Efficacy and safety of BRAF/MEK inhibitors in BRAFV600E-mutated anaplastic thyroid cancer: a systematic review and meta-analysis.

PURPOSE: Approximately 45% of anaplastic thyroid cancer (ATC) patients harbor a BRAFV600E mutation and are eligible for target therapy (TT) with BRAF and MEK inhibitors (BRAFi/MEKi), nevertheless, few data advocate for this. Hence, we've conducted a systematic review and meta-analysis investigating the effectiveness and safety of BRAFi/MEKi in BRAFV600E ATC patients. METHODS: PubMed, Embase, and the Cochrane Library were systematically searched for BRAFi/MEKi TT in BRAFV600E ATC patients. Outcomes included objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), duration of response (DOR) and adverse events (AEs). RESULTS: Nine studies with 168 patients were included. Median follow-up ranged from 2.0 to 47.9 months. 75% of patients had stage IVc. In a pooled analysis, ORR was 68.15% (95% CI 55.31-80.99, I2 = 47%) and DCR was 85.39% (95% CI 78.10-92.68, I2 = 0), with a median DOR of 14.4 months (95% CI 4.6-14.4) and a median PFS of 6.7 months (95% CI 4.7-34.2). Moreover, 1-year OS rate was 64.97% (95% CI 48.76-81.17, I2 = 84%) and 2-years OS rate was 52.08% (95% CI 35.71-68.45, I2 = 79%). Subgroup analysis showed patients in the neoadjuvant setting had higher rates of 1 and 2-years OS and observational studies tended to report higher rates of ORR than clinical trials. No new or unexpected adverse events were found. CONCLUSIONS: Our study demonstrated BRAFi/MEKi have a decent activity for BRAFV600E ATC patients, especially in the neoadjuvant setting, with a tolerable safety profile. However, further clinical trials are warranted to investigate these findings.

Efficacy and Safety of Clazosentan After Aneurysmal Subarachnoid Hemorrhage: An Updated Meta-Analysis.

BACKGROUND AND OBJECTIVES: Clazosentan has been studied to treat cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH).This meta-analysis of randomized controlled trials updates the current knowledge regarding the efficacy and safety of clazosentan compared with placebo after aSAH. METHODS: Databases were systematically searched for randomized controlled trials directly comparing the use of clazosentan and placebo for the treatment of cerebral vasospasm after aSAH. Additional eligibility criteria were the report of any of the outcomes of interest (vasospasm, morbidity, functional outcome, or mortality). The primary outcome was vasospasm-related delayed cerebral ischemia (DCI). The analyses were stratified by clazosentan dosage (low or high dose) and aneurysm treatment modality (clipping or coiling). The Cochrane RoB-2 tool was used for studies quality assessment. RESULTS: Six studies comprising 7 clinical trials were included, involving 2778 patients. Clazosentan decreased the risk of vasospasm-related DCI (risk ratio [RR] 0.56, 95% CI 0.38-0.81) and delayed ischemic neurological deficit (RR 0.63, 95% 0.50-0.80). Angiographic vasospasm (RR 0.54, 95% CI 0.47-0.61) was also decreased. Functional outcomes (favorable Glasgow Outcome Scale, RR 0.99, 95% CI 0.79-1.24) and death (RR 1.03, 95% CI 0.71-1.49) did not change. Meanwhile, adverse events were increased by clazosentan (RR 1.54, 95% CI 1.35-1.76). CONCLUSION: Clazosentan decreased vasospasm-related DCI and angiographic vasospasm but did not improve functional outcomes or mortality. Adverse events were increased by clazosentan.

Ultrasound techniques for the detection of developmental dysplasia of the hip: a systematic review and meta-analysis

ABSTRACT BACKGROUND: Developmental dysplasia of the hip (DDH) encompasses a broad spectrum of hip pathologies, including femoral or acetabular dysplasia, hip instability, or both. According to the medical literature, ultrasonography is the most reliable diagnostic method for DDH. Several techniques for the assessment of hips in newborns and infants, using ultrasonography, have been described. OBJECTIVE: To compare the accuracy of the Graf technique and other diagnostic techniques for DDH. DESIGN AND SETTING: A systematic review of studies that analyzed ultrasound techniques for the diagnosis of DDH within an evidence-based health program of a federal university in São Paulo (SP), Brazil. METHODS: A systematic search of relevant literature was conducted in the PubMed, EMBASE, Cochrane Library, CINAHL, and LILACS databases for articles published up to May 5, 2020, relating to studies evaluating the diagnostic accuracy of different ultrasound techniques for diagnosing DDH. The QUADAS 2 tool was used for methodological quality evaluation. RESULTS: All hips were analyzed using the Graf method as a reference standard. The Morin technique had the highest rate of sensitivity, at 81.12-89.47%. The Suzuki and Stress tests showed 100% specificity. The Harcke technique showed a sensibility of 18.21% and specificity of 99.32%. CONCLUSION: All the techniques demonstrated at least one rate (sensibility and specificity) lower than 90.00% when compared to the Graf method. The Morin technique, as evaluated in this systematic review, is recommended after the Graf method because it has the highest sensitivity, especially with the three-pattern classification of 89.47%. REGISTRATION NUMBER: Identifier: CRD42020189686 at the International Prospective Register of Systematic Reviews (identifier: CRD42020189686).

Growth modulation for angular knee deformities: a practical guideline.

PURPOSE OF REVIEW: This study aimed to review the established concepts and advances related to growth modulation for treating knee angular deformities. Although they are considered well tolerated procedures, careful indications and accurate techniques are necessary to ensure good results. RECENT FINDINGS: In addition to general clinical and radiographic evaluations, new tools such as two-dimensional low-dose radiography and gait analysis have been used to clarify angular and torsional combinations and the impact of mild angulations on the knee joint. Temporary epiphysiodesis is commonly the choice, and it can be performed with different implants such as staples, tension band plates (TBP), percutaneous transphyseal screws (PETS), sutures, and screws. SUMMARY: Considering its principles, TBP has been preferred for younger children. Cost can be a limitation, and research for alternative implants such as screws and nonabsorbable sutures indicate they might be an alternative in the future. In adolescents, PETS becomes an attractive alternative; however, its reversible character has been controversial, and further studies are needed to establish limits in younger patients.

Percepções e conhecimentos médicos sobre limitação de suporte de vida / Physician perceptions and knowledge about limiting life support / Percepciones y conocimientos médicos sobre la limitación del soporte vital

Resumo Este estudo descritivo e qualitativo identificou percepções e conhecimentos de médicos de unidades de terapia intensiva sobre a limitação do suporte de vida. Os resultados revelaram diferentes compreensões e estímulos acerca do uso da limitação do suporte de vida: tomadas de decisão isoladas e compartilhadas; empecilhos como família, profissionais, questões jurídicas e imprevisibilidade da morte; e relatos de casos específicos com benefícios, dilemas e especificidades por quadro e faixa etária. Existe consenso quanto à necessidade de limitação do suporte de vida, mas falta preparo na formação e persistem divergências de compreensão. Os diferentes estímulos para seu uso e as dificuldades para tomada de decisão e definição de condutas são permeados por conflitos éticos, culturais e pessoais e demonstram a necessidade de educar sobre o tema em diferentes níveis de formação de profissionais de saúde.

Abstract This qualitative, descriptive study identified perceptions and knowledge of intensive care unit physicians about limiting life support. Results revealed different understandings and reasons for limiting life support: shared and isolated decision-making; obstacles such as family, professionals, legal issues and unpredictability of death; and specific case reports with benefits, dilemmas, and specificities by clinical picture and age group. Physicians agree on the need to limit life support but lack training on the topic and differences in understanding remain. The multiple reasons for its use and difficulties in decision-making and definition of conduct are permeated by ethical, cultural and personal conflicts, demonstrating the need for better education on the theme at different levels of health professional training.

Resumen Este estudio descriptivo y cualitativo identificó las percepciones y el conocimiento de los médicos en las unidades de cuidados intensivos sobre la limitación del soporte vital. Los resultados revelaron diferentes comprensiones y estímulos sobre el uso de la limitación del soporte vital: toma de decisiones aislada y compartida; obstáculos como la familia, los profesionales, las cuestiones legales y la imprevisibilidad de la muerte; e informes de casos específicos con beneficios, dilemas y especificidades por condición y grupo de edad. Existe consenso sobre la necesidad de limitar el soporte vital, pero carece de preparación y persisten las diferencias de comprensión. Los diferentes estímulos para su uso y las dificultades para la toma de decisiones y la definición de conductas están impregnados de conflictos éticos, culturales y personales, además de que demuestran la necesidad de discutir sobre el tema en los diferentes niveles de formación de los profesionales de la salud.

Ultrasound techniques for the detection of developmental dysplasia of the hip: a systematic review and meta-analysis.

BACKGROUND: Developmental dysplasia of the hip (DDH) encompasses a broad spectrum of hip pathologies, including femoral or acetabular dysplasia, hip instability, or both. According to the medical literature, ultrasonography is the most reliable diagnostic method for DDH. Several techniques for the assessment of hips in newborns and infants, using ultrasonography, have been described. OBJECTIVE: To compare the accuracy of the Graf technique and other diagnostic techniques for DDH. DESIGN AND SETTING: A systematic review of studies that analyzed ultrasound techniques for the diagnosis of DDH within an evidence-based health program of a federal university in São Paulo (SP), Brazil. METHODS: A systematic search of relevant literature was conducted in the PubMed, EMBASE, Cochrane Library, CINAHL, and LILACS databases for articles published up to May 5, 2020, relating to studies evaluating the diagnostic accuracy of different ultrasound techniques for diagnosing DDH. The QUADAS 2 tool was used for methodological quality evaluation. RESULTS: All hips were analyzed using the Graf method as a reference standard. The Morin technique had the highest rate of sensitivity, at 81.12-89.47%. The Suzuki and Stress tests showed 100% specificity. The Harcke technique showed a sensibility of 18.21% and specificity of 99.32%. CONCLUSION: All the techniques demonstrated at least one rate (sensibility and specificity) lower than 90.00% when compared to the Graf method. The Morin technique, as evaluated in this systematic review, is recommended after the Graf method because it has the highest sensitivity, especially with the three-pattern classification of 89.47%. REGISTRATION NUMBER: Identifier: CRD42020189686 at the International Prospective Register of Systematic Reviews (identifier: CRD42020189686).

Measurement of Pubofemoral Distance in the Diagnosis of Developmental Dysplasia of the Hip: Sensitivity and Specificity.

OBJECTIVES: To evaluate the accuracy of measurement of the pubofemoral distance (PFD) for the diagnosis of developmental dysplasia of the hip (DDH), using the Graf method as the reference standard. METHODS: This was a prospective diagnostic accuracy study evaluating 1980 hips in at-risk neonates. The PFD measurement and the Graf method were performed at the same opportunity, with the hips in the same position (slightly flexed, adducted, and medially rotated). RESULTS: In our sample, the prevalence of DDH, defined as Graf type IIb or higher, was 15.6%. The mean PFD for dysplastic hips was 3.5 mm (median, 3.3 mm), whereas it was 3.0 mm (median, 2.9 mm) for nondysplastic hips. In both groups, there was a significant overlap between the PFD measurements and the Graf classifications. The PFD cutoff with the largest area under the receiver operating characteristic curve was 3.0 mm, which was found to have a sensitivity and specificity of 63.6 and 62.2%, respectively, with positive and negative predictive values of 31.2 and 71.4%, respectively, for the diagnosis of DDH. CONCLUSION: Measurement of the PFD shows good overall accuracy for the diagnosis of DDH. However, given its low-positive predictive value, it should not be considered to be a replacement for the Graf method.

Evaluation of Preconception Dietary Patterns in Women Enrolled in a Multisite Study.

Background: Diet indices are widely used in nutritional research across communities but do not "capture" the full extent of diet variability across multiple countries. Empirically derived dietary patterns can provide additional information because they reflect combinations of foods potentially associated with health outcomes. Limited studies have evaluated preconception dietary patterns in heterogeneous populations. Objectives: In the multisite Nutritional Intervention Preconception and During Pregnancy to Maintain Healthy Glucose Metabolism and Offspring Health (NiPPeR) study, the secondary aims included: 1) derive pooled and site-specific preconception dietary patterns, and 2) evaluate these patterns using anthropometric measures and metabolic biomarkers. Methods: Women planning pregnancy (n = 1720) in the United Kingdom, Singapore, and New Zealand completed interviewer-administered harmonized FFQs and lifestyle questionnaires at recruitment. Across-cohort ("pooled") and site-specific dietary patterns were derived, and associations between dietary pattern scores and BMI, waist-to-hip ratio, plasma lipids, and glycemia assessed using multivariable linear regression, expressing results as SD change in outcome per SD change in dietary pattern score. Results: The pooled analysis identified 3 dietary patterns: "Vegetables/Fruits/Nuts" ("Healthy"), "Fried potatoes/Processed meat/Sweetened beverages" ("Less Healthy"), and "Fish/Poultry/Noodles/Rice" ("Mixed"). The "Healthy" and "Less Healthy" pooled pattern scores were highly correlated with their corresponding site-specific dietary pattern scores ("Healthy": ρ = 0.87-0.93; "Less Healthy": ρ = 0.65-0.88). Women with higher scores for the "Healthy" pooled pattern had a lower waist-to-hip ratio (standardized ß: -0.10; 95% CI: -0.18, -0.01); those with higher scores for the "Less Healthy" pooled pattern had a higher BMI (standardized ß: 0.17; 95% CI: 0.09, 0.24), higher LDL cholesterol (standardized ß: 0.10; 95% CI: 0.01, 0.19), and less optimal glucose profiles. However, we noted higher adherence to the "Healthy" pooled pattern with higher BMI. Conclusions: The "Healthy" and "Less Healthy" pooled patterns were comparable to the corresponding site-specific patterns. Although the associations between these patterns and objective anthropometric/metabolic measures were largely in the expected directions, future studies are required to confirm these findings.This trial is registered at clinicaltrials.gov (NCT02509988).

Prevalence of Developmental Dysplasia of the Hip in a Maternity Hospital in São Paulo, Brazil.

Objective To evaluate the prevalence of developmental dysplasia of the hip (DDH), that is, hips classified as Graf type-IIc or higher, among a sample of the population of newborns aged from 0 to 3 days of life, and to correlate the findings with the main risk factors described in the literature. Methods An observational, cross-sectional, prospective study on a sample of newborns at a Maternity Hospital School in the city of São Paulo, Brazil, to assess the prevalence of DDH diagnosed by the Graf method and verify its correlation with the risk factors. Results A total of 678 newborns underwent hip ultrasound (1,356 hips). The prevalence of DDH was of 5.46%. The logistic regression analysis showed odds ratios (ORs) with statistical significance for the following parameters: white ethnicity (OR = 2.561; 95% confidence interval [95%CI]: 1.07 to 6.11); multiparity (OR = 3.50; 95%CI: 1.62 to 7.38), female gender (OR = 4.95; 95%CI: 1.86 to 13.13); and breech presentation (OR = 2.03; 95%CI: 1,01 to 4.11). Conclusion The prevalence of DDH in the sample was of 5.45% using ultrasound as a diagnostic method. This result is different from that of studies that assessed prevalence exclusively through physical examination (Ortolani maneuver). The main risk factors associated with a higher risk of developing DDH were newborns of the female gender, with breech presentation, firstborns, and of white ethnicity.

HEMIEPIPHYSIODESIS USING EIGHT-PLATE VERSUS BLOUNT STAPLE TO CORRECT GENU VALGUM AND GENU VARUM.

OBJECTIVE: Our objective is to evaluate whether the use of guided growth with eight-plates is more effective than the use of Blount staples for the correction of the idiopathic genu varum or idiopathic genu valgum. METHODS: A systematic review (SR) was carried out according to the appropriate methodology for randomized clinical trials (RCTs). We searched seven databases through a previously defined methodology, and we included RCTs, regardless of language, period of publication and status of publication. RESULTS: Resulted in 6830 articles retrieved. Of theses, we identified 14 potential eligible studies. but just one RCT was included for the SR. The included RCT compares the eight-plate and the Blount staple and showed no statistically significant difference for the outcomes of time to correct the deformity, postoperative pain after 24 hours and postoperative pain after 72 hours. The study is of low or very low level of evidence to determine the most effective technique. We didn't find a RCT that compared the correction of the genu varum. CONCLUSION: Good quality randomized clinical trials comparing Blount staples versus eight-plaque must be performed to determine which technique is superior for coronal plane corrections. Level of Evidence I, Systematic review of Level RCTs.

OBJETIVO: Avaliar se o uso do crescimento guiado com placas em oito é mais eficaz que os grampos de Blount na correção do geno varo idiopático ou geno valgo idiopático. MÉTODOS: Foi realizada uma revisão sistemática (RS), de acordo com a metodologia apropriada para busca de ensaios clínicos randomizados (ECR). Pesquisamos em sete bancos de dados por meio de uma metodologia definida anteriormente e incluímos ECR, independentemente do idioma, período ou status da publicação. RESULTADOS: Foram recuperados 6830 artigos. Destes, 14 estudos possivelmente elegíveis foram encontrados, mas apenas um ECR foi incluído para a RS. O ECR incluído compara placas em oito e grampos de Blount, não mostrando diferença estatisticamente significante para os resultados de tempo na correção da deformidade, dor pós-operatória após 24 horas e dor pós-operatória após 72 horas. O estudo é de nível baixo ou muito baixo de evidência para determinar a técnica mais eficaz. Não encontramos um ECR que comparasse a correção do geno varo. CONCLUSÃO: Ensaios clínicos randomizados de boa qualidade comparando grampos de Blount com oito placas devem ser realizados para determinar qual técnica é superior para correções do plano coronal. Nível de Evidência I, Revisão sistemática de ECRC.

Glycaemic, uricaemic and blood pressure response to beverages with partial fructose replacement of sucrose.

BACKGROUND/OBJECTIVES: The European Food Safety Authority approved a health claim (ID558) relating to lowered postprandial glycaemia when fructose replaces 30% of sucrose in foods and beverages. We assessed the effects of partial replacement of sucrose with fructose on serum glucose, uric acid and blood pressure. SUBJECTS/METHODS: A randomised, crossover, double blind trial of 12 normoglycaemic participants consuming beverages containing 50 g blends of fructose and sucrose in proportions; 67% sucrose/33% fructose (67%S:33%F); 50% each (50%S:50%F) and 33%S:67%F; a 100% sucrose reference beverage was tested twice. Serum glucose and uric acid concentrations were measured at 0, 15, 30, 45, 60, 90 and 120 min and incremental area-under-the-curve (iAUC) calculated. RESULTS: The geometric mean (95% CI) glycaemic iAUC following the 100% sucrose, 67%S:33%F, 50%S:50%F and 33%S:67%F blended beverages were 96 (63,145), 71 (46,109), 60 (39, 93) and 39 (12, 86) mmol/L min, respectively. At 33% fructose replacement, the proportionally lower iAUC of -28.5% (95% CI: -62.1, 5.2) mmol/L min was not different to sucrose alone. The response was lowered by fructose replacement of 50 and 67% and overall there was an inverse association (p < 0.001). The mean uricaemic iAUC to the respective beverages were 1320 (393, 2248), 3062 (1553, 4570), 3646 (2446, 4847), 3623 (2020, 5226) µmol/L min. Uric acid concentration was raised by all fructose-containing beverages with 33% fructose replacement causing an increase of 1741 (95% CI: 655, 2829) µmol/L min compared with sucrose alone. Blood pressure was not different among beverages. CONCLUSIONS: Reduced postprandial glycaemia was achieved by the substitution of sucrose with fructose although elevated uricaemic responses should be cautioned.

Variabilidade genética para caracteres morfométricos de matrizes de castanha-do-brasil da Amazônia Mato-grossense / Genetic variability for morphometric characteristics in Brazilian nut parent trees from northern Mato Grosso, Amazon rain forest

O presente estudo objetivou estudar a variabilidade genética de matrizes de Bertholletia excelsa através da estimação de parâmetros e ganhos genéticos para os caracteres peso/ouriço (g), peso de sementes/ouriço (g) e número de sementes/ouriço no pré-melhoramento da espécie. Foram utilizadas 90 matrizes de polinização aberta, sendo 30 matrizes de cada tipo, denominadas localmente de rajada, mirim e rosa, no município de Cotriguaçu, noroeste de Mato Grosso, região amazônica. O experimento foi estabelecido sob delineamento inteiramente ao acaso, com 90 tratamentos (matrizes) e seis ouriços por matriz, com suas respectivas sementes. As variáveis foram analisadas usando-se a metodologia de modelo linear misto do software SELEGEN-REML/BLUP. Os coeficientes de herdabilidades individuais no sentido amplo dos efeitos genotípicos totais (0,21, 0,14 e 0,34) para os caracteres peso/ouriço (g), peso de sementes/ouriço (g) e número de sementes/ouriço, respectivamente, são considerados moderados para os dois primeiros caracteres e alto para o caráter número de sementes/ouriço, sugerindo expressivo controle genético. A seleção das 10 melhores matrizes revelou predominância da procedência do tipo rosa, proporcionando ganhos genéticos expressivos de pelo menos 24,16% para peso/ouriço (g), 27,44% para peso de sementes/ouriço e 16,92% para o caráter número de sementes por ouriço. Os valores expressivos das matrizes do tipo rosa estimulam a utilização desses germoplasmas em programas de melhoramento genético da espécie, na seqüência das avaliações, bem como apontando para a possibilidade de obtenção de híbridos intraespecíficos para caracteres desejáveis.

The goal of the study was to detect genetic variability in Brazilian nuts parent trees through parameters estimation and genetic gains for the following indexes: fruit weight (g) seed weight per fruit (g) and number of seeds per fruit at species pre-improvement. Ninety (90) open pollination parent trees were used, 30 of which being of each type, locally called "rajada", "mirim" and "rosa" at the Cotriguacu municipality, Northeastern of Mato Grosso State. A completely randomized design was used, with 90 treatments (parent trees) and six fruits per parcel with their respective seeds. Variables were analyzed using the method of mixed univariate additive linear model from the software SELEGEN-REML/BLUP. Individual heritability coefficients in the broad sense for total genotypic effects (0,21, 0,14 e 0,34) for fruit weight (g) seed weight per fruit (g) and number of seeds per fruit (g) respectively, are considered moderate for the two first indexes and high for number of seeds per fruit, suggesting substantial genetic control. Selection of the 10 best provenances and parent trees showed predominance of the "rosa" type, allowing substantial genetic gains of at least 24,16% for fruit weight (g), 27,44% for seed weight per fruit and 16,92% for the number of seeds per fruit. The remarkable values for the "rosa" type suggest utilization of such germoplasms in genetic improvement programs of this species in the following evaluations. The results also point out the possibility of obtaining intraspecific hybrids for desirable characteristics.