To compare the safety and antiviral activity of once (QD) or twice (BID) daily lopinavir/ritonavir (LPV/r) in combination with investigator-selected nucleoside/nucleotide reverse transcriptase ...inhibitors (NRTIs) in treatment-experienced subjects.
Subjects failing treatment with HIV-1 RNA > 1000 copies per milliliter received LPV/r tablets 800/200 mg QD (n = 300) or 400/100 mg BID (n = 299) with investigator-chosen nucleoside/nucleotide reverse transcriptase inhibitors. Efficacy was determined by the intent-to-treat time to loss of virologic response (ITT-TLOVR) algorithm. Safety, tolerability, adherence, impact of baseline protease mutations on virologic response, and emergence of resistance on therapy were assessed.
Demographics were comparable across groups. By intent-to-treat time to loss of virologic response, 166 QD subjects (55.3%) and 155 BID subjects (51.8%) were responders at week 48 (P = 0.413), with similar mean increases in CD4 T-cell count. QD subjects demonstrated better adherence than BID subjects. The occurrence of treatment-related moderate/severe adverse events was comparable for all events except nausea, which was reported more frequently among BID-treated subjects. Emergence of new protease resistance mutations on treatment was similarly infrequent in both groups.
LPV/r dosed QD resulted in increased treatment adherence and was as efficacious as BID LPV/r while providing similar safety, tolerability, and limited resistance evolution.
RésuméEn institutions éducatives, la violence des adolescents placés insécurise et bouleverse les règles du vivre ensemble, heurte la groupalité professionnelle dans sa fonction contenante et ...interroge le sens du métier. Nous proposons et illustrons une réponse institutionnelle groupale nommée « commission violence » comme instance régulatrice et inclusive qui participe d’une forme de scénarisation positive du collectif en charge de l’adolescent et de la mission protectrice, pour tous, qui lui incombe.
Purpose
There is substantial evidence suggesting high levels of mental health problems in unaccompanied and separated children (UASC). However, there is less focus on the first years of adulthood ...characterised by increased vulnerability and fear of expulsion. We aimed to describe the mental health of UASC on reaching adulthood, and how this was affected by uncertainty regarding their right-to-stay in France.
Methods
One hundred and ten youth aged 18–22 were recruited via child protection reception centres. We administered the Patient Health Questionnaire somatic (PHQ-15), anxiety (GAD-7) and depression (PHQ-9) modules, the Post-Traumatic Stress Disorder Checklist (PCL-5) and Connor–Davidson Resilience Scale (CD-RISC-10). Logistic regression analysis was performed with the dependent variable, a secure (versus uncertain) situation, defined as (1) detaining a residence permit and being in school, an apprenticeship or a salaried job, or (2) waiting for residence permit whilst occupying a salaried job.
Results
Of the sample, 19.3% reached criteria for a probable somatic disorder, 17.6% for anxiety and 28.7% for depression (score ≥ 10); 41.8% were in an uncertain situation regarding their right-to-stay. Uncertainty was associated with higher anxiety ((OR per Interquartile range (95% CI), 1.77 (1.05–2.98)) and post-traumatic stress symptoms (2.05 (1.06–4.00)), lower resilience (0.50 (0.27–0.91)), and participants rating their anxiety (
p
= 0.02) and depressive symptoms (
p
= 0.003) as more severe since reaching adulthood.
Conclusions
Our findings suggest uncertainty regarding right-to-stay is associated with increased mental health symptoms, specifically anxiety and trauma-induced stress, thereby highlighting the vulnerability of UASC in their first years of adulthood. This calls for greater support during this transition period with regular symptom monitoring for timely psychological interventions.
Epidemiology evidenced the Bisphenol A (BPA), a chemical found in daily consumer products, as an environmental contributor to obesity and type II diabetes (T2D) in Humans. However, the BPA-mediated ...effects supporting these metabolic disorders are still unknown. Knowing that obesity and T2D are associated with low-grade inflammation and gut dysbiosis, we performed a longitudinal study in mice to determine the sequential adverse effects of BPA on immune system and intestinal microbiota that could contribute to the development of metabolic disorders. We observed that perinatal exposure to BPA (50 µg/kg body weight/day) induced intestinal and systemic immune imbalances at PND45, through a decrease of Th1/Th17 cell frequencies in the lamina propria concomitant to an increase of splenic Th1/Th17 immune responses. These early effects are associated with an altered glucose sensitivity, a defect of IgA secretion into faeces and a fall of faecal bifidobacteria relative to control mice. Such BPA-mediated events precede infiltration of pro-inflammatory M1 macrophages in gonadal white adipose tissue appearing with ageing, together with a decreased insulin sensitivity and an increased weight gain. Our findings provide a better understanding of the sequential events provoked by perinatal exposure to BPA that could support metabolic disorder development in later life.
The mental health of unaccompanied and separated minors (UASC) has been widely studied but not their first years of adulthood, often characterised by uncertainty after leaving child protection. The ...aim of this study was to estimate the prevalence of psychiatric disorders using standardised and validated research instruments and examine the effect of exposure to trauma.
One hundred and ten youth (92.7% male, median age 19.7 18.1-22.8) from Chambery, Montpellier and La Rochelle were recruited to a cross-sectional exploratory study. During a face-to-face interview, somatoform disorder, anxiety, and depression were assessed using the Patient Health Questionnaire (score≥10) and post-traumatic stress disorder (PTSD) with the PTSD Checklist for DSM-5 (score≥33). Traumatic life events were assessed using the Life Events Checklist.
Of the youth, 19.3% had a probable somatoform disorder, 17.6% anxiety, 28.7% depression, and 20% PTSD. The number of traumatic life events increased the risk of depression (multi-adjusted OR (95%CI): 1.56 (1.25-1.96)), PTSD (1.60 (1.23-2.08)), somatoform disorder (1.41 (1.10-1.82), and anxiety (1.33 (1.02-1.72)). Physical assault was the type of event positively associated with the most disorders (P≤0.01, except for anxiety), followed by witnessing sudden and violent death (P≤0.01 for depression and PTSD) and sexual assault (P=0.002 for PTSD).
Our study highlights the high prevalence of psychiatric disorders in young adults who arrived as UASC and the impact on their mental health of cumulative trauma and exposure to interpersonal and violent traumatic life events. A greater focus on their mental health with regular assessments is needed in order to provide rapid and adapted care.
Background
Interleukin 6 (IL-6) is a pleomorphic cytokine that can be found in the cerebrospinal fluid (CSF) in a wide spectrum of inflammatory pathologies of the central nervous system (CNS).
...Objective
Our aim was to characterize the diagnostic significance of CSF IL-6 among various CNS inflammatory diseases with pseudotumoral lesions (CNSID) and primary CNS lymphoma (PCNSL).
Methods
We retrospectively analyzed the CSF IL-6 concentrations in 43 consecutive patients with suspected PCNSL. A total of 28 patients were positively diagnosed with PCNSL and 15 with CNSID. We verified the results with CSF IL-10, an established biomarker for PCNSL.
Results
In the PCNSL group, the median CSF IL-6 concentration was 8 pg/ml, interquartile range (IQR) 5–18.5. For the patients with CNSID, the median concentration was 70 pg/ml, IQR 5–1368. A group comparison showed significantly higher CSF IL-6 levels in patients with CNSID than in those with PCNSL (
p
= 0.032). Moreover, IL-6 was correlated with CSF cell count in the CNSID group (
r
= 0.56,
p
= 0.028), but not in the PCNSL group (
r
= 0.3,
p
= 0.13).
We found significantly higher CSF IL-10 levels in patients with PCNSL than in patients with CNS inflammatory lesions (
p
< 0.001).
Discussion and conclusions
Our study suggests that CSF IL-6 levels could represent, in addition to CSF IL-10, a useful biomarker in the differential diagnosis of CNSID and suspected PCNSL.
In 2018 we celebrated 25 years of development of radar altimetry, and the progress achieved by this methodology in the fields of global and coastal oceanography, hydrology, geodesy and cryospheric ...sciences. Many symbolic major events have celebrated these developments, e.g., in Venice, Italy, the 15th (2006) and 20th (2012) years of progress and more recently, in 2018, in Ponta Delgada, Portugal, 25 Years of Progress in Radar Altimetry. On this latter occasion it was decided to collect contributions of scientists, engineers and managers involved in the worldwide altimetry community to depict the state of altimetry and propose recommendations for the altimetry of the future. This paper summarizes contributions and recommendations that were collected and provides guidance for future mission design, research activities, and sustainable operational radar altimetry data exploitation. Recommendations provided are fundamental for optimizing further scientific and operational advances of oceanographic observations by altimetry, including requirements for spatial and temporal resolution of altimetric measurements, their accuracy and continuity. There are also new challenges and new openings mentioned in the paper that are particularly crucial for observations at higher latitudes, for coastal oceanography, for cryospheric studies and for hydrology.
The paper starts with a general introduction followed by a section on Earth System Science including Ocean Dynamics, Sea Level, the Coastal Ocean, Hydrology, the Cryosphere and Polar Oceans and the “Green” Ocean, extending the frontier from biogeochemistry to marine ecology. Applications are described in a subsequent section, which covers Operational Oceanography, Weather, Hurricane Wave and Wind Forecasting, Climate projection. Instruments’ development and satellite missions’ evolutions are described in a fourth section. A fifth section covers the key observations that altimeters provide and their potential complements, from other Earth observation measurements to in situ data. Section 6 identifies the data and methods and provides some accuracy and resolution requirements for the wet tropospheric correction, the orbit and other geodetic requirements, the Mean Sea Surface, Geoid and Mean Dynamic Topography, Calibration and Validation, data accuracy, data access and handling (including the DUACS system). Section 7 brings a transversal view on scales, integration, artificial intelligence, and capacity building (education and training). Section 8 reviews the programmatic issues followed by a conclusion.
The development of direct-acting antiviral agents is a promising therapeutic advance in the treatment of hepatitis C virus (HCV) infection. However, rapid emergence of drug resistance can limit ...efficacy and lead to cross-resistance among members of the same drug class. ABT-450 is an efficacious inhibitor of HCV NS3/4A protease, with 50% effective concentration values of 1.0, 0.21, 5.3, 19, 0.09, and 0.69 nM against stable HCV replicons with NS3 protease from genotypes 1a, 1b, 2a, 3a, 4a, and 6a, respectively. In vitro, the most common amino acid variants selected by ABT-450 in genotype 1 were located in NS3 at positions 155, 156, and 168, with the D168Y variant conferring the highest level of resistance to ABT-450 in both genotype 1a and 1b replicons (219- and 337-fold, respectively). In a 3-day monotherapy study with HCV genotype 1-infected patients, ABT-450 was coadministered with ritonavir, a cytochrome P450 3A4 inhibitor shown previously to markedly increase peak, trough, and overall drug exposures of ABT-450. A mean maximum HCV RNA decline of 4.02 log10 was observed at the end of the 3-day dosing period across all doses. The most common variants selected in these patients were R155K and D168V in genotype 1a and D168V in genotype 1b. However, selection of resistant variants was significantly reduced at the highest ABT-450 dose compared to lower doses. These findings were informative for the subsequent evaluation of ABT-450 in combination with additional drug classes in clinical trials in HCV-infected patients. (Study M11-602 is registered at ClinicalTrials.gov under registration no. NCT01074008.).
Abstract
Objective
To assess the safety and the efficacy of TNF-α antagonists and tocilizumab in patients with Takayasu arteritis (TAK).
Methods
A total of 209 patients with TAK median age 29 years ...(interquartile range 7–62), 186 (89%) females were included. They received either TNF-α antagonists n = 132 (63%) with 172 lines; infliximab (n = 109), adalimumab (n = 45), golimumab (n = 8), certolizumab (n = 6) and etanercept (n = 5) or tocilizumab n = 77 (37%) with 121 lines; i.v. and s.c. in 95 and 26 cases, respectively.
Results
A complete response at 6 months was evidenced in 101/152 (66%) patients on TNF-α antagonists and 75/107 (70%) patients on tocilizumab. Age ≥30 years odds ratio 2.09 (95% CI 1.09, 3.99) was associated with complete response, whereas vascular signs OR 0.26 (95% CI 0.1, 0.65), baseline prednisone ≥20 mg/day OR 0.51 (95% CI 0.28, 0.93) were negatively associated with the complete response to TNF-α antagonists or tocilizumab. During a median follow-up of 36 months, 103 relapses were noted. Supra-aortic branches and thoracic aorta involvement HR 2.44 (95% CI 1.06, 5.65) and 3.66 (1.18, 11.4), respectively and systemic signs at baseline HR 2.01 (95% CI 1.30, 3.11) were significantly associated with relapse. The cumulative incidence of treatment discontinuation and relapse were similar in TNF-α antagonists and tocilizumab. Fifty-eight (20%) adverse effects occurred on biologic targeted therapies 37 (21%) on TNF-α antagonists and 21 (17%) on tocilizumab (P = 0.4), respectively.
Conclusion
This large multicentre study shows high efficacy of biologic targeted treatments in refractory TAK. Efficacy, relapse and drug retention rate were equivalent with TNF-α antagonists and tocilizumab.
Training with electronic collars/e-collars (e-stim, shock) is controversial, and regulations concerning electric collars vary from absence to bans across European countries. The main goal of this ...study was to characterize the everyday use of e-collars by dog owners, in France where there are currently no regulations on their use. A sample (n = 1,251) of dog owners were recruited using an online questionnaire. Data were collected using Google Forms. Factors associated with the use of e-collars were determined using a Chi-squared test. Twenty-six percent (n = 330) of the owners enrolled in this survey did use such devices; 11.9% (n = 149) of the owners reported the use of bark-activated collars, 4.5% (n = 56) reported the use of electronic boundary fence collars, and 14.2% (n = 178) reported the use of remote-controlled collars. E-collar use was found to be significantly associated with 3 factors: dogs weighing over 40 kg, non-neutered status, and dogs used for hunting or security activities. In addition, the data collected showed that e-collars were mainly used on young dogs (<2 years). The vast majority of e-collar users (71.8%) used the collar without professional advice, and 75% of e-collar users tried 2 or fewer other solutions before using the collar. Seven percent of the dogs on which the collar was used presented with physical wounds (n = 23). The efficacy reported was lower than that in many previous studies where conditions of use as specified were designed to be ideal as part of the experimental design (qualified trainer, perfect timing). All collar types were not equal: bark-activated collars appeared to be the least efficient and the most injurious type, whereas remote-controlled collars were mainly used for owner's convenience. In conclusion, this survey highlights a high ratio of e-collar use in a country without regulations. It also shows that real-life conditions are far from the idealized conditions in which experimental studies were undertaken, thereby putting dog welfare at higher risk than what is presented in scientific literature. In addition, this study reveals differences between collar types in terms of efficacy and effects on welfare. These factors should be taken into account to determine a precise regulation. Furthermore, this study shows the urgency to regulate this tool in Europe because dangers of use, which were already known, are proven to be aggravated in real-life situations.
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