Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/mTOR axis in metastatic pheochromocytoma/paraganglioma

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that present variable outcomes. To date, no effective therapies or reliable prognostic markers are available for patients who develop metastatic PPGL (mPPGL). Our aim was to discover robust prognostic markers validated through models, and define specific therapeutic options according to tumor genomic features. : We analyzed three PPGL miRNome datasets (n=443), validated candidate markers and assessed them in serum samples (n=36) to find a metastatic miRNA signature. An integrative study of miRNome, transcriptome and proteome was performed to find miRNA targets, which were further characterized . : A signature of six miRNAs (miR-21-3p, miR-183-5p, miR-182-5p, miR-96-5p, miR-551b-3p, and miR-202-5p) was associated with metastatic risk and time to progression. A higher expression of five of these miRNAs was also detected in PPGL patients' liquid biopsies compared with controls. The combined expression of miR-21-3p/miR-183-5p showed the best power to predict metastasis (AUC=0.804, =4.67·10), and was found associated with pro-metastatic features, such as neuroendocrine-mesenchymal transition phenotype, and increased cell migration rate. A pan-cancer multi-omic integrative study correlated miR-21-3p levels with TSC2 expression, mTOR pathway activation, and a predictive signature for mTOR inhibitor-sensitivity in PPGLs and other cancers. Likewise, we demonstrated a repression and an enhanced rapamycin sensitivity upon miR-21-3p expression. : Our findings support the assessment of miR-21-3p/miR-183-5p, in tumors and liquid biopsies, as biomarkers for risk stratification to improve the PPGL patients' management. We propose miR-21-3p to select mPPGL patients who may benefit from mTOR inhibitors

Mielomeningocele e anomalias associadas: uma série de casos e revisão sistemática

A mielomeningocele é uma malformação congênita grave do sistema nervoso central, representando um dos tipos mais complexos de defeitos do tubo neural. A condição é marcada pela exposição das meninges e, em alguns casos, da medula espinhal, através de uma abertura na coluna vertebral, desafiando tanto o prognóstico do paciente quanto as estratégias de tratamento. O presente estudo visa explorar os avanços recentes no diagnóstico, intervenções cirúrgicas e desfechos neurológicos associados à mielomeningocele, com foco particular na eficácia e segurança das abordagens atuais. Para isso, foi realizada uma revisão sistemática da literatura de 2016 a 2024 nas bases de dados PubMed (Medline), Cochrane Library e SciELO, aplicando critérios de inclusão e exclusão rigorosos para selecionar estudos que abordassem esses aspectos. Três estudos chave foram analisados, destacando-se pelas técnicas de diagnóstico antenatal, pela utilização de intervenções cirúrgicas inovadoras, como o fechamento fetal, e pelos cuidados pós-operatórios visando melhorias nos desfechos neurológicos. Os resultados indicam uma tendência positiva na melhoria da qualidade de vida dos pacientes, com avanços significativos no controle e na prevenção de complicações a longo prazo. No entanto, foi observada a necessidade de uma abordagem multidisciplinar no tratamento, integrando cuidados neurocirúrgicos, ortopédicos e reabilitativos. A mielomeningocele, apesar dos desafios, tem testemunhado progressos notáveis nas últimas décadas, sugerindo um futuro mais promissor para os pacientes afetados. Ainda assim, são necessários mais estudos para consolidar essas abordagens e otimizar as estratégias de tratamento na prática clínica

Global economic burden of unmet surgical need for appendicitis

Background: There is a substantial gap in provision of adequate surgical care in many low-and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods: Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results: Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion: For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/ mTOR axis in metastatic pheochromocytoma/ paraganglioma

Rationale: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that present variable outcomes. To date, no effective therapies or reliable prognostic markers are available for patients who develop metastatic PPGL (mPPGL). Our aim was to discover robust prognostic markers validated through in vitro models, and define specific therapeutic options according to tumor genomic features. Methods: We analyzed three PPGL miRNome datasets (n=443), validated candidate markers and assessed them in serum samples (n=36) to find a metastatic miRNA signature. An integrative study of miRNome, transcriptome and proteome was performed to find miRNA targets, which were further characterized in vitro. Results: A signature of six miRNAs (miR-21-3p, miR-183-5p, miR-182-5p, miR-96-5p, miR-551b-3p, and miR-202-5p) was associated with metastatic risk and time to progression. A higher expression of five of these miRNAs was also detected in PPGL patients’ liquid biopsies compared with controls. The combined expression of miR-21-3p/miR-183-5p showed the best power to predict metastasis (AUC=0.804, P=4.67·10-18), and was found associated in vitro with pro-metastatic features, such as neuroendocrine-mesenchymal transition phenotype, and increased cell migration rate. A pan-cancer multi-omic integrative study correlated miR-21-3p levels with TSC2 expression, mTOR pathway activation, and a predictive signature for mTOR inhibitor-sensitivity in PPGLs and other cancers. Likewise, we demonstrated in vitro a TSC2 repression and an enhanced rapamycin sensitivity upon miR-21-3p expression. Conclusions: Our findings support the assessment of miR-21-3p/miR-183-5p, in tumors and liquid biopsies, as biomarkers for risk stratification to improve the PPGL patients’ management. We propose miR-21-3p to select mPPGL patients who may benefit from mTOR inhibitors

Mortality of emergency abdominal surgery in high-, middle- and low-income countries

Background: Surgical mortality data are collected routinely in high-income countries, yet virtually no low- or middle-income countries have outcome surveillance in place. The aim was prospectively to collect worldwide mortality data following emergency abdominal surgery, comparing findings across countries with a low, middle or high Human Development Index (HDI). Methods: This was a prospective, multicentre, cohort study. Self-selected hospitals performing emergency surgery submitted prespecified data for consecutive patients from at least one 2-week interval during July to December 2014. Postoperative mortality was analysed by hierarchical multivariable logistic regression. Results: Data were obtained for 10 745 patients from 357 centres in 58 countries; 6538 were from high-, 2889 from middle- and 1318 from low-HDI settings. The overall mortality rate was 1⋅6 per cent at 24 h (high 1⋅1 per cent, middle 1⋅9 per cent, low 3⋅4 per cent; P < 0⋅001), increasing to 5⋅4 per cent by 30 days (high 4⋅5 per cent, middle 6⋅0 per cent, low 8⋅6 per cent; P < 0⋅001). Of the 578 patients who died, 404 (69⋅9 per cent) did so between 24 h and 30 days following surgery (high 74⋅2 per cent, middle 68⋅8 per cent, low 60⋅5 per cent). After adjustment, 30-day mortality remained higher in middle-income (odds ratio (OR) 2⋅78, 95 per cent c.i. 1⋅84 to 4⋅20) and low-income (OR 2⋅97, 1⋅84 to 4⋅81) countries. Surgical safety checklist use was less frequent in low- and middle-income countries, but when used was associated with reduced mortality at 30 days. Conclusion: Mortality is three times higher in low- compared with high-HDI countries even when adjusted for prognostic factors. Patient safety factors may have an important role. Registration number: NCT02179112 (http://www.clinicaltrials.gov)

Efeito da frequência de fornecimento de suplemento proteico energético sobre o desempenho de novilhos da raça Nelore no período da seca

The objective of this study was to evaluate the effect of the frequency of provision of protein energy supplementation on pasture during the dry period of the year on the performance of Nelore steers in rearing phase. FAZU teaching school conducted the experiment from July to September 2017. Twenty-two animals of the Nelore breed, aged 12 months and mean initial weight of 232.22 (± 20) kg, modules of 2 ha each, subdivided in six paddocks of Panicum maximum cultivars Mombaça and Tanzânia. The experimental design was completely randomized (DIC) and the averages were compared by the Tukey test at 5% significance. There was no significant difference between the three frequencies of supply of energy protein supplementation, in relation to the average daily weight gain, which were 837; 881 and 855g, at the frequencies of 7; 5 and 3 times per week, respectively. However, there was a significant difference (P &lt;0.05) for the mean daily weight gain between the treatment in which the animals received mineral supplementation (434g), which was lower than the treatments in which the animals were fed with protein energy supplement at the level of 0.25% of body weight. In conclusion, during the period and in the evaluation conditions of this experiment, there was no difference in the effect of the frequency of supply of a protein energy supplement in the supply level of 0.25% of the animals' body weight. The average daily gain was higher for the animals that received the protein energy supplement compared to those supplemented with mineral. Five times a week supplementation obtained the best economic benefit among the evaluated frequencies.El objetivo de este estudio fue evaluar el efecto de la frecuencia de provisión de suplementos energéticos proteicos en el pasto durante el período seco del año sobre el desempeño de novillos Nelore en fase de crianza. La escuela de enseñanza FAZU realizó el experimento de julio a septiembre de 2017. Veintidós animales de la raza Nelore, de 12 meses de edad y peso inicial medio de 232,22 (± 20) kg, módulos de 2 ha cada uno, subdivididos en seis potreros de cultivares Panicum maximum Mombaça y Tanzânia. El diseño experimental fue completamente al azar (DIC) y los promedios se compararon mediante la prueba de Tukey al 5% de significancia. No hubo diferencia significativa entre las tres frecuencias de suministro de suplementos de proteínas energéticas, en relación con el aumento de peso diario promedio, que fueron 837; 881 y 855g, en las frecuencias de 7; 5 y 3 veces por semana, respectivamente. Sin embargo, hubo una diferencia significativa (P &lt;0.05) para la ganancia de peso diaria promedio entre el tratamiento en el que los animales recibieron suplementación mineral (434g), que fue menor que los tratamientos en los que los animales fueron alimentados con suplemento energético proteico en el nivel del 0,25% del peso corporal. En conclusión, durante el período y en las condiciones de evaluación de este experimento, no hubo diferencia en el efecto de la frecuencia de suministro de un suplemento energético proteico en el nivel de suministro del 0,25% del peso corporal de los animales. La ganancia diaria promedio fue mayor para los animales que recibieron el suplemento energético proteico en comparación con los que recibieron el suplemento mineral. La suplementación cinco veces por semana obtuvo el mejor beneficio económico entre las frecuencias evaluadas.Objetivou-se avaliar o efeito da frequência de fornecimento de suplementação proteica energética em pastagens, no período seco do ano, sobre o desempenho de novilhos de raça Nelore na fase de recria. O experimento foi conduzido na Fazenda-Escola da FAZU, no período de julho a setembro de 2017. Foram utilizados 21 animais da raça Nelore, com 12 meses de idade e peso médio inicial de 232,22 (± 20) kg, alocados em quatro módulos de 2 ha cada um, subdivididos em seis piquetes de Panicum maximum cultivares Mombaça e Tanzânia. O delineamento experimental foi inteiramente casualizado (DIC) e as médias foram comparadas pelo teste de Tukey a 5 % significância. Não houve diferença significativa entre as três frequências de fornecimento da suplementação proteica energética, em relação ao ganho de peso médio diário, que foram de 837; 881 e 855g, nas frequências de 7; 5 e 3 vezes por semana, respectivamente. Porém, houve diferença significativa (P&lt;0,05) para o ganho de peso médio diário entre o tratamento em que os animais receberam suplemento mineral (434g), que foi inferior aos tratamentos em que os animais foram alimentados com suplemento proteico energético no nível de 0,25 % do peso corporal. Conclui-se que, no período e nas condições de avaliação deste experimento, não houve diferença do efeito da frequência de fornecimento de um suplemento proteico energético no nível de fornecimento de 0,25% do peso corporal dos animais. O ganho médio diário foi superior para os animais que receberam o suplemento proteico energético comparado com aqueles suplementados apenas com mineral. A suplementação cinco vezes por semana obteve o melhor benefício econômico entre as frequências avaliadas

Um novo método fotogramétrico adequado a análises biomecânicas: comparação com o método DLT (transformação Linear Direta)

O presente estudo teve por objetivo descrever e obter dados, para fins de comparação, de dois métodos fotograméticos que possibilitam a análise especial em estudos biomecânicos, utilizando-se câmeras não-métricas: o método desenvolvido por Fonseca &amp; Ávila (1991) e o método da Transformação Liner Direta (DLT) elaborado por Abdel-Aziz &amp; Karara (1971). Através da obtenção das coordenadas espaciais de 25 pontos distribuídos no espaço, segundo cada método, foi possível compará-los entre si e com as médias das coordenadas X, Y e Z, previamente medidas, utilizando-se análise de variância e regressão linear. Os resultados indicaram não haver diferença estatisticamente significante entre as médias das coordenadas em relação aos eixos X, Y ou Z, para qualquer um dos métodos, notando-se, no entanto, uma maior precisão nos resultados do Método DLT. A regressão linear mostrou uma elevada correlação entre erros absolutos, variações no valor da distância focal e variações no fator de aplicação, como esperado, tendo-se observado maior influência deste último com relação à precisão no cálculo das coordenadas. Acredita-se que o método Fonseca &amp; Ávila possa ser uma alternativa quando o método DLT não puder ser empregado