Miracle-dz/UniFAR-FTUs huggingface dataset:
In vivo reversal of the anticoagulant effect of rivaroxaban with four‐factor prothrombin complex concentrate

Four‐factor prothrombin complex concentrate (PCC) 50 iu/kg is able to swiftly restore haemostatic parameters in healthy subjects on rivaroxaban. We hypothesized that lower dosages of PCC may be sufficient to restore normal haemostasis. In this double‐blind, crossover, placebo‐controlled study, we compared the effects of PCC 37·5 iu/kg, PCC 25 iu/kg, and placebo on thrombin generation (endogenous thrombin potential, ETP) and prothrombin time in six healthy subjects receiving twice‐daily rivaroxaban 15 mg for 2·5 days. Fifteen min after infusion of PCC 37·5 iu/kg, ETP increased from 47 ± 16% to 64 ± 22% (P = 0·03; pre‐rivaroxaban ETP: 92 ± 14%) and remained higher than after placebo over 24 h (P = 0·001). PCC 25 iu/kg did not modify ETP within 15 min (53 ± 11% to 59 ± 12%; P = 0·14) and was not different from placebo over 24 h (P = 0·31). ETP reached pre‐rivaroxaban levels within 6 h after PCC 37·5 iu/kg infusion and within 12–24 h after PCC 25 iu/kg infusion. Both dosages restored rivaroxaban‐induced prothrombin time prolongation after 15 min (P < 0·001). Placebo did not have an effect on coagulation parameters. 37·5 iu/kg of PCC leads to partial restoration of thrombin generation, whereas 25 iu/kg does not. PCC 37·5 iu/kg may be insufficient for immediate full reversal of peak therapeutic rivaroxaban levels.
Histone deacetylase inhibition modulates E-cadherin expression and suppresses migration and invasion of anaplastic thyroid cancer cells.

CONTEXT Anaplastic thyroid cancer cells are characterized by a mesenchymal phenotype, as revealed by spindle-shaped cells and absent or reduced levels of E-cadherin. Epigenetic silencing is considered one of the leading mechanisms of E-cadherin impairment, which causes the acquisition of the invasive and metastatic phenotype of anaplastic thyroid cancer. OBJECTIVES In this study we investigated the effects of histone deacetylase inhibition on E-cadherin expression, cell motility, and invasion in anaplastic thyroid cancer cell cultures. DESIGN Three stabilized cell lines and primary cultures of anaplastic thyroid cancer were treated with various histone deacetylase inhibitors. After treatment, we evaluated histone acetylation by Western blotting and E-cadherin expression by RT-real time PCR. The proper localization of E-cadherin/β-catenin complex was assessed by immunofluorescence and Western blot. Transcription activity of β-catenin was measured by luciferase reporter gene and cyclin D1 expression. The effect on cell motility and invasion was studied both in vitro using scratch-wound and transwell invasion assays and in anaplastic thyroid carcinomas tumor xenografts in mice in vivo. RESULTS Histone deacetylase inhibition induced the E-cadherin expression and the proper membrane localization of the E-cadherin/β-catenin complex, leading to reduced cancer cell migration and invasion. CONCLUSIONS We here demonstrate an additional molecular mechanism for the anticancer effect of histone deacetylase inhibition. The antiinvasive effect in addition to the cytotoxic activity of histone deacetylase inhibitors opens up therapeutic perspectives for the anaplastic thyroid tumor that does not respond to conventional therapy.
The natural history of subclinical hypothyroidism in the elderly: the cardiovascular health study.

CONTEXT Studies of long-term outcomes of subclinical hypothyroidism have assessed only baseline thyroid function, despite natural transitions to euthyroidism and overt hypothyroidism over time. OBJECTIVE We provide estimates of persistence, resolution, and progression of subclinical hypothyroidism over 4 yr, stratified by baseline TSH, anti-thyroid peroxidase antibody (TPOAb) status, age, and sex. DESIGN, SETTING, AND PARTICIPANTS Participants were 3996 U.S. individuals at least 65 yr old enrolled in the Cardiovascular Health Study. Subclinical hypothyroidism was detected at baseline in 459 individuals not taking thyroid medication. MAIN OUTCOME MEASURE Thyroid function was evaluated at 2 and 4 yr and initiation of thyroid medication annually. Results were stratified by baseline TSH, TPOAb status, age, and sex. RESULTS Persistence of subclinical hypothyroidism was 56% at 2 and 4 yr. At 2 yr, resolution was more common with a TSH of 4.5-6.9 mU/liter (46 vs. 10% with TSH 7-9.9 mU/liter and 7% with TSH ≥10 mU/liter; P < 0.001) and with TPOAb negativity (48 vs. 15% for positive; P < 0.001). Higher TSH and TPOAb positivity were independently associated with lower likelihood of reversion to euthyroidism (P < 0.05). TSH of 10 mU/liter or higher was independently associated with progression to overt hypothyroidism (P < 0.05). Transitions between euthyroidism and subclinical hypothyroidism were common between 2 and 4 yr. Age and sex did not affect transitions. CONCLUSIONS Subclinical hypothyroidism persists for 4 yr in just over half of older individuals, with high rates of reversion to euthyroidism in individuals with lower TSH concentrations and TPOAb negativity. Future studies should examine the impact of transitions in thyroid status on clinical outcomes.
Circulating microRNA profiles as potential biomarkers for diagnosis of papillary thyroid carcinoma.

CONTEXT There are no known effective and reliable biomarkers to distinguish benign thyroid nodules from papillary thyroid carcinomas (PTC). Previous studies have indicated that serum microRNA (miRNA) profiles may be diagnostic and/or prognostic markers for numerous other cancers. OBJECTIVE We studied circulating miRNA profiles in patients with PTC or benign nodules and healthy controls to identify serum miRNA that may be useful as markers for PTC. DESIGN, SETTING, AND PARTICIPANTS Genome-wide serum miRNA expression profiles were determined using Solexa sequencing followed by extensive quantitative RT-PCR validation in 245 subjects (106 patients with PTC, 95 patients with benign nodules, and 44 healthy controls). A panel of miRNA was used to assess the expression of specific miRNA in the sera and thyroid tissues of patients with PTC or benign nodules. RESULTS The expression of serum let-7e, miR-151-5p, and miR-222 was significantly increased in PTC cases relative to benign cases and healthy controls. Receiver operating characteristic curve analyses indicated that use of these three miRNA had a high diagnostic sensitivity and specificity for PTC. Serum let-7e, miR-151-5p, and miR-222 levels were found to be well correlated with certain clinicopathological variables, such as nodal status, tumor size, multifocal lesion status, and Tumor-Node-Metastasis stage. Expression of serum miR-151-5p and miR-222 in a subset of PTC patients decreased significantly after tumor excision. Increased expression of miR-151-5p and miR-222 was also found in the tissue of PTC patients. CONCLUSIONS Our study demonstrates that serum miRNA profiles may be used as novel and minimally invasive diagnostic markers for PTC.
Serum sclerostin and risk of hip fracture in older Caucasian women.

CONTEXT Sclerostin, a protein secreted by osteocytes, inhibits bone formation. Individuals with genetic mutations that decrease the availability of sclerostin have very high bone mass. OBJECTIVE The aim of this study was to examine the hypothesis that elevated serum sclerostin levels are associated with increased risk of hip fracture in older women. DESIGN, SETTING, AND PARTICIPANTS This was a case-cohort study of a prospective, community-based cohort of 9704 women aged 65 yr or older. Sclerostin levels were measured in serum collected in 1989-1990 in 228 women with incident hip fractures and 227 women in a randomly selected sample; average follow-up time was 9.8 yr. RESULTS Serum sclerostin levels were correlated with total hip bone mineral density (BMD; r = 0.27, P < 0.001). The risk of hip fracture increased across quartiles of serum sclerostin (test for trend, P < 0.001) and was significantly elevated among those in the fourth quartile (hazard risk 3.4, 95% confidence interval 1.7-7.0) compared with women in the lowest quartile, after adjusting for age, body mass index, estrogen use, history of fracture since age 50 yr, and total hip BMD. When dividing the cohort into eight groups by sclerostin quartile and median hip BMD, women with lower total hip BMD in the highest sclerostin quartile had a 22.3-fold (95% confidence interval 5.8-86.3) increased risk of fracture compared with women with higher total hip BMD in the lowest sclerostin quartile. CONCLUSIONS We conclude that higher serum sclerostin levels are associated with a greater risk of hip fractures in older women. In addition, the risk of hip fracture is amplified when high sclerostin levels are combined with lower BMD.
Anti‐leukaemic effects induced by APR‐246 are dependent on induction of oxidative stress and the NFE2L2/HMOX1 axis that can be targeted by PI3K and mTOR inhibitors in acute myeloid leukaemia cells

The small molecule APR‐246 (PRIMA‐1MET) is a novel drug that restores the activity of mutated and unfolded TP53 protein. However, the mechanisms of action and potential off‐target effects are not fully understood. Gene expression profiling in TP53 mutant KMB3 acute myeloid leukaemia (AML) cells showed that genes which protected cells from oxidative stress to be the most up‐regulated. APR‐246 exposure also induced reactive oxygen species (ROS) formation and depleted glutathione in AML cells. The genes most up‐regulated by APR‐246, confirmed by quantitative real time polymerase chain reaction, were heme oxygenase‐1 (HMOX1, also termed HO‐1), SLC7A11 and RIT1. Up‐regulation of HMOX1, a key regulator of cellular response to ROS, was independent of TP53 mutational status. NFE2L2 (also termed Nrf2), a master regulator of HMOX1 expression, showed transcriptional up‐regulation and nuclear translocation by APR‐246. Down‐regulation of NFE2L2 by siRNA in AML cells significantly increased the antitumoural effects of APR‐246. The PI3K inhibitor wortmannin and the mTOR inhibitor rapamycin inhibited APR‐246‐induced nuclear translocation of NFE2L2 and counteracted the protective cellular responses to APR‐246, resulting in synergistic cell killing together with APR‐246. In conclusion, ROS induction is important for antileukaemic activities of APR‐246 and inhibiting the protective response of the Nrf‐2/HMOX1 axis using PI3K inhibitors, enhances the antileukaemic effects.
A phase 2 study of inotuzumab ozogamicin in patients with indolent B‐cell non‐Hodgkin lymphoma refractory to rituximab alone, rituximab and chemotherapy, or radioimmunotherapy

This phase 2 study evaluated the efficacy and safety of inotuzumab ozogamicin (InO) in patients with indolent B‐cell non‐Hodgkin lymphoma (NHL) refractory to rituximab alone, rituximab plus chemotherapy or anti‐CD20 radioimmunotherapy. Patients received InO 1·8 mg/m2 intravenously on a 28‐d cycle for a planned 4–8 cycles. The initial InO dose and schedule could be adjusted for tolerability and patients were allowed to receive 2 additional cycles (up to 8 total) after achieving a complete response (CR). The primary endpoint was overall response. Eighty‐one patients were enrolled, among whom 48 (59%) received ≥3 InO cycles and 13 (16%) completed the treatment phase. The overall response rate was 67% (CR, 31%). Median (95% confidence interval) progression‐free survival was 12·7 (8·9–26·9) months; median overall survival was not reached. Haematological adverse events (AEs) were common, particularly thrombocytopenia (74%) and neutropenia (56%). These were also the most common AEs leading to treatment discontinuation (37% and 11%, respectively); 58% of patients reported AEs leading to treatment discontinuation. InO demonstrated robust activity in these heavily pretreated patients, although treatment duration was limited by haematological toxicities. Additional studies may determine dosing regimens that allow for reduced toxicity.
Spreading depolarization, a pathophysiological mechanism of stroke and migraine aura

Spreading depolarization is a mechanism of abrupt, massive ion translocation between intraneuronal and extracellular space that entails cytotoxic edema in the brain’s gray matter. It is observed in patients as a large change of the slow electrical potential. Dependent on the energy status of the tissue, spreading depolarization is either preceded by nonspreading silencing due to neuronal hyperpolarization or accompanied by spreading silencing of electrical brain activity due to a depolarization block. Nonspreading silencing seems to translate into the initial clinical symptoms of ischemic stroke and spreading silencing translates into migraine aura. Direct electrophysiological evidence exists that spreading depolarization occurs in abundance in aneurysmal subarachnoid hemorrhage, delayed ischemic stroke after subarachnoid hemorrhage, malignant hemispheric stroke, spontaneous intracerebral hemorrhage and traumatic brain injury. Indirect evidence suggests its occurrence during migraine aura. In animals, spr.
Amoxicillin for non-severe pneumonia in young children:Authors' reply

EDITOR—The need for newer antibiotics must be addressed, but we disagree with Wrennall's other points. Our study was in a low resource setting to identify strategies for improving child health. Data on the appropriate duration of antibiotic treatment for pneumonia in children are scarce. Inappropriate use of antibiotics and increasing antimicrobial resistance are major public health problems. We believe that our results can be applied to a broader population. Our indicators of treatment failure were stringent. Cases were classified as failed if pulse oximetry results were < 90% on day 3, even if a patient's respiratory …
The Effect of &agr;2 Agonist-Induced Sedation and Its Reversal with an &agr;2 Antagonist on Organ Blood Flow in Sheep

We investigated changes in cardiac output and organ blood flow induced by medetomidine in sheep and determined changes in cardiac output and organ blood flow after reversal of medetomidine-induced sedation by atipamezole. Eight sheep were chronically instrumented. Medetomidine was infused IV to target plasma levels of 0, 0.8, 1.6, 3.2, 6.4, and 12.8 ng/mL for 25 min each, followed by a 5-min infusion of atipamezole. Hemodynamic values and organ blood flow (using colored microspheres) were measured just before medetomidine infusion (baseline), at the end of each medetomidine infusion step, and 30 min after the administration of atipamezole. Medetomidine (12.8 ng/mL) decreased cardiac output from 6.3 ± 1.0 to 3.2 ± 0.7 L/min (P < 0.0001) and increased systemic vascular resistance from 1310 ± 207 to 3467 ± 1299 dynes · s−1 · cm−5 (P < 0.0001). Blood flow decreased in the cerebral cortex from 1.29 ± 0.40 to 0.66 ± 0.12 mL · g−1 · min−1 (P < 0.0001), left ventricle from 2.11 ± 0.61 to 1.40 ± 0.40 mL · g−1 · min−1 (P < 0.0001), kidney from 8.28 ± 3.17 to 6.07 ± 2.65 mL · g−1 · min−1 (P < 0.0001), skin from 0.09 ± 0.04 to 0.05 ± 0.02 mL · g−1 · min−1 (P < 0.0001), intestine from 0.56 ± 0.13 to 0.27 ± 0.07 mL · g−1 · min−1 (P < 0.0001), and skeletal muscle from 0.28 ± 0.15 to 0.04 ± 0.01 mL · g−1 · min−1 (P < 0.0001). Blood flow in the liver (hepatic artery) increased from 0.05 ± 0.03 to 0.24 ± 0.16 mL · g−1 · min−1 (P < 0.0001). After atipamezole infusion, cardiac output and systemic vascular resistance returned to baseline, but the cerebral cortex, left ventricle, and renal blood flows remained below baseline at 0.89 ± 0.22, 1.37 ± 0.50, and 6.25 ± 2.76 mL · g−1 · min−1, respectively; skeletal muscle blood flow increased above baseline to 0.44 ± 0.27 mL · g−1 · min−1, spleen blood flow decreased below baseline to 1.65 ± 0.61 mL · g−1 · min−1 (P < 0.0001), and liver, intestine, and lung blood flows returned to baseline values. In conclusion, medetomidine decreased and redistributed organ blood flow in sheep. Atipamezole reversed the medetomidine-induced hemodynamic changes, but redistributed blood flow from the brain, heart, and kidney to the skeletal muscle. Implications The &agr;2 agonist, medetomidine, decreased and redistributed organ blood flow in sheep. Although the highly selective &agr;2 antagonist, atipamezole, reversed medetomidine-induced hemodynamic changes, blood flow to the heart and kidney rmeoaned significantly depressed, whereas skeletal muscle blood flow increased to twice baseline values.
Identification of somatic mutations in parathyroid tumors using whole-exome sequencing.

CONTEXT The underlying molecular alterations causing sporadic parathyroid adenomas that drive primary hyperparathyroidism have not been thoroughly defined. OBJECTIVE The aim of the study was to investigate the occurrence of somatic mutations driving tumor formation and progression in sporadic parathyroid adenoma using whole-exome sequencing. DESIGN Eight matched tumor-constitutional DNA pairs from patients with sporadic parathyroid adenomas underwent whole-exome capture and high-throughput sequencing. Selected genes were analyzed for mutations in an additional 185 parathyroid adenomas. RESULTS Four of eight tumors displayed a frame shift deletion or nonsense mutation in MEN1, which was accompanied by loss of heterozygosity of the remaining wild-type allele. No other mutated genes were shared among the eight tumors. One tumor harbored a Y641N mutation of the histone methyltransferase EZH2 gene, previously linked to myeloid and lymphoid malignancy formation. Targeted sequencing in the additional 185 parathyroid adenomas revealed a high rate of MEN1 mutations (35%). Furthermore, this targeted sequencing identified an additional parathyroid adenoma that contained the identical, somatic EZH2 mutation that was found by exome sequencing. CONCLUSION This study confirms the frequent role of the loss of heterozygosity of chromosome 11 and MEN1 gene alterations in sporadic parathyroid adenomas and implicates a previously unassociated methyltransferase gene, EZH2, in endocrine tumorigenesis.
Systematic review of the relationships between objectively measured physical activity and health indicators in school-aged children and youth.

Moderate-to-vigorous physical activity (MVPA) is essential for disease prevention and health promotion. Emerging evidence suggests other intensities of physical activity (PA), including light-intensity activity (LPA), may also be important, but there has been no rigorous evaluation of the evidence. The purpose of this systematic review was to examine the relationships between objectively measured PA (total and all intensities) and health indicators in school-aged children and youth. Online databases were searched for peer-reviewed studies that met the a priori inclusion criteria: population (apparently healthy, aged 5-17 years), intervention/exposure/comparator (volumes, durations, frequencies, intensities, and patterns of objectively measured PA), and outcome (body composition, cardiometabolic biomarkers, physical fitness, behavioural conduct/pro-social behaviour, cognition/academic achievement, quality of life/well-being, harms, bone health, motor skill development, psychological distress, self-esteem). Heterogeneity among studies precluded meta-analyses; narrative synthesis was conducted. A total of 162 studies were included (204 171 participants from 31 countries). Overall, total PA was favourably associated with physical, psychological/social, and cognitive health indicators. Relationships were more consistent and robust for higher (e.g., MVPA) versus lower (e.g., LPA) intensity PA. All patterns of activity (sporadic, bouts, continuous) provided benefit. LPA was favourably associated with cardiometabolic biomarkers; data were scarce for other outcomes. These findings continue to support the importance of at least 60 min/day of MVPA for disease prevention and health promotion in children and youth, but also highlight the potential benefits of LPA and total PA. All intensities of PA should be considered in future work aimed at better elucidating the health benefits of PA in children and youth.
Biological variability of plasma intact and C-terminal FGF23 measurements.

CONTEXT FGF23 measurement may have a role in the management of patients with chronic kidney disease (CKD). OBJECTIVE Our objective was to study the biological variability of plasma intact FGF23 (iFGF23) and C-terminal FGF23 (cFGF23) concentrations. DESIGN Plasma samples were taken from 12 healthy adults at multiple time points on 2 consecutive days to assess diurnal variability of FGF23 concentrations. Early-morning fasting and nonfasting samples were also taken over a 6-wk period to estimate components of biological variation. Samples from 170 volunteers were used to define reference intervals. FGF23 concentrations were measured by commercial ELISA. Western blotting was used to analyze FGF23 species from the plasma of healthy adults and patients with predialysis CKD and those undergoing dialysis. PARTICIPANTS AND SETTING A total of 180 healthy adults and 18 adults with stage 3-5D CKD participated in this study at a hospital research unit. MAIN OUTCOME MEASURE Estimates were made of the biological variability of plasma FGF23 concentrations. RESULTS iFGF23, but not cFGF23, showed significant diurnal variation. cFGF23 had a significantly lower intra-individual variation than iFGF23 (8.3 vs. 18.3%) but higher inter-individual variation than iFGF23 (28.9 vs. 19.2%). Fourteen samples would be needed to estimate an individual's homeostatic set point (within 10%) for iFGF23 compared with only three samples for cFGF23. Using Western blotting, C-terminal FGF23 fragments were detected in the plasma of individuals with normal renal function and at all stages of renal disease. The percent cFGF23 was significantly higher in those without renal impairment (P < 0.001) and was positively correlated with plasma phosphate concentration in those with normal renal function. CONCLUSIONS The high intra-individual biological variability of iFGF23 may limit its clinical use as a diagnostic or management tool. Risk-related thresholds may be more appropriate for clinical decision making based on cFGF23 measurements than conventional reference intervals. FGF23 cleavage pathways may be an important natural regulatory mechanism for phosphate control.
Fatores de risco cardiovascular em adolescentes: prevalência e associação com fatores sociodemográficos

OBJETIVOS: Determinar a prevalencia de fatores de risco cardiovascular (individual e co-ocorrencia); e investigar a relacao entre esses fatores e indicadores sociodemograficos em adolescentes. METODOS: A amostra, selecionada por conglomerados em dois estagios (escolas, turmas), foi constituida de 782 adolescentes (14-17 anos de idade, 54,9% do sexo feminino) do ensino medio no municipio de Joao Pessoa - PB, Brasil. As variaveis independentes foram sexo, idade e condicao economica. Os desfechos investigados foram: niveis insuficientes de atividade fisica, habitos alimentares inadequados, pressao arterial elevada, etilismo, excesso de peso corporal e tabagismo. RESULTADOS: Niveis insuficientes de atividade fisica (59,5%) e habitos alimentares inadequados (49,5%) foram os fatores de risco cardiovascular mais prevalentes. Pressao arterial elevada, etilismo e excesso de peso foram mais prevalentes no sexo masculino, e niveis insuficientes de atividade fisica no sexo feminino. Cerca de 10% dos adolescentes nao apresentaram nenhum fator de risco, e 51,4% apresentaram dois ou mais fatores de forma simultânea. Os adolescentes do sexo masculino (OR = 1,89; 1,35 - 2,65) e aqueles que pertenciam aos estratos economicos mais pobres tiveram maiores chances de apresentar um ou mais fatores de risco biologicos (OR = 1,69; IC95% = 1,16 - 2,47). CONCLUSAO: A prevalencia de fatores de risco cardiovascular foi elevada, com destaque para a exposicao simultânea a multiplos fatores de risco. Os adolescentes do sexo masculino e os mais pobres foram os subgrupos com maior exposicao a fatores de risco biologicos de forma simultânea.