Appetitive traits from childhood to adolescence: Analysis of their stability, derivation of trajectory profiles, and associated characteristics.

This study aimed to assess the potential stability of appetitive traits from childhood to early adolescence, identify groups of individuals with distinct trajectories for these traits, and explore their association with other child and family characteristics. Participants were 5040 children from the Generation XXI cohort. Appetitive traits were assessed with the Children's Eating Behaviour Questionnaire (CEBQ) at ages seven, 10, and 13 (eight subscales). Mixed-effect models estimated individual trajectories of appetitive traits and Gaussian mixture models identified groups following different trajectories (appetitive trait trajectory profiles). Appetitive traits showed moderate-to-high stability across the three ages (intra-class correlation coefficients:0.66-0.83); most of the variance observed across time were due to persistent individual differences rather than age-related changes. Six appetitive trait trajectory profiles were identified: 'Moderate appetite' (scores close to the average) (29% of children), 'Small to moderate appetite' (lowest food approach and emotional eating) (26%), 'Increasing appetite' (increasing food approach) (15%), 'Avid appetite' (highest food approach and lowest food avoidance) (12%), 'Smallest appetite' (highest food avoidance and low food approach) (10%), and 'Small appetite but increasing' (decreasing high food avoidance and Desire to Drink) (8%). In multinomial logistic regression, these profiles were associated with different child and family characteristics. Compared to children with a 'Moderate appetite' profile, those with higher BMI, who desired a thinner body, whose mothers were younger, had lower education, higher pre-pregnancy BMI (OR = 1.07; 95%CI:1.04,1.09), smoked during pregnancy (OR = 1.51; 95%CI:1.21,1.90), and used more restrictive feeding practices (OR = 1.79; 95%CI:1.57,2.03) had increased odds of belonging to the 'Avid Appetite'. In conclusion, distinct appetitive trait trajectory profiles emerged, differentiating individuals with avid and small appetites. These findings have implications for identifying children at higher risk for obesogenic profiles.

Sleep duration is associated with appetitive traits in school-age years - results from the Generation XXI birth cohort.

Sleep may influence appetite regulation through physiological and neurocognitive pathways. However, the association between sleep and appetite in childhood has been scarcely reported, particularly using a prospective design. We aimed to test associations between sleep duration at 7 years of age (y) and appetitive traits at both 7 and 10 y. Participants are from the population-based birth cohort Generation XXI (Porto, Portugal), at 7 (n = 2437) and 10 y (n = 1938) follow-ups. Data on sleep was gathered at 7 y and, considering bedtime and get-up time, total mean sleep duration was calculated and further categorized according to the 10th and 90th percentiles. Appetitive traits were assessed at 7 and 10 y using the parent-reported Children's Eating Behaviour Questionnaire. Associations were tested through Generalized Linear Models (co-variates: child's sex; maternal age, education and pre-pregnancy body mass index at 7 y). At 10 y, associations were further adjusted for the respective appetitive trait at 7 y. Children slept a mean of 10.2 h/night, and 13% and 9% slept ≤9.5 and ≥ 11.0 h/night at 7 y, respectively. For each additional hour in sleep duration, children scored 0.078 (99%CI: -0.145; -0.011) lower on Food Responsiveness, 0.065 (99%CI: -0.129; -0.002) lower on Emotional Undereating and 0.096 (99%CI: -0.161; -0.032) lower on Food Fussiness. Lastly, children sleeping ≤9.5 h/night scored higher on Food Responsiveness (ß = 0.145 99%CI: 0.020; 0.271); while those sleeping ≥11.0 h/night scored lower on Food Fussiness (ß = -0.255 99%CI: -0.370; -0.079). No significant prospective associations were found. In conclusion, in 7 y children, sleep duration was cross-sectionally associated with lower scores on food approach (Food Responsiveness) and avoidant traits (Emotional Undereating and Food Fussiness). However, the magnitude of the associations was small and further studies are warranted.

Molecular Docking and GC/MS-Based Approach for Identification of Anxiolytic Alkaloids from Griffinia (Amaryllidaceae) Species in a Zebrafish Model.

Griffinia gardneriana Ravenna, Griffinia liboniana Morren and Griffinia nocturna Ravenna (Amarillydaceae) are bulbous plants found in tropical regions of Brazil. Our work aimed to determine the alkaloid profiles of Griffinia spp. and evaluate their anxiolytic potential through in vivo and in silico assays. The plants grown in greenhouses were dried and their ground bulbs were subjected to liquid-liquid partitions, resulting in alkaloid fractions that were analyzed by gas chromatography coupled to mass spectrometry (GC-MS). Anxiolytic activity was evaluated in zebrafish (Danio rerio) through intraperitoneal injection at doses of 40, 100 and 200 mg/kg in light-dark box test. GC-MS analyses revealed 23 alkaloids belonging to different skeleton types: lycorine, homolychorine, galanthamine, crinine, haemanthamine, montanine and narcisclasine. The chemical profiles were relatively similar, presenting 8 alkaloids common to the three species. The major component for G. gardneriana and G. liboniana was lycorine, while G. nocturna consisted mainly of anhydrolycorine. All three alkaloid fractions demonstrated anxiolytic effect. Furthermore, pre-treatment with diazepam and pizotifen drugs was able to reverse the anxiolytic action, indicating involving the GABAergic and serotonergic receptors. Molecular docking showed that the compounds vittatine, lycorine and 11,12-dehydro-2-methoxyassoanine had high affinity with both receptors, suggesting them to be responsible for the anxiolytic effect.

The impact of inorganic fillers, organic content, and polymerization mode on the degree of conversion of monomers in resin-matrix cements for restorative dentistry: a scoping review.

PURPOSE: The main aim of the present study was to carry out a scoping review on the differences in degree of conversion of monomers regarding several types resin cements, indirect restorative materials, and light-curing procedures used in dentistry. METHOD: A bibliographic review was performed on PubMed using the following search items: "degree of conversion" OR "filler" AND "resin cement" OR "inorganic cement" AND "organic" OR "radiopacity" OR "refractive" OR "transmittance" OR "type" AND "resin composite." The search involved articles published in English language within the last thirteen years. A research question has been formulated following the PICO approach as follow: "How different is the degree of conversion of monomers comparing several types of resin-matrix cements?". RESULTS: Within the 15 selected studies, 8 studies reported a high degree of conversion (DC) of the organic matrix ranging from 70 up to 90% while 7 studies showed lower DC values. Dual-cured resin-matrix cements revealed the highest mean values of DC, flexural strength, and hardness when compared with light- and self-polymerized ones. DC mean values of resin-matrix cements light-cured through a ceramic veneer with 0.4 mm thickness were higher (~ 83%) than those recorded for resin-matrix cements light-cured through a thicker ceramic layer of 1.5 mm (~ 77%). CONCLUSIONS: The highest percentage of degree of conversion of monomers was reported for dual-cured resin-matrix cements and therefore both chemical and light-induced pathways promoted an enhanced polymerization of the material. Similar degree of conversion of the same resin-matrix cement were recorded when the prosthetic structure showed a low thickness. On thick prosthetic structures, translucent materials are required to allow the light transmission achieving the resin-matrix cement. CLINICAL RELEVANCE: The chemical composition of resin-matrix cements and the light-curing mode can affect the polymerization of the organic matrix. Thus, physical properties of the materials can vary leading to early clinical failures at restorative interfaces. Thus, the analysis of the polymerization pathways of resin-matrix cements is significantly beneficial for the clinical performance of the restorative interfaces.

An Assessment of the Effectiveness and Safety of Chimeric Antigen Receptor T-Cell Therapy in Multiple Myeloma Patients with Relapsed or Refractory Disease: A Systematic Review and Meta-Analysis.

Multiple myeloma (MM), the second most common hematologic malignancy, remains incurable, and its incidence is rising. Chimeric Antigen Receptor T-cell (CAR-T cell) therapy has emerged as a novel treatment, with the potential to improve the survival and quality of life of patients with relapsed/refractory multiple myeloma (rrMM). In this systematic review and meta-analysis, conducted in accordance with PRISMA guidelines, we aim to provide a concise overview of the latest developments in CAR-T therapy, assess their potential implications for clinical practice, and evaluate their efficacy and safety outcomes based on the most up-to-date evidence. A literature search conducted from 1 January 2019 to 12 July 2023 on Medline/PubMed, Scopus, and Web of Science identified 2273 articles, of which 29 fulfilled the specified criteria for inclusion. Our results offer robust evidence supporting CAR-T cell therapy's efficacy in rrMM patients, with an encouraging 83.21% overall response rate (ORR). A generally safe profile was observed, with grade ≥ 3 cytokine release syndrome (CRS) at 7.12% and grade ≥ 3 neurotoxicity at 1.37%. A subgroup analysis revealed a significantly increased ORR in patients with fewer antimyeloma regimens, while grade ≥ 3 CRS was more common in those with a higher proportion of high-risk cytogenetics and prior exposure to BCMA therapy.

Intermittent high-intensity exercise for pre- to established hypertension: A systematic review and meta-analysis.

OBJECTIVE: To determine the impact of intermittent high-intensity exercise training ([IHIE], including high-intensity interval training [HIIT] and recreational team sports [RTS]) on systolic (SBP) and diastolic blood pressure (DBP) in adults with pre- to established arterial hypertension. DATA SOURCES: MEDLINE, Cochrane Library, Embase, and SPORTDiscus. ELIGIBILITY CRITERIA: Randomized controlled trials (RCTs) comparing the impact of IHIE on BP versus a non-exercise control. DATA COLLECTION AND ANALYSIS: Two authors independently conducted all procedures. Mean differences were calculated using random-effects model. The certainty of the evidence was assessed with GRADE. RESULTS: Twenty-seven RCTs (18 HIIT and 9 RTS) were analyzed, with median duration of 12 weeks. Participants' (n = 946) median age was 46 years. Overall, IHIE decreased SBP (-3.29 mmHg; 95% CI: -5.19, -1.39) and DBP (-2.62 mmHg; 95% CI: -3.79, -1.44) compared to the control group. IHIE elicited higher decreases in office SBP and DBP of hypertensive subjects (SBP: -7.13 mmHg, [95% CI: -10.12, -4.15]; DBP: -5.81 mmHg, [95% CI: -7.94, -3.69]) than pre-hypertensive (SBP: -2.14 mmHg, [95% CI: -4.36, -0.08]; DBP: -1.83 mmHg, [95% CI: -2.99, -0.67]). No significant differences were found between HIIT (SBP: -2.12 mmHg, [95% CI: -4.78, -0.54]; DBP: -1.89 mmHg, [95% CI: -3.32, -0.48]) and RTS (SBP: -4.18 mmHg, [95% CI: -7.19, -2.43]; DBP: -4.04 mmHg, [95% CI: -6.00, -2.09]). These findings present low/very low certainty of evidence. No adverse cardiovascular events were reported. CONCLUSIONS: IHIE appears to be safe and to promote substantial decreases in BP, particularly in patients with hypertension. However, the certainty of evidence was low/very low. PROTOCOL: CRD42020163575.

In vitro anthelmintic activity of Lippia alba essential oil chemotypes against Haemonchus contortus.

The aim of the present study was to evaluate the effects of the essential oils of Lippia alba chemotypes carvone and citral on H. contortus. Chemical characterization was performed by means of gas chromatography coupled to mass spectrometry (GC/MS). The anthelmintic effects of the essential oils were assessed through the egg hatch test (EHT) and the adult worm motility test (AWMT) using a multidrug-resistant H. contortus Kokstad isolate. Confocal laser scanning microscopy (CLSM) of eggs and adults of H. contortus and scanning electron microscopy (SEM) of adults were performed after treatment with oils for qualitative observations of their effects. The carvone chemotype of L. alba (LaCV) presented 70% carvone, and the citral chemotype of L. alba (LaCT) presented 29.4% geranial and 20.4% neral, respectively. In the EHT, the EC50 values of LaCV and LaCT were 0.2 and 0.3 mg/mL, respectively. In AWMT, after 12 h of exposure to 2 mg/mL LaCV and 2 mg/mL LaCT, 100% of adult nematodes were immobile. CLSM showed changes in larval motility inside the egg caused by LaCV, while LaCT promoted changes in larval formation. In adults exposed to both chemotypes, alterations in the anterior portion of the oesophagus were observed. In SEM, morphological changes were observed in the buccal capsule and in the medial portion of H. contortus adults. It is concluded that the two essential oils of L. alba, the chemotypes carvone and citral, caused morphological changes and inhibited the hatching of eggs and the motility of adult H. contortus nematodes.

Statistical heterogeneity in meta-analysis of hypertension and exercise training: A meta-review.

We aim to evaluate the prevalence of reporting and the extent of statistical heterogeneity of systematic reviews with meta-analyses (SRMAs) of exercise training for hypertension and to provide practical recommendations for dealing with statistical heterogeneity. We systematically searched on four databases (from 2002 to September of 2023) for SRMAs comparing exercise interventions vs. a non-exercise control on blood pressure (BP) control in adults with hypertension. Fifty-nine SRMAs, with a median of 14 studies, were analysed. Cochran's Q (41%), I2 (24%), forest plots (44%), and particularly τ2 (54%) and prediction intervals (96.6%) frequently were not reported for the hypertension subgroup. The recalculated prediction intervals were discrepant (i.e., crossed the null effect) of significant 95% confidence intervals of most meta-analyses (systolic BP: 65%; diastolic BP: 92%). This suggests substantial heterogeneity across studies, which was often not acknowledged by authors' conclusions (78%). Consequently, downgrading the certainty of the available evidence may be justified alone due to heterogeneity across studies. Finally, we illustrate areas for improving I2 interpretation and provide practical recommendations on how to address statistical heterogeneity across all stages of a SRMA.

Recreational futsal provides broad-spectrum fitness and health benefits but no blood pressure effects in men with treated hypertension - a randomised controlled trial.

We determined the coadjuvant effect of a recreational futsal (RF) programme versus standard care alone (CON) in men with treated arterial hypertension (TAHT). Thirty-nine men with TAHT were randomised to RF (N = 20; 48 ± 8 years; systolic blood pressure [SBP]: 122 ± 14 mmHg) with 2-3 one-hour sessions/week for 3 months, or to CON (N = 19; 51 ± 6 years; SBP: 126 ± 13 mmHg). Participants were assessed at baseline, at 3 months, and after 1 month of training cessation (4 months). Mean training attendance was 60 ± 23%. At 3-months, there were no between-group differences in BP parameters (SBP: 0.44 mmHg; 95% CI: -5.79, 6.67). However, compared to CON, RF was effective for peak oxygen uptake (2.76 mL.min-1.kg-1; 95% CI: 0.26, 5.26), time to exhaustion (1.15 min; 95% CI: 0.59, 1.69), Yo-Yo IE1 performance (365 m; 95% CI: 175, 556), resting heart rate (RHR; -5 b.min-1; 95% CI: -10, -1), glycated haemoglobin (-0.52 mmol/L; 95% CI: -0.84, -0.19), blood glucose (-0.25 mmol/L; 95% CI: -0.44, -0.06), left femur bone mineral content (1.96 g; 95% CI: 0.29, 3.65), and postural balance (-2.3 falls; 95% CI: -3.9, -0.6). Similar findings were observed after 1-month of training cessation, except for RHR and blood glucose that returned to baseline levels in the RF group. In conclusion, RF provides broad-spectrum fitness and health benefits but no BP effects in men with TAHT.

Effect of inorganic fillers on the light transmission through traditional or flowable resin-matrix composites for restorative dentistry.

OBJECTIVES: The aim of this in vitro study was to evaluate the light transmission through five different resin-matrix composites regarding the inorganic filler content. METHODS: Resin-matrix composite disc-shaped specimens were prepared on glass molds. Three traditional resin-matrix composites contained inorganic fillers at 74, 80, and 89 wt. % while two flowable composites revealed 60 and 62.5 wt. % inorganic fillers. Light transmission through the resin-matrix composites was assessed using a spectrophotometer with an integrated monochromator before and after light curing for 10, 20, or 40s. Elastic modulus and nanohardness were evaluated through nanoindentation's tests, while Vicker's hardness was measured by micro-hardness assessment. Chemical analyses were performed by FTIR and EDS, while microstructural analysis was conducted by optical microscopy and scanning electron microscopy. Data were evaluated using two-way ANOVA and Tukey's test (p < 0.05). RESULTS: After polymerization, optical transmittance increased for all specimens above 650-nm wavelength irradiation since higher light exposure time leads to increased light transmittance. At 20- or 40-s irradiation, similar light transmittance was recorded for resin composites with 60, 62, 74, or 78-80 wt. % inorganic fillers. The lowest light transmittance was recorded for a resin-matrix composite reinforced with 89 wt. % inorganic fillers. Thus, the size of inorganic fillers ranged from nano- up to micro-scale dimensions and the high content of micro-scale inorganic particles can change the light pathway and decrease the light transmittance through the materials. At 850-nm wavelength, the average ratio between polymerized and non-polymerized specimens increased by 1.6 times for the resin composite with 89 wt. % fillers, while the composites with 60 wt. % fillers revealed an increased ratio by 3.5 times higher than that recorded at 600-nm wavelength. High mean values of elastic modulus, nano-hardness, and micro-hardness were recorded for the resin-matrix composites with the highest inorganic content. CONCLUSIONS: A high content of inorganic fillers at 89 wt.% decreased the light transmission through resin-matrix composites. However, certain types of fillers do not interfere on the light transmission, maintaining an optimal polymerization and the physical properties of the resin-matrix composites. CLINICAL SIGNIFICANCE: The type and content of inorganic fillers in the chemical composition of resin-matrix composites do affect their polymerization mode. As a consequence, the clinical performance of resin-matrix composites can be compromised, leading to variable physical properties and degradation.

Toxicity of resin-matrix cements in contact with fibroblast or mesenchymal cells.

The main aim of this study was to perform an integrative review on the toxic effects of resin-matrix cements and their products in contact with fibroblasts or mesenchymal cells. A bibliographic search was performed on PubMed using the following search terms: "cytotoxicity" AND "fibroblast" OR "epithelial" OR "mesenchymal" AND "polymerization" OR "degree of conversion" OR "methacrylate" OR "monomer" AND "resin cement" OR "resin-based cement". The initial search in the available database yielded a total of 277 articles of which 21 articles were included in this review. A decrease in the viability of mouse fibroblasts ranged between 13 and 15% that was recorded for different resin-matrix cements after light curing exposure for 20 s. The viability of human fibroblasts was recorded at 83.11% after light curing for 20 s that increased up to 90.9% after light curing exposure for 40 s. Most of the studies linked the highest toxicity levels when the cells were in contact with Bis-GMA followed by UDMA, TEGDMA and HEMA. Resin-matrix cements cause a cytotoxic reaction when in contact with fibroblasts or mesenchymal cells due to the release of monomers from the polymeric matrix. The amount of monomers released from the resin matrix and their cytotoxicity depends on the polymerization parameters.

The influence of inorganic fillers on the light transmission through resin-matrix composites during the light-curing procedure: an integrative review.

PURPOSE: The objective of this study was to perform an integrative review on the effect the inorganic fillers on the light transmission through the resin-matrix composites during the light-curing procedure. METHOD: A bibliographic review was performed on PubMed using the following search terms: "fillers" OR "particle" AND "light curing" OR "polymerization" AND "light transmission" OR "light absorption" OR "light irradiance" OR "light attenuation" OR "light diffusion" AND "resin composite." The search involved articles published in English language in the last 10 years. RESULTS: Selected studies reported a decrease in biaxial strength and hardness in traditional resin-matrix composites in function of the depth of polymerization. However, there were no significant differences in biaxial strength and hardness recorded along the polymerization depth of Bulk-Fill™ composites. Strength and hardness were enhanced by increasing the size and content of inorganic fillers although some studies revealed a progressive decrease in the degree of conversion on increasing silica particle size. The translucency of glass-ceramic spherical fillers promoted light diffusion mainly in critical situations such as in the case of deep proximal regions of resin-matrix composites. CONCLUSIONS: The amount of light transmitted through the resin-matrix composites is influenced by the size, content, microstructure, and shape of the inorganic filler particles. The decrease of the degree of conversion affects negatively the physical and mechanical properties of the resin-matrix composites. CLINICAL RELEVANCE: The type and content of inorganic fillers in the chemical composition of resin-matrix composites do affect their polymerization. As a consequence, the clinical performance of resin-matrix composites can be compromised leading to variable physical properties and degradation. The polymerization mode of resin-matrix composites can be improved according to the type of inorganic fillers in their chemical composition.

Retinal structural changes in preterm children without retinopathy of prematurity.

PURPOSE: The aim of this study was to compare all retinal layers' thickness in full-term and preterm children without retinopathy of prematurity (ROP). METHODS: Cross-sectional study including two groups of patients: group 1 children with history of preterm gestation without ROP (gestational age < 37 weeks) and group 2 healthy children with history of full-term gestation. All subjects underwent an ophthalmic examination including spectral domain-optical coherence tomography. After automatic retinal segmentation, each retinal layer thickness (eight separate layers and overall thickness) was calculated in all nine Early Treatment Diabetic Retinopathy Study areas. Demographic, systemic, gestational, and birth data were collected. Generalized additive regression models were used to analyze the data. RESULTS: Fifty-one children (51 eyes) were recruited, 19 full-term and 32 preterm children, mean age at ophthalmic examination of 10.58 (4.21) and 14.13 (3.16), respectively. In multivariable analysis, the preterm group's retinal thickness was significantly decreased in total retina nasal outer sector, ganglion cell layer (GCL), and inner plexiform layer (IPL), specifically GCL temporal outer (p = 0.010), GCL superior outer (p = 0.009), IPL temporal outer (p = 0.022), and IPL superior outer (p = 0.004), when compared with full-term group. From the variables compared only with birth head circumference that influenced the models, a non-linear association was identified and consequently modeled with splines through a generalized additive model. CONCLUSION: This study suggests that preterm children without ROP have structural retinal alterations, mostly in GCL and IPL in outer areas of the macula. Therefore, it is crucial to question gestational history since these retinal changes may be found later in life leading to useless investigation.

Discovery of a Necroptosis Inhibitor Improving Dopaminergic Neuronal Loss after MPTP Exposure in Mice.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, mainly characterized by motor deficits correlated with progressive dopaminergic neuronal loss in the substantia nigra pars compacta (SN). Necroptosis is a caspase-independent form of regulated cell death mediated by the concerted action of receptor-interacting protein 3 (RIP3) and the pseudokinase mixed lineage domain-like protein (MLKL). It is also usually dependent on RIP1 kinase activity, influenced by further cellular clues. Importantly, necroptosis appears to be strongly linked to several neurodegenerative diseases, including PD. Here, we aimed at identifying novel chemical inhibitors of necroptosis in a PD-mimicking model, by conducting a two-step screening. Firstly, we phenotypically screened a library of 31 small molecules using a cellular model of necroptosis and, thereafter, the hit compound effect was validated in vivo in a sub-acute 1-methyl-1-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) PD-related mouse model. From the initial compounds, we identified one hit-Oxa12-that strongly inhibited necroptosis induced by the pan-caspase inhibitor zVAD-fmk in the BV2 murine microglia cell line. More importantly, mice exposed to MPTP and further treated with Oxa12 showed protection against MPTP-induced dopaminergic neuronal loss in the SN and striatum. In conclusion, we identified Oxa12 as a hit compound that represents a new chemotype to tackle necroptosis. Oxa12 displays in vivo effects, making this compound a drug candidate for further optimization to attenuate PD pathogenesis.

Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial.

BACKGROUND: Metastatic castration-resistant prostate cancer is enriched in DNA damage response (DDR) gene aberrations. The TOPARP-B trial aims to prospectively validate the association between DDR gene aberrations and response to olaparib in metastatic castration-resistant prostate cancer. METHODS: In this open-label, investigator-initiated, randomised phase 2 trial following a selection (or pick-the-winner) design, we recruited participants from 17 UK hospitals. Men aged 18 years or older with progressing metastatic castration-resistant prostate cancer previously treated with one or two taxane chemotherapy regimens and with an Eastern Cooperative Oncology Group performance status of 2 or less had tumour biopsies tested with targeted sequencing. Patients with DDR gene aberrations were randomly assigned (1:1) by a computer-generated minimisation method, with balancing for circulating tumour cell count at screening, to receive 400 mg or 300 mg olaparib twice daily, given continuously in 4-week cycles until disease progression or unacceptable toxicity. Neither participants nor investigators were masked to dose allocation. The primary endpoint of confirmed response was defined as a composite of all patients presenting with any of the following outcomes: radiological objective response (as assessed by Response Evaluation Criteria in Solid Tumors 1.1), a decrease in prostate-specific antigen (PSA) of 50% or more (PSA50) from baseline, or conversion of circulating tumour cell count (from ≥5 cells per 7·5 mL blood at baseline to <5 cells per 7·5 mL blood). A confirmed response in a consecutive assessment after at least 4 weeks was required for each component. The primary analysis was done in the evaluable population. If at least 19 (43%) of 44 evaluable patients in a dose cohort responded, then the dose cohort would be considered successful. Safety was assessed in all patients who received at least one dose of olaparib. This trial is registered at ClinicalTrials.gov, NCT01682772. Recruitment for the trial has completed and follow-up is ongoing. FINDINGS: 711 patients consented for targeted screening between April 1, 2015, and Aug 30, 2018. 161 patients had DDR gene aberrations, 98 of whom were randomly assigned and treated (49 patients for each olaparib dose), with 92 evaluable for the primary endpoint (46 patients for each olaparib dose). Median follow-up was 24·8 months (IQR 16·7-35·9). Confirmed composite response was achieved in 25 (54·3%; 95% CI 39·0-69·1) of 46 evaluable patients in the 400 mg cohort, and 18 (39·1%; 25·1-54·6) of 46 evaluable patients in the 300 mg cohort. Radiological response was achieved in eight (24·2%; 11·1-42·3) of 33 evaluable patients in the 400 mg cohort and six (16·2%; 6·2-32·0) of 37 in the 300 mg cohort; PSA50 response was achieved in 17 (37·0%; 23·2-52·5) of 46 and 13 (30·2%; 17·2-46·1) of 43; and circulating tumour cell count conversion was achieved in 15 (53·6%; 33·9-72·5) of 28 and 13 (48·1%; 28·7-68·1) of 27. The most common grade 3-4 adverse event in both cohorts was anaemia (15 [31%] of 49 patients in the 300 mg cohort and 18 [37%] of 49 in the 400 mg cohort). 19 serious adverse reactions were reported in 13 patients. One death possibly related to treatment (myocardial infarction) occurred after 11 days of treatment in the 300 mg cohort. INTERPRETATION: Olaparib has antitumour activity against metastatic castration-resistant prostate cancer with DDR gene aberrations, supporting the implementation of genomic stratification of metastatic castration-resistant prostate cancer in clinical practice. FUNDING: Cancer Research UK, AstraZeneca, Prostate Cancer UK, the Prostate Cancer Foundation, the Experimental Cancer Medicine Centres Network, and the National Institute for Health Research Biomedical Research Centres.

Maximal heart rate assessment in recreational football players: A study involving a multiple testing approach.

This study aimed at examining the suitability of a standard treadmill test (TT), popular intermittent field tests, and small-sided football matches to induce maximal heart rate (HRmax ) in recreational football players. Sixty-six inactive untrained male subjects (age: 39.3 ± 5.8 years, VO2max : 41.2 ± 6.2 mL kg-1  min-1 , body mass: 81.9 ± 10.8 kg, height: 173.2 ± 6.4 cm) were evaluated. On separate occasions, the players were randomly submitted to a progressive VO2max TT, to the Yo-Yo intermittent endurance level 1 (YYIE1) and level 2 (YYIE2) tests, to the Yo-Yo intermittent recovery level 1 (YYIR1) test, and to 7v7 (43 × 27 m pitch, 83 m2 /player) football matches (45 minutes; 2-4 matches/player). To ensure data consistency, exercise HR was recorded using the same HR monitors in all the experimental conditions. A total of 73%, 24%, 18%, 17%, and 30% of the players achieved their HRmax during the YYIE1, YYIE2, YYIR1, TT, and the small-sided football matches, respectively. The probability of achieving HRmax increased proportionally to test duration, with 7.8 minutes as the cutoff time. Variations in HRpeak of ±2 b min-1 should be regarded as of practical relevance. YYIE1 HRpeak provided the most accurate estimation of a subject's individual HRmax and much higher probability of reaching HRmax . Nevertheless, the results of this study suggest caution in considering a reference test for HRmax assessment in this population. The use of confirmation tests is still highly advisable when the test duration is shorter than 7.8 minutes. In this regard, field tests seem to be suitable and accurate for individual HRmax assessment in recreational football players.

Reliability of Submaximal Yo-Yo Tests in 9- to 16-Year-Old Untrained Schoolchildren.

PURPOSE: To examine the reliability of age-adapted submaximal Yo-Yo (Yo-Yosubmax) intermittent tests in untrained schoolchildren aged 9-16 years (n = 139; 72 boys and 67 girls) and within children with high and low percentage of body fat (%BF). METHODS: Yo-Yo intermittent recovery level 1 children's (YYIR1C), Yo-Yo intermittent endurance level 1 (YYIE1), and Yo-Yo intermittent endurance level 2 (YYIE2) tests were performed 7 days apart by 9- to 11-, 12- to 13-, and 14- to 16-year-old children, respectively. Reliability was tested for Yo-Yosubmax heart rate (HRsubmax), peak HR, and maximal distance. RESULTS: HRsubmax typical errors of measurement (TEM) in YYIR1C, YYIE1, and YYIE2 were 2.2% (1.7%-2.9%), 2.4% (1.9%-3.3%), 1.9% (1.6%-2.5%) and 2.4% (1.9%-3.3%), 2.4% (1.9%-3.2%), 1.9% (1.5%-2.4%) for girls and boys, respectively. HRsubmax intraclass correlation coefficient values were good to excellent (.62-.87) in all age groups and in schoolchildren of different %BF. TEM for HRsubmax ranged from 2.1% to 2.3% in high and low %BF groups. Maximal distance intraclass correlation coefficients were excellent and TEM values ranged from 11% to 12% in both %BF groups. HRsubmax was moderately to largely associated (r = -.46 to -.64; P < .002) with Yo-Yo maximal distance across the age groups. CONCLUSION: Yo-Yosubmax tests are a reliable tool providing useful and sustainable aerobic performance testing in physical education, irrespective of individual %BF.

Decrease in Dengue virus-2 infection and reduction of cytokine/chemokine production by Uncaria guianensis in human hepatocyte cell line Huh-7.

BACKGROUND: Dengue fever may present hemorrhages and cavitary effusions as result of exacerbated immune responses. We investigated hydro-alcoholic extracts from leaves (UGL) and bark (UGB) of the medicinal species Uncaria guinanensis with respect to antiviral effects in Dengue virus (DENV) infection and in immunological parameters associated with in vivo physiopathological features. METHODS: Chemical profiles from UGB or UGL were compared in thin layer chromatography and 1H nuclear magnetic resonance using flavonoid compounds and a pentacyclic oxindole alkaloid-enriched fraction as references. DENV-2-infected hepatocytes (Huh-7) were treated with extracts. Cell viability, DENV antigens and immunological factors were detected by enzyme-linked immunosorbent assay (ELISA) or flow cytometry. FINDINGS: The UGL mainly differed from UGB by selectively containing the flavonoid kaempferitrin. UGB and UGL improved hepatocyte viability. Both extracts reduced intracellular viral antigen and inhibited the secretion of viral non-structural protein (NS1), which is indicative of viral replication. Reduction in secretion of macrophage migration inhibitory factor was achieved by UGB, of interleukin-6 by UGL, and of interleukin-8 by both UGB and UGL. MAIN. CONCLUSIONS: The U. guianensis extracts presented, antiviral and immunomodulatory effects for DENV and possibly a hepatocyte-protective activity. Further studies may be performed to consider these products as potential candidates for the development of an herbal product for the future treatment of dengue.

Impact of a multidisciplinary evaluation in pediatric patients with nocturnal monosymptomatic enuresis.

BACKGROUND: Enuresis (NE) is a clinical condition of multifactorial etiology that leads to difficulties in child/adolescent social interaction. METHODS: This was a prospective study on the impact of multidisciplinary assessment of 6- to 17-year-old patients with monosymptomatic nocturnal enuresis (MNE), including a structured history, clinical/neurological examination, bladder and bowel diaries, sleep diary and questionnaires, psychological evaluation [Child Behavior Checklist (CBCL) and PedsQL 4.0 questionnaires], urinary sonography, blood and urine laboratory tests, polysonography (PSG), and balance evaluation. RESULTS: A total of 140 enuretic participants were evaluated, of whom 27 were diagnosed with NE complicated by urinary disorder, four with hypercalciuria, three with nephropathy and one with attention-deficit hyperactivity disorder. Among the 87 participants who underwent PSG, six were diagnosed with severe apnea. Of the 82 MNE patients who underwent full assessment, 62 were male (75.6 %), and the mean age was 9.5 (±2.6) years. A family history of NE was diagnosed in 91.1 % of first- and second-degree relatives, constipation in 89.3 % and mild/moderate apnea in 40.7 %. Balance control alteration was identified by physical therapy evaluation of MNE patients. Participants' quality of life evaluation scores were significantly lower than those of their parents. CONCLUSION: Enuresis is a multifactorial disorder that requires a structured diagnostic approach.

Effect of Accessions and Environment Conditions on Coumarin, O-Coumaric and Kaurenoic Acids Levels of Mikania laevigata.

Coumarin, o-coumaric, and kaurenoic acid are bioactive compounds usually found in the leaves of Mikania laevigata. Genetic and environmental variations in the secondary metabolites of plants may have implications for their biological effects. Three different accessions of M. laevigata cultivated in four sites between the Equator and the Tropic of Capricorn in Brazil were evaluated aiming to present potential raw materials and discuss relationships among these three bioactive compounds. The results revealed effects of plant accessions and environmental factors and suggested two contrasting chemical phenotypes of M. laevigata. The first phenotype presented the highest levels of kaurenoic acid (2283 ± 316 mg/100 g) besides lower levels of coumarin (716 ± 61 mg/100 g), which was also stimulated by the environment and mild climate at the site nearest to the Tropic of Capricorn. The other phenotype presented the lowest levels of kaurenoic acid (137 ± 17 mg/100 g) besides higher levels of coumarin (1362 ± 108 mg/100 g), which was also stimulated by the environment and tropical climate at the site nearest to the Equatorial beach.