Phenotypic heterogeneity in 22q11.2 deletion syndrome: Copy Number Variants as genetic modifiers for congenital heart disease in a Brazilian cohort.

The clinical heterogeneity in 22q11.2 deletion syndrome (22q11.2DS) underlies complex genetic mechanisms including variants in other regions of the genome, known as genetic modifiers. Congenital heart disease (CHD) is one of the most relevant phenotypes in the syndrome and copy number variants (CNVs) outside the 22q11.2 region could play a role in its variable expressivity. Since those described loci account for a small proportion of the variability, the CNV analysis in new cohorts from different ancestry-based populations constitutes a valuable resource to identify a wider range of modifiers. We performed SNP-array in 117 Brazilian patients with 22q11.2DS, with and without CHD, and leveraged genome-wide CNV analysis. After quality control, we selected 50 CNVs in 38 patients for downstream analysis. CNVs' genetic content and implicated biological pathways were compared between patients with and without CHD. CNV-affected genes in patients with CHD were enriched for several functional terms related to ubiquitination, transcription factor binding sites and miRNA targets, highlighting the complexity of the phenotype's expressivity. Cardiac-related genes were identified in both groups of patients suggesting that increasing risk and protective mechanisms could be involved. These genes and enriched pathways could indicate new modifiers to the cardiac phenotype in 22q11.2DS patients.

Cost-effectiveness of mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage: an economic evaluation based on the MifeMiso trial.

OBJECTIVE: To assess the cost-effectiveness of mifepristone and misoprostol (MifeMiso) compared with misoprostol only for the medical management of a missed miscarriage. DESIGN: Within-trial economic evaluation and model-based analysis to set the findings in the context of the wider economic evidence for a range of comparators. Incremental costs and outcomes were calculated using nonparametric bootstrapping and reported using cost-effectiveness acceptability curves. Analyses were performed from the perspective of the UK's National Health Service (NHS). SETTING: Twenty-eight UK NHS early pregnancy units. SAMPLE: A cohort of 711 women aged 16-39 years with ultrasound evidence of a missed miscarriage. METHODS: Treatment with mifepristone and misoprostol or with matched placebo and misoprostol tablets. MAIN OUTCOME MEASURES: Cost per additional successfully managed miscarriage and quality-adjusted life years (QALYs). RESULTS: For the within-trial analysis, MifeMiso intervention resulted in an absolute effect difference of 6.6% (95% CI 0.7-12.5%) per successfully managed miscarriage and a QALYs difference of 0.04% (95% CI -0.01 to 0.1%). The average cost per successfully managed miscarriage was lower in the MifeMiso arm than in the placebo and misoprostol arm, with a cost saving of £182 (95% CI £26-£338). Hence, the MifeMiso intervention dominated the use of misoprostol alone. The model-based analysis showed that the MifeMiso intervention is preferable, compared with expectant management, and this is the current medical management strategy. However, the model-based evidence suggests that the intervention is a less effective but less costly strategy than surgical management. CONCLUSIONS: The within-trial analysis found that based on cost-effectiveness grounds, the MifeMiso intervention is likely to be recommended by decision makers for the medical management of women presenting with a missed miscarriage. TWEETABLE ABSTRACT: The combination of mifepristone and misoprostol is more effective and less costly than misoprostol alone for the management of missed miscarriages.

The cost-effectiveness of progesterone in preventing miscarriages in women with early pregnancy bleeding: an economic evaluation based on the PRISM trial.

OBJECTIVES: To assess the cost-effectiveness of progesterone compared with placebo in preventing pregnancy loss in women with early pregnancy vaginal bleeding. DESIGN: Economic evaluation alongside a large multi-centre randomised placebo-controlled trial. SETTING: Forty-eight UK NHS early pregnancy units. POPULATION: Four thousand one hundred and fifty-three women aged 16-39 years with bleeding in early pregnancy and ultrasound evidence of an intrauterine sac. METHODS: An incremental cost-effectiveness analysis was performed from National Health Service (NHS) and NHS and Personal Social Services perspectives. Subgroup analyses were carried out on women with one or more and three or more previous miscarriages. MAIN OUTCOME MEASURES: Cost per additional live birth at ≥34 weeks of gestation. RESULTS: Progesterone intervention led to an effect difference of 0.022 (95% CI -0.004 to 0.050) in the trial. The mean cost per woman in the progesterone group was £76 (95% CI -£559 to £711) more than the mean cost in the placebo group. The incremental cost-effectiveness ratio for progesterone compared with placebo was £3305 per additional live birth. For women with at least one previous miscarriage, progesterone was more effective than placebo with an effect difference of 0.055 (95% CI 0.014-0.096) and this was associated with a cost saving of £322 (95% CI -£1318 to £673). CONCLUSIONS: The results suggest that progesterone is associated with a small positive impact and a small additional cost. Both subgroup analyses were more favourable, especially for women who had one or more previous miscarriages. Given available evidence, progesterone is likely to be a cost-effective intervention, particularly for women with previous miscarriage(s). TWEETABLE ABSTRACT: Progesterone treatment is likely to be cost-effective in women with early pregnancy bleeding and a history of miscarriage.

Prospective evaluation of IOTA logistic regression models LR1 and LR2 in comparison with subjective pattern recognition for diagnosis of ovarian cancer in an outpatient setting.

OBJECTIVE: To determine whether International Ovarian Tumor Analysis (IOTA) logistic regression models LR1 and LR2 developed for the preoperative diagnosis of ovarian cancer could also be used to differentiate between benign and malignant adnexal tumors in the population of women attending gynecology outpatient clinics. METHODS: This was a single-center prospective observational study of consecutive women attending our gynecological diagnostic outpatient unit, recruited between May 2009 and January 2012. All the women were first examined by a Level-II ultrasound operator. In those diagnosed with adnexal tumors, the IOTA-LR1/2 protocol was used to evaluate the masses. The LR1 and LR2 models were then used to assess the risk of malignancy. Subsequently, the women were also examined by a Level-III examiner, who used pattern recognition to differentiate between benign and malignant tumors. Women with an ultrasound diagnosis of malignancy were offered surgery, while asymptomatic women with presumed benign lesions were offered conservative management with a minimum follow-up of 12 months. The initial diagnosis was compared with two reference standards: histological findings and/or a comparative assessment of tumor morphology on follow-up ultrasound scans. All women for whom the tumor classification on follow-up changed from benign to malignant were offered surgery. RESULTS: In the final analysis, 489 women who had either or both of the reference standards were included. Their mean age was 50 years (range, 16-91 years) and 45% were postmenopausal. Of the included women, 342/489 (69.9%) had surgery and 147/489 (30.1%) were managed conservatively. The malignancy rate was 137/489 (28.0%). Overall, sensitivities of LR1 and LR2 for the diagnosis of malignancy were 97.1% (95% CI, 92.7-99.2%) and 94.9% (95% CI, 89.8-97.9%) and specificities were 77.3% (95% CI, 72.5-81.5%) and 76.7% (95% CI, 71.9-81.0%), respectively (P > 0.05). In comparison with pattern recognition (sensitivity 94.2% (95% CI, 88.8-97.4%), specificity 96.3% (95% CI, 93.8-98.0%)), the specificities of the IOTA models were significantly lower (P < 0.0001). A significantly higher number of women would have been offered surgery for suspected cancer if the women had been assessed using the IOTA models instead of pattern recognition (213/489 (43.6%) vs 142/489 (29.0%); P < 0.001). CONCLUSIONS: The IOTA models maintained their high sensitivity when used in an outpatient setting. Specificity was relatively low, which indicates that a significant proportion of the women would have been offered unnecessary surgery for suspected ovarian cancer. These findings show that the IOTA models could be used as a first-stage test to diagnose ovarian cancer in an outpatient setting, but a different second-stage test is required to minimize the number of false-positive findings. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Single-dose systemic methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo-controlled randomized trial.

OBJECTIVE: Methotrexate is used routinely worldwide for the medical treatment of clinically stable women with a tubal ectopic pregnancy. This is despite the lack of robust evidence to show its superior effectiveness over expectant management. The aim of our multicenter randomized controlled trial was to compare success rates of methotrexate against placebo for the conservative treatment of tubal ectopic pregnancy. METHODS: This study took place in two early-pregnancy units in the UK between August 2005 and June 2014. Inclusion criteria were clinically stable women with a conclusive ultrasound diagnosis of a tubal ectopic pregnancy, presenting with a low serum beta human chorionic gonadotropin (ß-hCG) level of < 1500 IU/L. Women were assigned randomly to a single systemic injection of either 50 mg/m2 methotrexate or placebo. The primary outcome was a binary indicator for success of conservative management, defined as resolution of clinical symptoms and decline of serum ß-hCG to < 20 IU/L or a negative urine pregnancy test without the need for any additional medical intervention. An intention-to-treat analysis was followed. RESULTS: We recruited a total of 80 women, 42 of whom were assigned to methotrexate and 38 to placebo. The arms of the study were matched in terms of age, ethnicity, obstetric history, pregnancy characteristics and serum levels of ß-hCG and progesterone. The rates of success were similar for the two study arms: 83% with methotrexate and 76% with placebo. On univariate analysis, this difference was not statistically significant (χ2 (1 degree of freedom) = 0.53; P = 0.47). On multivariate logistic regression, the serum level of ß-hCG was the only covariate found to be significantly associated with outcome. The odds of failure increased by 0.15% for each unit increase in ß-hCG (odds ratio, 1.0015 (95% CI, 1.0002-1.003); P = 0.02). In 14 women presenting with serum ß-hCG of 1000-1500 IU/L, the success rate was 33% in those managed expectantly compared with 62% in those receiving methotrexate. This difference was not statistically significant and a larger sample size would be needed to give sufficient power to detect a difference in the subgroup of women with higher ß-hCG. In women with successful conservative treatment, there was no significant difference in median ß-hCG resolution times between study arms (17.5 (interquartile range (IQR), 14-28.0) days (n = 30) in the methotrexate group vs 14 (IQR, 7-29.5) days (n = 25) in the placebo group; P = 0.73). CONCLUSIONS: The results of our study do not support the routine use of methotrexate for the treatment of clinically stable women diagnosed with tubal ectopic pregnancy presenting with low serum ß-hCG (< 1500 IU/L). Further work is required to identify a subgroup of women with tubal ectopic pregnancy and ß-hCG ≥ 1500 IU/L in whom methotrexate may offer a safe and cost-effective alternative to surgery. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. Comparación entre una sola dosis de metotrexate sistémico y la conducta expectante en el tratamiento de casos de embarazo ectópico tubárico: un ensayo aleatorio controlado con placebo RESUMEN OBJETIVO: El metotrexate se utiliza de modo rutinario en todo el mundo para el tratamiento de las mujeres clínicamente estables con un embarazo ectópico tubárico. Esto sucede a pesar de la falta de evidencia rigurosa que demuestre que su eficacia es superior a la conducta expectante. El objetivo de este ensayo controlado aleatorio multicéntrico fue comparar las tasas de éxito del metotrexate con las de un placebo para el tratamiento cauteloso del embarazo ectópico tubárico. MÉTODOS: Este estudio se llevó a cabo en dos clínicas de control de gestación temprana en el Reino Unido entre agosto de 2005 y junio de 2014. Los criterios de inclusión fueron mujeres clínicamente estables con un diagnóstico ecográfico concluyente de embarazo ectópico tubárico, las cuáles presentaban una concentración sérica baja de la ß hormona coriónica gonadotrópica (ß-hCG) inferior a 1500 UI/L. Las mujeres fueron asignadas aleatoriamente a una sola inyección sistémica de 50 mg/m2 de metotrexate o a placebo. El resultado primario fue un indicador binario del éxito del tratamiento conservador, definido como la resolución de los síntomas clínicos y la disminución en el suero de la ß-hCG a <20 UI/L o una prueba de embarazo negativa en orina sin la necesidad de ninguna intervención médica adicional. Se hizo un análisis por intención de tratar. RESULTADOS: Se reclutó un total de 80 mujeres; a 42 de ellas se les asignó el metotrexate y a 38 el placebo. Los grupos del estudio se realizaron en función de la edad, el origen étnico, los antecedentes obstétricos, las características del embarazo y los niveles séricos de la ß-hCG y la progesterona. Las tasas de éxito fueron similares para los dos grupos de estudio: 83% con metotrexate y 76% con placebo. En el análisis univariante, esta diferencia no fue estadísticamente significativa (χ2 (1 grado de libertad) = 0,53; P = 0,47). En la regresión logística multivariante, el nivel sérico de la ß-hCG fue la única covariable que se encontró significativamente asociada con el resultado. Las probabilidades de fracaso aumentaron en un 0,15% por cada unidad de aumento de la ß-hCG (cociente de probabilidad 1,0015 (IC 95%, 1,0002-1,003); P = 0,02). La tasa de éxito en las 14 mujeres con un nivel sérico de la ß-hCG de 1000-1500 UI/L fue del 33% en las tratadas con conducta expectante frente al 62% en las que recibieron metotrexate. Esta diferencia no fue estadísticamente significativa, por lo que se necesitaría un tamaño de muestra mayor, lo suficiente como para poder detectar diferencias en el subgrupo de mujeres con una ß-hCG más elevada. En las mujeres en las que el tratamiento conservador tuvo éxito, no hubo una diferencia significativa en la mediana de los tiempos de resolución de la ß-hCG entre los grupos del estudio (17,5 (amplitud intercuartílica (IQR), 14-28,0) días (n = 30) en el grupo de metotrexate frente a 14 (IQR, 7-29.5) días (n = 25) en el grupo de placebo; P = 0,73). CONCLUSIONES: Los resultados de este estudio no apoyan el uso rutinario de metotrexate para el tratamiento de las mujeres clínicamente estables diagnosticadas con un embarazo ectópico tubárico que presenta un nivel sérico bajo la ß-hCG (<1500 UI/L). Serán necesarios estudios adicionales para identificar un subgrupo de mujeres con embarazo ectópico tubárico y ß-hCG ≥1500 UI/L para quienes el metotrexate puede ofrecer una alternativa segura y rentable en comparación con la cirugía. : : ,,。。 : 2005820146,2。,,ß(beta human chorionic gonadotropin,ß-hCG)<1500 IU/L。,(50 mg/m2 )。,ß-hCG<20 IU/L,。。 : 80,42,38。2、、、ß-hCG。2:83%,76%。,[χ2 (1)=0.53;P=0.47]。logistic,ß-hCG。ß-hCG,0.15%[,1.0015(95% CI,1.0002~1.003);P=0.02]。14ß-hCG1000~1500 IU/L,33%,62%。,ß-hCG。,2ß-hCG(P=0.73),17.5[(interquartile range,IQR),14~28.0](n=30),14 (IQR,7~29.5)(n=25)。 : 、、ß-hCG(<1500 IU/L)。,ß-hCG>1500 IU/L、。.

Association between ultrasound features of adenomyosis and severity of menstrual pain.

OBJECTIVE: To investigate the association between the ultrasound features of adenomyosis and the severity of menstrual pain. METHODS: This was a prospective observational study set in the general gynecology clinic of a university teaching hospital between January 2009 and January 2010. A total of 718 consecutive premenopausal women aged between 17 and 55 years attended the clinic and underwent structured clinical and transvaginal ultrasound examinations in accordance with the study protocol. Morphological features of adenomyosis on ultrasound scan were recorded systematically. A quantitative assessment of menstrual pain was made by completion of a numerical rating scale (NRS). RESULTS: One hundred and fifty-seven (21.9% (95% CI, 18.8-24.9%)) women were diagnosed with adenomyosis on ultrasound. Multiple linear regression analysis showed that an ultrasound diagnosis of adenomyosis and ultrasound and laparoscopic diagnoses of endometriosis were significantly associated with menstrual pain when measured by an NRS. In addition, there was a statistically significant positive correlation between the severity of menstrual pain and the number of ultrasound features of adenomyosis seen. CONCLUSIONS: Women with ultrasound features of adenomyosis have more severe menstrual pain than do women without these features. The positive correlation between the number of ultrasound features of adenomyosis and the severity of menstrual pain could form the basis of a clinically relevant grading system for adenomyosis. A classification of severity of adenomyosis based on the number of ultrasound features present is a novel concept that should be evaluated prospectively in different populations. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Techniques for restoring enlarged canals: an evaluation of fracture resistance and bond strength.

AIM: To verify the influence of fibreglass post diameter, as well as use of accessory posts on fracture resistance and bond strength, when used for restoring enlarged root canals. METHODOLOGY: One hundred maxillary single-rooted canine human teeth were decoronated and root canals were prepared using a No.4 drill (White Post, FGM, Joinville, SC, Brazil). The roots were assigned to five groups: (EC1) post No.1 (Exacto Cônico, Angelus, Londrina, PR, Brazil); (EC2) post No.2 (Exacto Cônico, Angelus); (EC3) post No.3 (Exacto Cônico, Angelus); (ECA) post No.1 (Exacto Cônico, Angelus) plus two accessory posts (Reforpin, Angelus); (WP) post No.4 (White Post, FGM). Posts 1-4 have a crescent diameter. Posts were luted (Rely X-Arc, 3M ESPE, USA) and composite resin filling cores were prepared for the fracture resistance test (n = 10). For the push-out test (n = 10), roots were sectioned into 1 mm thick slices. Both tests were performed in a universal testing machine. Data were analysed using anova and Tukey's test. RESULTS: Groups WP and EC3 had higher fracture resistance than the other groups (P < 0.05), which were statistically similar. Root fractures occurred in 14% of the specimens. Groups EC1 and EC2 had lower bond strength values than Groups EC3 and ECA which were lower than the WP Group (P < 0.05). Bond strength was lower in the apical and middle third than in the cervical third of root canals (P < 0.05). CONCLUSIONS: Thicker posts were associated with higher resistance to fracture and bond strength to root canals. Using a post plus two accessory posts improved the bond strength but not the fracture resistance.

Color flow Doppler sonography for the etiologic diagnosis of thyrotoxicosis.

The objective of this prospective study was to compare the results of color flow Doppler sonography (CFDS) and radioiodine scintigraphy in patients with thyrotoxicosis. A total of 176 patients, 102 with clinical thyrotoxicosis and 74 with subclinical dysfunction, were included. Pregnant and breast-feeding women, patients using amiodarone or recently exposed to iodinated contrast, and patients treated with antithyroid drugs were excluded. Total T3, free T4, TSH, and anti-TSH receptor antibodies were measured before scintigraphy and CFDS. Excluding one patient whose etiology of thyrotoxicosis remained undefined, CFDS showed 100% specificity. In fact, in all 10 cases in which scintigraphy and CFDS provided discordant results, the diagnosis suggested by the latter was correct. In patients with clinical thyrotoxicosis, the sensitivity of CFDS was 96% for diffuse toxic goiter, 95% for the absence of hyperfunction, and 100% for toxic nodular disease. In patients with subclinical dysfunction, the sensitivity of CFDS was 72.7% for diffuse toxic goiter, 90% for toxic adenoma, and 86.6% for toxic multinodular disease. CFDS was inconclusive in patients with parenchymal blood flow with patchy uneven distribution or with macronodules in which nodule vascularity compared to the remaining parenchyma did not permit to establish the diagnosis with certainty. CFDS can be used instead of scintigraphy not only in situations in which the latter is contraindicated or of limited value to define the etiology of thyrotoxicosis.

Use of IOTA simple rules for diagnosis of ovarian cancer: meta-analysis.

OBJECTIVES: To present data on prospective evaluation of the International Ovarian Tumor Analysis (IOTA) 'simple-rules' tool for the diagnosis of ovarian cancer and to perform a meta-analysis of studies that utilized the same diagnostic method. METHODS: In the present study a level-II ultrasound operator systematically assessed the tumors of women with an ultrasound diagnosis of adnexal tumor(s) according to the IOTA simple-rules protocol to determine the risk of the tumor being malignant. The results of simple rules were compared with the 'pattern recognition' method and with histological findings. This validation study was included in the subsequent meta-analysis, for which we searched MEDLINE, EMBASE and Cochrane from the publication of the first study in 2008. The terms used were 'simple rules', 'simple rules ovarian', 'ovar tumor' and 'ultrasound'. Quality assessment was performed using the modified Quality Assessment of the Diagnostic Accuracy of Studies (QUADAS-2) checklist. Random effects meta-analysis was used to calculate pooled estimates of sensitivity and specificity for the simple-rules tool, and meta-regression was used to investigate heterogeneity across the studies. RESULTS: Three hundred and three women were included in the validation study with 168 (55.4%) benign, 19 (6.3%) borderline and 116 (38.3%) malignant tumors on histological examination. The rules were applicable in 237 (78.2%) of the tumors and for these tumors, sensitivity was 96.2% (95% CI, 90.5-99.0%) and specificity was 88.6% (95% CI, 82.0-93.5%). Six of the 88 discovered studies were included in the meta-analysis along with the current validation study, which resulted in inclusion of a total of 3568 patients. When the meta-analysis was performed the pooled sensitivity (when the rules were applicable) was 93% (95% CI, 90-96%) (I(2) = 32.1%) and the pooled specificity was 95% (95% CI, 93-97%) (I(2) = 78.1%). Heterogeneity was observed across the studies. Sensitivity was higher and specificity lower in the study populations in which the prevalence of malignant tumors was greatest. CONCLUSION: The simple rules protocol could be used in 76-89% of tumors and is an accurate test for the diagnosis of ovarian cancer. Assessment by an ultrasound expert is required when the protocol cannot be applied.

Managing B2 periprosthetic femoral fractures: ORIF vs stem-revision.

BACKGROUND: The gold-standard treatment for Vancouver type B2 and B3 fractures is revision arthroplasty. This procedure can be prolonged and complex, posing challenges for patients with severe medical comorbidities and reduced physical status. Recently, osteosynthesis has been proposed as an alternative treatment for B2 periprosthetic femoral fractures (PFF) in frail patients, though its efficacy compared to revision arthroplasty has not been studied in detail. METHODS: A retrospective study was conducted from 2012 to 2022, comparing complications, mortality, length of stay, gait ability, hemoglobin decrease, and blood transfusion rates between 44 patients undergoing treatment for B2 or B3 PPF with either stem-revision arthroplasty (n = 28) or open reduction and internal fixation (ORIF) with plates and screws (n = 16). RESULTS: The results showed no significant differences in mortality, complications, hemoglobin decrease, blood transfusion rate, or length of stay between the two groups. In the stem-revision group, 11 patients (60.7 %) experienced a medical complication, while 7 patients (43.8 %) in the ORIF group had complications (p = 0.778). The mortality rate within the first year post-surgery was 17.9 % (5 patients) in the stem-revision group compared to 18.8 % (3 patients) in the ORIF group (p = 0.943). Surgical complications occurred in 2 patients (7.1 %) in the stem-revision group and in 4 patients (25 %) in the ORIF group (p = 0.101). Blood transfusions were required in 17 patients (60.7 %) in the stem-revision group and in 8 patients (50 %) in the ORIF group (p = 0.829). CONCLUSIONS: This study suggests that ORIF is an acceptable treatment option for patients with B2 or B3 PFF, especially for those with severe medical comorbidities and reduced physical status who may not tolerate revision arthroplasty. However, further research with larger sample sizes and longer follow-up periods is needed to confirm these findings. LEVEL OF EVIDENCE: IV.

Biallelic EPCAM deletions induce tissue-specific DNA repair deficiency and cancer predisposition.

We report a case of Mismatch Repair Deficiency (MMRD) caused by germline homozygous EPCAM deletion leading to tissue-specific loss of MSH2. Through the use of patient-derived cells and organoid technologies, we performed stepwise in vitro differentiation of colonic and brain organoids from reprogrammed EPCAMdel iPSC derived from patient fibroblasts. Differentiation of iPSC to epithelial-colonic organoids exhibited continuous increased EPCAM expression and hypermethylation of the MSH2 promoter. This was associated with loss of MSH2 expression, increased mutational burden, MMRD signatures and MS-indel accumulation, the hallmarks of MMRD. In contrast, maturation into brain organoids and examination of blood and fibroblasts failed to show similar processes, preserving MMR proficiency. The combined use of iPSC, organoid technologies and functional genomics analyses highlights the potential of cutting-edge cellular and molecular analysis techniques to define processes controlling tumorigenesis and uncovers a new paradigm of tissue-specific MMRD, which affects the clinical management of these patients.

Endometrial cancer and ultrasound: why measuring endometrial thickness is sometimes not enough.

Endometrial cancer is the commonest cancer of the female genital tract in the developed world. Ultrasound measurement of endometrial thickness is commonly used to triage patients with postmenopausal bleeding for histological sampling. The sensitivity of ultrasound in diagnosing endometrial cancer is high, but it has a small, well-defined false-negative rate. In this report we describe two cases, with histological confirmation, of postmenopausal women without any vaginal bleeding, who were subsequently diagnosed with advanced endometrial cancer. They were found to have a thin, normal endometrium on ultrasound. In both cases, histological examination was suggestive of endometrial cancer originating from foci of adenomyosis. These findings suggest that a proportion of the false-negative diagnoses of endometrial cancer on ultrasound could be caused by the disease being confined to the myometrium rather than as a result of suboptimal performance of ultrasound examination.

Inter- and intraobserver variability in three-dimensional ultrasound assessment of the endometrial-myometrial junction and factors affecting its visualization.

OBJECTIVE: To assess the inter- and intraobserver variability of three-dimensional (3D) ultrasound assessment of the endometrial-myometrial junction (EMJ), and to assess demographic and physiological factors that affect the quality of its imaging. METHODS: Women attending our gynecology clinic, who were deemed to have normal uteri on transvaginal ultrasound examination, were enrolled in this prospective study. They underwent 3D volume acquisition of the entire uterus in order to acquire a coronal view of the organ. Visualization of EMJs was classified as optimal, satisfactory or unsatisfactory. In order to assess the intra- and interobserver variabilities of the classification system, the volumes were classified by two independent observers on two separate occasions. The same classification system was then used to evaluate the EMJs of 101 women who were deemed to have normal uteri on transvaginal ultrasound examination. The results were correlated with age, parity, stage of cycle, menopausal status and endometrial thickness in order to assess whether any of these factors affect visualization of the EMJ. RESULTS: A total of 30 uterine volumes were examined in the first analysis. Both the inter- and intraobserver variability were good (kappa values of 0.77 and 0.83). Of the 101 EMJs assessed in the second analysis, 47 were classified as optimal, 42 as satisfactory and 12 as unsatisfactory. Endometrial thickness was positively associated with EMJ visualization and parity was negatively associated with EMJ visualization. CONCLUSIONS: Assessment of EMJ visualization has both good inter- and intraobserver variability in women with normal uteri. Parity and endometrial thickness have contrasting, statistically significant, effects on visualization of the EMJ.

Prospective evaluation of the IOTA logistic regression model LR2 for the diagnosis of ovarian cancer.

OBJECTIVES: To assess the accuracy of the IOTA logistic regression model LR2 for the diagnosis of ovarian cancer. METHODS: This was a prospective single-center study of women with an ultrasound diagnosis of an adnexal tumor. They were all examined by a single Level-II ultrasound operator, who had received training in the systematic examination of ovarian tumors in accordance with the IOTA guidelines. In all women the likelihood of the adnexal lesion being malignant was calculated using the IOTA LR2 model. All women underwent surgery within 120 days of ultrasound examination and the ultrasound findings were compared with operative findings and the final histological diagnosis. RESULTS: One hundred and twenty-four women were included in the final analysis. The mean age was 53.2 (range, 20-91) years and 61/124 (49.2%) women were postmenopausal. 66/124 (53.2%) women had malignant lesions on postoperative histological examination. The IOTA LR2 model had a sensitivity of 97.0% (95% CI, 89.5-99.6%) and a specificity of 69.0% (95% CI, 55.5-80.5%). The area under the receiver-operating characteristics curve was 0.93 (SE, 0.022; 95% CI, 0.89-0.97), which was not significantly different from 0.92 (SE, 0.018) reported in the original study (P > 0.05). CONCLUSION: When evaluated prospectively, the accuracy of the IOTA LR2 model was similar to that reported in the original study.

Patient-centered Outcomes in Breast Cancer: Description of EQ-5D-5L and EORTC-QLQ-BR23 Measurements in Real-world Data and Their Association With Survival.

AIMS: In recent years, major improvements in breast cancer treatments have led to a significant increase in survival. Despite that, this population's quality of life (QoL) information is lacking, especially real-world data. MATERIALS AND METHODS: This was a prospective, multicentre, observational study of female breast cancer patients, without prior systemic treatment, treated between 2012 and 2019 in private health care in Brazil. QoL was assessed by two questionnaires, the EQ-5D-5L and the EORTC-QLQ-BR23. Additional data were retrospectively collected. RESULTS: The study comprised 1372 patients, most with early-stage disease (80.2% stages 0-II). At a median follow-up of 25.6 months, the estimated 3-year overall survival was 93.6%. Patients with locally advanced and metastatic breast cancer had the lowest visual analogue scale scores and the highest symptom burden in all dimensions of EQ-5D-5L, but with the most significant improvement after treatment. With the EORTC-QLQ-BR23 questionnaire, patients undergoing lumpectomy had a better perception of body image. Axillary dissection led to greater arm symptoms after 12 months, radiotherapy enhanced breast symptoms and patients treated with chemotherapy had significant worsening in the effects of systemic therapy compared with endocrine or HER2 therapy. Staging and immunohistochemical subtype correlated with survival and with several QoL parameters, but overall survival was not independently affected by patient-reported outcomes in this cohort. CONCLUSION: Our results show that early diagnosis and access to treatments with fewer side-effects, such as endocrine or targeted therapy, and less aggressive surgeries are the best strategies to achieve a better QoL for breast cancer patients.

Early weight gain trajectories in first episode anorexia: predictors of outcome for emerging adults in outpatient treatment.

BACKGROUND: Early response to treatment has been shown to be a predictor of later clinical outcomes in eating disorders (EDs). Specifically, early weight gain trajectories in anorexia nervosa (AN) have been shown to predict higher rates of later remission in inpatient treatment. However, no study has, as of yet, examined this phenomenon within outpatient treatment of first episode cases of AN or in emerging adults. METHODS: One hundred seven patients with AN, all between the ages of 16 and 25 and with an illness duration of < 3 years, received treatment via the first episode rapid early intervention in eating disorders (FREED) service pathway. Weight was recorded routinely across early treatment sessions and recovery outcomes (BMI > 18.5 kg/m2 and eating psychopathology) were assessed up to 1 year later. Early weight gain across the first 12 treatment sessions was investigated using latent growth mixture modelling to determine distinct classes of change. Follow-up clinical outcomes and remission rates were compared between classes, and individual and clinical characteristics at baseline (treatment start) were tested as potential predictors. RESULTS: Four classes of early treatment trajectory were identified. Three of these classes (n = 95), though differing in their early change trajectories, showed substantial improvement in clinical outcomes at final follow-up. One smaller class (n = 12), characterised by a 'higher' start BMI (> 17) and no early weight gain, showed negligible improvement 1 year later. Of the three treatment responding groups, levels of purging, depression, and patient reported carer expressed emotion (in the form of high expectations and low tolerance of the patient) determined class membership, although these findings were not significant after correcting for multiple testing. A higher BMI at treatment start was not sufficient to predict optimal clinical outcomes. CONCLUSION: First episode cases of AN treated via FREED fit into four distinct early response trajectory classes. These may represent subtypes of first episode AN patients. Three of these four trajectories included patients with substantial improvements 1 year later. For those in the non-response trajectory class, treatment adjustments or augmentations could be considered earlier, i.e., at treatment session 12.

A key feature of anorexia nervosa (AN) is an unhealthily low body weight. Previous studies show that more weight gained early in inpatient treatment leads to better outcomes. This study tried to see if this was also true for outpatients receiving treatment for the first time. All participants were emerging adults between the ages of 16 and 25 who had been ill for less than 3 years. Weight was recorded across the first 12 weekly treatment sessions. Statistics showed that the patients fit roughly into four different groups in early treatment, each with different starting weights and rates of weight gain in the first 12 treatment sessions. The group a patient belonged to could sometimes be predicted by vomiting behaviours, level of depression, and patients' perception of parental tolerance and expectations at the start of treatment. Out of the four groups, three did relatively well 1 year later, but one small group of patients did not. This small group had a higher starting weight than many of the other groups but did not gain any weight across the first 12 sessions. These patients could benefit from a change or increase in the amount or intensity of treatment after the first 12 treatment sessions.

Nutraceutical potential of Asparagopsis taxiformis (Delile) Trevisan extracts and assessment of a downstream purification strategy.

The main goal of the present work was to determine the nutraceutical potential of Asparagopsis taxiformis D. extracts from Madeira Archipelago south coast. Extraction methodologies consisted either/or in 72 hours stirring, at room temperature (M1), or 6 cycles of Soxhlet extraction (M2), both with re-extraction. Solvents used were distilled water, ethanol, methanol and ethyl acetate. M1 allowed to obtain the highest values for extraction yield (31.65 g.100g-1 dw) using water, whereas iodine content (3.37 g.100g-1 dw), TPC (1.71 g GAE.100g-1 dw) and chlorophyll a (45.96 mg.100g-1 dw) were obtained using ethanol, and TCC (36.23 mg.100g-1 dw) with methanol. Extracts that showed higher reduction activity in M1 were derived from ethanol extraction (1,908 mg AAE.100g-1 dw). Water and ethanol were the best solvents for higher DPPH scavenging activity in M2, both with same result (IC50 1.37 mg.mL-1). The lowest value of IC50 for chelating activity (1.57 mg.mL-1) was determined in M1, using ethyl acetate. The remaining residue was used to obtain other products, i.e. lipid extraction (M1, 2.05 g.100g-1 dw), carrageenans (M2, 21.18 g.100g-1 dw) and cellulose (M1, 23.81 g.100g-1 dw) with subsequent FTIR ATR analysis. Our results show that A. taxiformis is a valuable source of bioactive compounds. The M1 extraction methodology using ethanol is the most effective solvent to produce an iodine rich bioactive extract with potential of being used as a nutraceutical supplement. Also, we have demonstrated a possible downstream strategy that could be implemented for multiple compound extraction from A. taxiformis residue. This has a vital importance for future feasibility, when using this biomass as an industrial feedstock for multiple products production. Statistical analysis, using SPSS 24.0, was also performed and important correlations were found between assays and methods.

Phenology, reproductive biology and growing degree days of the grapevine 'Isabel' (Vitis labrusca, Vitaceae) cultivated in northeastern Brazil.

Phenology and reproductive biology of cultivated species are important for the comprehension of the requirements for fruit and seed production and the management of pollinators. This study aimed to characterise the phenology, reproductive biology and growing degree days of the grapevine 'Isabel' (Vitis labrusca) in northeastern Brazil during January 2011 (P1), Augst 2011 (P2), April 2012 (P3) and August 2012 (P4). We recorded the duration (days) of the phenological stages, pruning (P), woolly bud (W), budburst (B), inflorescence development (ID), flowering (F), ripening (R) and harvest (H). We analysed the floral biology, the sexual system and the breeding system. We measured the growing degree days (GDD) required to reach the subperiods P-B, B-F and F-H. The periods P1, P2, P3 and P4 lasted for 116, 125, 117 and 130 days, respectively. The number of days of harvest were similar in the same dry (P1 and P3) and rainy (P2 and P4) periods. All the periods that we recorded were shorter than those observed in other regions of Brazil, which may be attributable to the mean temperature and carbohydrate metabolism. The flowers are green, hermaphroditic, with an odour of mignonette, low pollen viability and autogamous. The base temperature of 10°C was considered the most adequate for the subperiods as has been documented for other grape varieties in Brazil. Thus, temperature was also the most adequate for the cycles, presenting a smaller standard deviation (0.119, 0.147, 0.156 and 0.153 to P1, P2, P3 and P4, respectively) when compared to a base temperature of 12°C (0.122, 0.158, 0.165 and 0.160 to P1, P2, P3 and P4, respectively). The higher and the lower observed GDD were 1972.17 and 1870.05, respectively, both above the values recorded in other parts of Brazil for same variety. The phonological results, including knowledge of growing degree days, are important to the planning of cultures at the study site and in other regions that have similar climatic conditions and make it possible to pre-determine the harvest.

Different expression patterns of LGALS1 and LGALS3 in polycythemia vera, essential thrombocythemia and primary myelofibrosis.

Despite all the knowledge, the cellular and molecular mechanisms involved in myeloproliferative neoplasm (MPN) pathophysiology remain unclear. Authors have shown galectin-1 (Gal-1) and 3 playing roles in tumour angiogenesis and fibrosis, which were correlated with poor prognosis in patients with MPN. In the present study LGALS1 and LGALS3 were differently expressed between polycythemia vera, essential thrombocythemia (ET) and primary myelofibrosis (PMF) diseases. Increased LGALS3 expression was associated with a negative JAK2 V617F status mutation in leucocytes from PMF but not in patients with ET without this mutation. However, a positive Janus kinase 2 (JAK2) V617F cell line established from patients with ET (SET-2 cells) when treated with JAK inhibitor presented high levels of LGALS3. Additionally, high LGALS1 expression was found in CD34(+) cells but not in leucocytes from patients with PMF, in absence of JAK2 V617F mutation, and also in SET-2 cells treated with JAK inhibitor. Thus, our findings indicate that differential expression of LGALS1 and/or LGALS3 in patients with MPN is linked with JAK2 V617F status mutation in these diseases and state of cell differentiation.

Parâmetros hemodinâmicos e ventilatórios em coelhos anestesiados com isoflurano, submetidos à ventilação controlada à pressão com ou sem PEEP / Hemodynamic and ventilatory parameters in rabbits anesthetized with isoflurane submitted to pressure controlled ventilation with or without PEEP

Foi comparada a ventilação controlada à pressão com ou sem pressão positiva expiratória final (PEEP), em coelhos, distribuídos em três grupos, denominados GP (grupo ventilação ciclada à pressão), GPP (grupo ventilação ciclada à pressão com PEEP) e GE (grupo ventilação espontânea - grupo controle). Os animais foram anestesiados com isoflurano, em circuito com reinalação de gases, durante duas horas. As médias de pressão arterial média (PAM) e pressão arterial sistólica (PAS) permaneceram discretamente abaixo dos valores normais em todos os grupos. Houve diminuição significativa da PAM e da PAS no grupo submetido à PEEP (GPP) ao longo do tempo. A pressão parcial de dióxido de carbono arterial (PaCO2) foi maior no GPP quando comparado aos outros grupos no último momento, gerando acidemia respiratória após uma hora de procedimento. A concentração de dióxido de carbono ao final da expiração (ETCO2) apresentou médias discretamente elevadas no grupo não tratado com PEEP (GP) e no grupo controle, enquanto o GPP apresentou maiores médias, possivelmente, relacionadas à diminuição do volume corrente neste grupo. Com base nesses resultados, foi possível concluir que a utilização da PEEP levou à acidemia, que se agravou ao longo do tempo anestésico. Ademais, a anestesia prolongada com isoflurano promove depressão cardiorrespiratória, independentemente do modo ventilatório empregado.(AU)

Pressure controlled ventilation with or without positive end-expiratory pressure (PEEP) was compared in rabbits, which were divided into three groups denominated GP (pressure cycled ventilation group), GPP (pressure cycled ventilation with PEEP group) and GE (spontaneous ventilation group - control group). The animals were anesthetized with isoflurane in a gas rebreathing circuit for two hours. The means of mean arterial pressure (MAP) and systolic blood pressure (SBP) remained slightly below normal values ​​in all groups. There was a significant decrease in MAP and SBP in the group submitted to PEEP (GPP) over time. The partial pressure of arterial carbon dioxide (PaCO2) was higher in GPP when compared to the other groups, inducing respiratory acidosis after one hour. The end-expired carbon dioxide concentration (ETCO2) presented slightly elevated means in the GP, while the GPP presented higher means, possibly related to the decrease in tidal volume in this group. Based on these results it was concluded that the use of PEEP led to acidemia that worsened over anesthetic time. In addition, prolonged isoflurane anesthesia promotes cardiorespiratory depression, regardless the ventilatory mode employed.(AU)