross-sectional study with data from the 2013 and 2019 National Health Survey. We used linear regression weighted by least squares of variance to verify time evolution of the outcome estimating the annual percentage change (APC) presented according to sex, skin color, age group, and quintiles of wealth index. The analytical sample in 2013 was 11,129 individuals with hypertension and 3,182 individuals with diabetes, and in 2019 19,107 individuals with hypertension and 6,317 individuals with diabetes. For those with hypertension, there were statistically significant reductions in receiving advice for not smoking (APC: -1.49), not drinking excessive alcoholic beverages (APC: -1.48), ingesting less salt (APC: -0.56), and for all healthy habits (APC: -1.17). For those with diabetes, statistically significant reductions were observed only for not smoking (APC: -1.13) and not drinking excessive alcoholic beverages (APC: -1.11). The results suggest a reduction in all types of advice on healthy habits evaluated for hypertension and diabetes, with greater magnitude among individuals belonging to the richest quintiles.

Resumo O objetivo foi avaliar a evolução temporal do recebimento de orientações sobre hábitos saudáveis entre brasileiros com hipertensão arterial e diabetes mellitus. Estudo transversal com dados da Pesquisa Nacional de Saúde de 2013 e 2019. Para verificar a evolução temporal das prevalências de orientações sobre hábitos saudáveis, realizadas por profissionais de saúde nos atendimentos para as morbidades, utilizou-se regressão linear ponderada pelos quadrados mínimos da variância, estimando a variação percentual anual (VPA) apresentada de acordo com sexo, cor da pele, faixa etária e quintis do índice de bens. A amostra analítica, em 2013, foi de 11.129 indivíduos com hipertensão e 3.182 com diabetes, e em 2019, de 19.107 indivíduos com hipertensão e 6.317 com diabetes. Para hipertensão, observou-se reduções nas orientações para não fumar (VPA: -1.49), não ingerir bebidas alcoólicas em excesso (VPA: -1.48), ingerir menos sal (VPA: -0.56) e, ainda, para todas as orientações (VPA: -1.17). Para diabetes, foram observadas reduções estatisticamente significativas apenas para não fumantes (APC: -1.13) e para os que não consomem bebidas alcoólicas em excesso (APC: -1.11). Os resultados sugerem redução de todas as orientações avaliadas para hipertensão e diabetes, com maior magnitude entre os indivíduos pertencentes aos quintis mais ricos.

Knockdown of regulatory associated protein of TOR (raptor) in hypothalamus-stimulated folliculogenesis and induced ovarian cysts.

CONTEXT: Mammalian target of rapamycin complex 1 (mTORC1) is an essential sensor that regulates fundamental biological processes like cell growth, proliferation and energy metabolism. The treatment of disease by sirolimus, a mTORC1 inhibitor, causes adverse effects, such as female fertility disorders. AIMS: The objective of the study was to decipher the reproductive consequences of a downregulation of mTORC1 in the hypothalamus. METHODS: The reduced expression of mTORC1 was induced after intracerebroventricular injection of lentivirus expressing a short hairpin RNA (shRNA) against regulatory associated protein of TOR (raptor) in adult female mice (ShRaptor mice). KEY RESULTS: The ShRaptor mice were fertile and exhibited a 15% increase in the litter size compared with control mice. The histological analysis showed an increase in antral, preovulatory follicles and ovarian cysts. In the hypothalamus, the GnRH mRNA and FSH levels in ShRaptor mice were significantly elevated. CONCLUSIONS: These results support the hypothesis that mTORC1 in the central nervous system participates in the regulation of female fertility and ovarian function by influencing the GnRH neuronal activity. IMPLICATIONS: These results suggest that a lower mTORC1 activity directly the central nervous system leads to a deregulation in the oestrous cycle and an induction of ovarian cyst development.

Time evolution of advice on healthy habits in Brazilians with hypertension and diabetes: National Health Survey.

To evaluate time evolution of receiving advice on healthy habits among Brazilians with hypertension and diabetes mellitus. Cross-sectional study with data from the 2013 and 2019 National Health Survey. We used linear regression weighted by least squares of variance to verify time evolution of the outcome estimating the annual percentage change (APC) presented according to sex, skin color, age group, and quintiles of wealth index. The analytical sample in 2013 was 11,129 individuals with hypertension and 3,182 individuals with diabetes, and in 2019 19,107 individuals with hypertension and 6,317 individuals with diabetes. For those with hypertension, there were statistically significant reductions in receiving advice for not smoking (APC: -1.49), not drinking excessive alcoholic beverages (APC: -1.48), ingesting less salt (APC: -0.56), and for all healthy habits (APC: -1.17). For those with diabetes, statistically significant reductions were observed only for not smoking (APC: -1.13) and not drinking excessive alcoholic beverages (APC: -1.11). The results suggest a reduction in all types of advice on healthy habits evaluated for hypertension and diabetes, with greater magnitude among individuals belonging to the richest quintiles.

Optimization of anti-tachycardia pacing efficacy through scar-specific delivery and minimization of re-initiation: a virtual study on a cohort of infarcted porcine hearts.

AIMS: Anti-tachycardia pacing (ATP) is a reliable electrotherapy to painlessly terminate ventricular tachycardia (VT). However, ATP is often ineffective, particularly for fast VTs. The efficacy may be enhanced by optimized delivery closer to the re-entrant circuit driving the VT. This study aims to compare ATP efficacy for different delivery locations with respect to the re-entrant circuit, and further optimize ATP by minimizing failure through re-initiation. METHODS AND RESULTS: Seventy-three sustained VTs were induced in a cohort of seven infarcted porcine ventricular computational models, largely dominated by a single re-entrant pathway. The efficacy of burst ATP delivered from three locations proximal to the re-entrant circuit (septum) and three distal locations (lateral/posterior left ventricle) was compared. Re-initiation episodes were used to develop an algorithm utilizing correlations between successive sensed electrogram morphologies to automatically truncate ATP pulse delivery. Anti-tachycardia pacing was more efficacious at terminating slow compared with fast VTs (65 vs. 46%, P = 0.000039). A separate analysis of slow VTs showed that the efficacy was significantly higher when delivered from distal compared with proximal locations (distal 72%, proximal 59%), being reversed for fast VTs (distal 41%, proximal 51%). Application of our early termination detection algorithm (ETDA) accurately detected VT termination in 79% of re-initiated cases, improving the overall efficacy for proximal delivery with delivery inside the critical isthmus (CI) itself being overall most effective. CONCLUSION: Anti-tachycardia pacing delivery proximal to the re-entrant circuit is more effective at terminating fast VTs, but less so slow VTs, due to frequent re-initiation. Attenuating re-initiation, through ETDA, increases the efficacy of delivery within the CI for all VTs.

Tipos de leite consumidos durante o primeiro ano de vida e estado nutricional de lactentes do Sul do Brasil / Types of milk consumed during the first year of life and nutritional status of infants in Southern Brazil

Resumo Introdução A Organização Mundial da Saúde (OMS) recomenda o aleitamento materno exclusivo até o 6º mês de vida da criança e a sua manutenção com alimentação complementar até pelo menos os 2 anos de idade. Apesar da sua importância, a ingestão de substitutos do leite materno é altamente prevalente, sendo uma preocupação em saúde pública. Objetivo Avaliar a associação entre os tipos de leite ingeridos e o estado nutricional no primeiro ano de vida. Método Estudo longitudinal observacional com crianças brasileiras pertencentes a um estudo multicêntrico. Aos 3, 6, 9 e 12 meses de idade foram investigados os tipos de leite consumidos por meio de questionário de frequência alimentar (QFA) e foi realizada antropometria. As associações brutas e ajustadas foram avaliadas por intermédio de regressão linear. Resultados Das 2.965 duplas de mães-bebês rastreadas, 362 atenderam aos critérios e aceitaram participar do estudo (50% meninos). Aos 12 meses de idade, os maiores escores-z de peso para idade e de peso para comprimento foram observados nos meninos que consumiam apenas fórmula ou apenas leite de vaca. Os maiores escores-z de comprimento para idade foram encontrados entre as meninas que ingeriam apenas fórmula ou apenas leite de vaca aos 9 e 12 meses. Ambos foram comparados àqueles que ingeriam apenas leite materno nas mesmas idades. Conclusão Os tipos de leite consumidos associaram-se ao estado nutricional no primeiro ano de vida, sendo observadas diferenças entre os sexos. Os maiores índices antropométricos nas crianças que não recebiam leite materno chamam a atenção para a persistência futura desses desvios, em direção ao excesso de peso.

Abstract Introduction The World Health Organization (WHO) recommends exclusive breastfeeding up to the 6th month of life of the child and its maintenance with complementary feeding until at least 2 years of age. Despite its importance, the intake of breast milk substitutes is highly prevalent and a public health concern. Objective To evaluate the association between the types of milk ingested and nutritional status in the first year of life. Method Observational longitudinal study with Brazilian children from a multicentric study. At 3, 6, 9, and 12 months of age, the types of milk consumed were investigated using a food frequency questionnaire (FFQ), and anthropometric measurements were performed. Crude and adjusted associations were assessed by linear regression. Results Of the 2,965 pairs of mothers-babies screened, 362 met the criteria and accepted to participate in the study (50% of boys). At 12 months of age, higher weight-for-age and weight-for-length z-scores were observed in boys who consumed only formula or only cow's milk, compared to boys who consumed only breast milk. Higher length-for-age z-scores were found among girls who consumed only formula or only cow's milk at 9 and 12 months, compared to girls who consumed only breast milk at the same ages. Conclusion The types of milk consumed were associated with nutritional status during the first year of life, with differences between boys and girls. The higher anthropometric indexes in children who did not receive breastmilk call our attention to the persistence of such deviations toward excessive weight status in the future.

A influência do recebimento de recursos financeiros e a participação em eventos para a obtenção de resultados esportivos: o caso brasileiro / The influence of receiving financial resources and participation in events on obtaining sports results: the brazilian case

RESUMO O presente estudo teve por objetivo verificar a influência do recebimento de recursos financeiros por intermédio de políticas esportivas e da participação em eventos relevantes na obtenção de resultados esportivos em competições internacionais. A amostra deste estudo baseou-se em 907 atletas brasileiros que representaram o Brasil nas seguintes competições internacionais: Jogos Pan-Americanos de Lima 2019, Jogos Mundiais Militares (JMM) de Wuhan 2019 e Jogos Olímpicos de Verão de Tóquio 2020 (2021). Por meio da análise, pode-se observar que o fato de ser beneficiário de programas públicos esportivos e o fato de participar de competições internacionais influenciou na obtenção de resultados esportivos em competições internacionais. Pode-se perceber que receber recursos por meio de mais de um programa apresentou influência positiva, do que ser beneficiário de apenas um. Com base nestes achados, ficou exposto que o incentivo ao esporte por meio de bolsas, a participação em eventos esportivos e a quantidade de medalhas obtidas, tiveram correlação positiva com o financiamento concedido.

ABSTRACT The present study aimed to verify the influence of receiving financial resources through sports policies and participation in relevant events in obtaining sports results in international competitions. The sample of this study consisted of 907 Brazilian athletes who represented Brazil in the last international competitions: Pan American Games in Lima 2019, Military World Games (JMM) in Wuhan 2019 and Summer Olympic Games in Tokyo 2020 (2021). Through analysis, it can be observed that both the fact of being a beneficiary of public sports programs and the fact of participating in international competitions influenced the achievement of sports results in international competitions. Furthermore, it can be seen that receiving resources through more than one program had a positive influence, than being a beneficiary of just one. Based on these findings, it was shown that encouraging sports through scholarships, participation in sporting events and the number of medals obtained had a positive correlation with the funding granted.

Discovery of Putative Dual Inhibitor of Tubulin and EGFR by Phenotypic Approach on LASSBio-1586 Homologs.

Combretastatin A-4 (CA-4, 1) is an antimicrotubule agent used as a prototype for the design of several synthetic analogues with anti-tubulin activity, such as LASSBio-1586 (2). A series of branched and unbranched homologs of the lead-compound 2, and vinyl, ethinyl and benzyl analogues, were designed and synthesized. A comparison between the cytotoxic effect of these homologs and 2 on different human tumor cell lines was performed from a cell viability study using MTT with 48 h and 72 h incubations. In general, the compounds were less potent than CA-4, showing CC50 values ranging from 0.030 µM to 7.53 µM (MTT at 72 h) and 0.096 µM to 8.768 µM (MTT at 48 h). The antimitotic effect of the target compounds was demonstrated by cell cycle analysis through flow cytometry, and the cellular mechanism of cytotoxicity was determined by immunofluorescence. While the benzyl homolog 10 (LASSBio-2070) was shown to be a microtubule stabilizer, the lead-compound 2 (LASSBio-1586) and the methylated homolog 3 (LASSBio-1735) had microtubule destabilizing behavior. Molecular docking studies were performed on tubulin protein to investigate their binding mode on colchicine and taxane domain. Surprisingly, the benzyl homolog 10 was able to modulate EGFR phosphorylate activity in a phenotypic model. These data suggest LASSBio-2070 (10) as a putative dual inhibitor of tubulin and EGFR. Its binding mode with EGFR was determined by molecular docking and may be useful in lead-optimization initiatives.

A strong association between VEGF-A rs28357093 and amyotrophic lateral sclerosis: a brazilian genetic study.

BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disease that affects motor neurons and promotes progressive muscle atrophy. Vascular Endothelial Growth Factor A (VEGF-A) plays multiple roles in the central nervous systems (CNS). The purpose of this study was to evaluate the association between single nucleotide polymorphism (SNP) VEGF-A rs28357093 and ALS. METHODS AND RESULTS: This case-control study was conducted in 101 ALS patients and 119 healthy individuals. Genotyping was performed by Polymerase Chain Reaction - Restriction Fragment Length Polymorphism (PCR-RFLP). The statistical analysis was carried out using the RStudio® and SNPStats© software's. Analysis of genetic inheritance models was performed by logistic regression. Our findings demonstrated a strong association between VEGF- A rs28357093 and ALS in all genetic inheritance models, with a 9-fold increased risk for A/C - C/C genotypes (95%CI = 3.70-21.88; p < 0.001). CONCLUSIONS: The mutant allele was more frequent in ALS patients (p < 0.001) and this finding could be associated with ALS risk. This first study from the Brazilian central population was conducted to provide new insight into the pathogenesis of ALS.

Complex Regional Pain Syndrome after Carpal Tunnel Syndrome Surgery: A Systematic Review.

Background: Carpal tunnel syndrome (CTS) is the most common peripheral nerve entrapment. One of the most devastating complications is complex regional pain syndrome. Objectivities: The aim of this study was to systematically analyze available evidence about complex regional pain syndrome after carpal tunnel syndrome surgery (CTSS), its risks, associated factors, and treatments. Material and Methods: Research conducted from 1962 through December 31, 2018, in the following databases: PubMed, Web of Science, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials. The quality assessment of the methodology followed the definitions by the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence. The GRADE system (Grades of Recommendation, Assessment, Development, and Evaluation) was applied to evaluate the efficacy of the stellate ganglion block, one of the most cited and recurrent treatments. Results: Of the 246 studies retrieved, 44 articles were included. Concerning patients' gender, we identified a ratio of 5 females: 3 males. The mean age for women was 57.79, a standard deviation of 14.96, and for men 60.75, a standard deviation of 9.4. Considering the total of primary publications of CTSS outcomes, the accumulated incidence reached the maximum of 0.15 CRPS after CTSS patients/CTSS patients. The known risk factors for CRPS after CTSS: female gender, from the fifth decade of life, tourniquet time, immobilization and surgery on dominant hand. Conclusion: CRPS affects 2-5% of people undergoing CTSS. Its diagnosis is still a challenge and its risk factors are unclear, although it seems more likely to affect women, in the dominant hand. The most used treatments include physiotherapy and stellate ganglion block. Most patients show improvement of symptoms within one year. Further clinical trials comparing treatment modalities are required.

Impact of the consumption of ultra-processed foods on children, adolescents and adults' health: scope review. / Impacto do consumo de alimentos ultraprocessados na saúde de crianças, adolescentes e adultos: revisão de escopo.

The aim of this study was to conduct a literature scope review of the association between the consumption of ultra-processed foods and health outcomes. The search was carried out in the PubMed, Web of Science and LILACS databases. Studies that assessed the association between the consumption of ultra-processed foods, identified on the NOVA classification, and health outcomes were eligible. The review process resulted in the selection of 63 studies, which were analyzed in terms of quality using a tool from the National Institutes of Health. The outcomes found included obesity, metabolic risk markers, diabetes, cardiovascular diseases, cancer, asthma, depression, frailty, gastrointestinal diseases and mortality indicators. The evidence was particularly consistent for obesity (or indicators related to it) in adults, whose association with the consumption of ultra-processed foods was demonstrated, with dose-response effect, in cross-sectional studies with representative samples from five countries, in four large cohort studies and in a randomized clinical trial. Large cohort studies have also found a significant association between the consumption of ultra-processed foods and the risk of cardiovascular diseases, diabetes and cancer - even after adjusting for obesity. Two cohort studies have shown an association of ultra-processed foods consumption with depression and four cohort studies with all-cause mortality. This review summarized the studies' results that described the association between the consumption of ultra-processed foods and various non-communicable diseases and their risk factors, which has important implications for public health.

O objetivo deste trabalho foi realizar uma revisão de escopo da literatura acerca da associação entre o consumo de alimentos ultraprocessados e desfechos em saúde. A busca foi realizada nas bases PubMed, Web of Science e LILACS. Foram elegíveis os estudos que avaliaram a associação entre o consumo de alimentos ultraprocessados identificados com base na classificação NOVA e os desfechos em saúde. O processo de revisão resultou na seleção de 63 estudos, os quais foram analisados em termos de qualidade com base em ferramenta do Instituto Nacional de Saúde dos Estados Unidos. Os desfechos encontrados incluíram indicadores de obesidade, marcadores de risco metabólico, diabetes, doenças cardiovasculares, câncer, asma, depressão, fragilidade, doenças gastrointestinais e mortalidade. A evidência foi particularmente consistente para obesidade (ou indicadores relacionados a ela) em adultos, cuja associação com o consumo de ultraprocessados foi demonstrada, com efeito dose-resposta, em estudos transversais com amostras representativas de cinco países, em quatro grandes estudos de coorte e em um ensaio clínico randomizado. Grandes estudos de coorte também encontraram associação significativa entre o consumo de alimentos ultraprocessados e o risco de doenças cardiovasculares, diabetes e câncer, mesmo após ajuste para obesidade. Dois estudos de coorte demonstraram associação do consumo de alimentos ultraprocessados com depressão e quatro estudos de coorte com mortalidade por todas as causas. Esta revisão sumarizou os resultados de trabalhos que descreveram a associação entre o consumo de alimentos ultraprocessados e as diversas doenças crônicas não transmissíveis e seus fatores de risco, o que traz importantes implicações para a saúde pública.

El objetivo de este estudio fue realizar una revisión de alcance de la literatura sobre la asociación entre el consumo de alimentos ultraprocesados y los resultados de salud. La búsqueda se realizó en las bases de datos PubMed, Web of Science y LILACS. Fueron elegibles los estudios que evaluaron la asociación entre el consumo de alimentos ultraprocesados identificados según la clasificación NOVA y los resultados de salud. El proceso de revisión resultó en la selección de 63 estudios, cuya calidad se analizó con base en una herramienta delo Instituto Nacional de Salud de Estados Unidos Los resultados encontrados incluyeron indicadores de obesidad, marcadores de riesgo metabólico, diabetes, enfermedad cardiovascular, cáncer, asma, depresión, fragilidad, enfermedad gastrointestinal y mortalidad. La evidencia fue particularmente consistente para la obesidad (o indicadores relacionados con ella) en adultos, cuya asociación con el consumo de alimentos ultraprocesados se demostró, con un efecto dosis-respuesta, en estudios transversales con muestras representativas de cinco países, en cuatro grandes estudios de cohortes y en un ensayo clínico aleatorizado. Grandes estudios de cohortes también encontraron una asociación significativa entre el consumo de alimentos ultraprocesados y el riesgo de enfermedades cardiovasculares, diabetes y cáncer, incluso después de ajustar la obesidad. Dos estudios de cohortes mostraron una asociación entre el consumo de alimentos ultraprocesados y la depresión y cuatro estudios de cohortes con mortalidad por todas las causas. Esta revisión resumió los resultados de estudios que describieron la asociación entre el consumo de alimentos ultraprocesados y las diversas enfermedades crónicas no transmisibles y sus factores de riesgo, lo que tiene importantes implicaciones para la salud pública.

Efficient adoptive transfer of autologous modified B cells: a new humanized platform mouse model for testing B cells reprogramming therapies.

Here, we report a novel experimental setup to perform adoptive transfer of gene-edited B cells using humanized immune system mice by infusing autologous HIS mouse-derived human B cells "educated" in a murine context and thus rendered tolerant to the host. The present approach presents two advantages over the conventional humanized PBMC mouse models: (i) it circumvents the risk of xenogeneic graft-versus-host reaction and (ii) it mimics more closely human immune responses, thus favoring clinical translation. We show that the frequencies and numbers of transduced B cells in recipient's spleens one week post-transfer are within the range of the size of the pre-immune B cell population specific for a given protein antigen in the mouse. They are also compatible with the B cell numbers required to elicit a sizeable immune response upon immunization. Altogether, our findings pave the way for future studies aiming at assessing therapeutic interventions involving B cell reprogramming for instance by an antibody transgene in a "humanized" hematopoietic setting.

Disruption of HIV-1 co-receptors CCR5 and CXCR4 in primary human T cells and hematopoietic stem and progenitor cells using base editing.

Disruption of CCR5 or CXCR4, the main human immunodeficiency virus type 1 (HIV-1) co-receptors, has been shown to protect primary human CD4+ T cells from HIV-1 infection. Base editing can install targeted point mutations in cellular genomes, and can thus efficiently inactivate genes by introducing stop codons or eliminating start codons without double-stranded DNA break formation. Here, we applied base editors for individual and simultaneous disruption of both co-receptors in primary human CD4+ T cells. Using cytosine base editors we observed premature stop codon introduction in up to 89% of sequenced CCR5 or CXCR4 alleles. Using adenine base editors we eliminated the start codon in CCR5 in up to 95% of primary human CD4+ T cell and up to 88% of CD34+ hematopoietic stem and progenitor cell target alleles. Genome-wide specificity analysis revealed low numbers of off-target mutations that were introduced by base editing, located predominantly in intergenic or intronic regions. We show that our editing strategies prevent transduction with CCR5-tropic and CXCR4-tropic viral vectors in up to 79% and 88% of human CD4+ T cells, respectively. The engineered T cells maintained functionality and overall our results demonstrate the effectiveness of base-editing strategies for efficient and specific ablation of HIV co-receptors in clinically relevant cell types.