Three doses of the licensed tetravalent dengue vaccine CYD-TDV (Dengvaxia, Sanofi Pasteur, Lyon France) are immunogenic and effective against symptomatic dengue in individuals aged 9 years and older ...who are dengue seropositive. Previous trials have provided some evidence that antibody responses elicited after just one dose or two doses of CYD-TDV might be similar to those elicited after three doses. We compared antibody responses following one-dose, two-dose, and three-dose vaccination regimens in individuals who were dengue seropositive at baseline up to 1 year after the last injection.
In this randomised, controlled, phase 2, non-inferiority study (CYD65), healthy individuals aged 9–50 years were recruited from the community in three sites in Colombia and three sites in the Philippines. Participants were randomly assigned (1:1:1), using a permuted block method with stratification by site and age group, to receive, at 6-month intervals (on day 0, month 6, and month 12), three doses of CYD-TDV (three-dose group), one dose of placebo (on day 0) and two doses of CYD-TDV (at months 6 and 12; two-dose group), or two doses of placebo (on day 0 and month 6) and one dose of CYD-TDV (at month 12; one-dose group). Each dose of CYD-TDV was 0·5 mL, administered subcutaneously into the deltoid of the upper arm. Participants, study staff, investigators, and the funder were masked to group assignment. The co-primary endpoints were geometric mean titres (GMTs) of neutralising antibodies against each dengue virus serotype at 28 days and 1 year after the last vaccine injection. After a protocol amendment during the conduct of the study, the original co-primary objectives of non-inferiority of the one-dose and two-dose groups to the three-dose group were altered to include non-inferiority of the two-dose group to the three-dose group only, to be assessed in individuals who were dengue seropositive at baseline. Non-inferiority was shown if the lower limit of the 95% CI for the ratio of GMTs (GMR) at 28 days and 1 year between groups was more than 0·5 for each serotype. The analysis of the coprimary objectives was done in the per-protocol analysis dataset, which included all participants who had been vaccinated, had no protocol deviations, and had a valid serology test result for at least one dengue serotype at 28 days after the third injection. Safety was assessed throughout in all participants who received at least one injection of study drug, regardless of serostatus. This trial is registered with ClinicalTrials.gov, NCT02628444, and is closed to accrual.
Between May 2, 2016, and Sept 16, 2016, we recruited and enrolled 1050 individuals, of whom 1048 received at least one injection and 993 had at least one blood sample taken (full-analysis dataset; 333 in three-dose group, 328 in two-dose group, and 332 in one-dose group). 860 (86·6%) of 993 participants in the full-analysis dataset were dengue seropositive at baseline. Non-inferiority (two dose vs three dose) was shown for each serotype at both 28 days and 1 year among dengue-seropositive participants (number of participants assessed: 272 two-dose group, 265 three-dose group at 28 days; and 190 two-dose group, 185 three-dose group at 1 year). At 28 days after the last injection, neutralising antibody GMTs were 899 (95% CI 752–1075) in the two-dose group versus 822 (700–964) in the three dose group against dengue serotype 1 (GMR 1·09 95% CI 0·86–1·39); 869 (754–1002) versus 875 (770–995) against serotype 2 (GMR 0·99 0·82–1·20); 599 (524–685) versus 610 (535–694) against serotype 3 (GMR 0·98 0·82–1·18); and 510 (453–575) versus 531 (470–601) against serotype 4 (GMR 0·96 0·81–1·14). At year 1, GMTs had decreased but remained above baseline for all serotypes: 504 (95% CI 403–630) in the two-dose group versus 490 (398–604) in the three-dose group against serotype 1 (GMR 1·03 0·76–1·40); 737 (611–888) versus 821 (704–957) against serotype 2 (GMR 0·90 0·71–1·14); 437 (368–519) versus 477 (405–561) against serotype 3 (GMR 0·92 0·72–1·16); and 238 (205–277) versus 270 (235–310) against serotype 4 (GMR 0·88 0·72–1·09). Reactogenicity profiles were similar across treatment groups. Most unsolicited adverse events after any injection were non-serious and systemic in nature. During the study, 60 serious adverse events were reported in 58 participants (14 in three-dose group, 26 in two-dose group, 18 in one-dose group), mostly infection and infestations or injury, poisoning, and procedural complications. No serious adverse events of special interest or admissions to hospital for dengue occurred. Two deaths occurred, unrelated to study treatment.
A two-dose CYD-TDV regimen might be an alternative to the licensed three-dose regimen in individuals who are dengue seropositive at baseline and aged 9 years and older. Vaccination with a reduced number of doses could lead to improved vaccine compliance and coverage, especially in low-resource settings.
Sanofi Pasteur.
Marine environment pollution has increased in recent decades as a result of anthropogenic activities. Macrophytes can assimilate the compounds dissolved in the water and respond to changes in ...surround conditions, for that, they can be used as bioindicators of pollution in aquatic environments.
Currently organic ultraviolet (UV) filters have shown ever-increasing in pollution levels in marine ecosystems. The anthropogenic pollution produced by eight organic ultraviolet (UV) filters in coastal macrophytes was studied. A microwave-assisted extraction (MAE), followed by ultrahigh-performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) was applied to 76 macrophyte (seaweeds and seagrass) samples from three different beaches on the Gran Canaria Island (Spain), collected for 6 months. All studied UV filters were found with different detection frequencies from 16% to 100% in macrophyte samples. Octocrylene (OC) was detected in all the analysed samples throughout the sampling period. The highest concentration, 19,369 ng·g−1 dry weight (dw), was for this compound in the seagrass Cymodocea nodosa.
The bioconcentration ratio was determined for several seaweed groups (red, brown, green). Different bioconcentration grades were obtained. Those above 1000 indicated significant accumulation, which increases the possibility of chronic effects on seaweed and at upper tropic levels.
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•An analytical method for eight organic UV filters was optimized for macrophytes.•All target compounds have been detected in different frequencies.•Octocrylene was detected in all samples and it was found in the highest concentration.•First monitoring of organic UV filters and bioconcentration assessment on macrophytes•Detection of target compounds in macrophytes indicates their potential as bioindicators.
Increasing evidence indicates that endocannabinoid (EC) signalling is dysregulated during hyperglycemia and obesity, particularly at the level of anandamide (AEA) and/or 2-arachidonoylglycerol (2-AG) ...concentrations in tissues involved in the control of energy intake and processing, such as the liver, white adipose tissue and pancreas. Here we review this previous evidence and provide new data on the possible dysregulation of EC levels in organs with endocrine function (adrenal glands and thyroid), involved in energy expenditure (brown adipose tissue and skeletal muscle), or affected by the consequences of metabolic disorders (heart and kidney), obtained from mice fed for 3, 8 and 14 weeks with two different high fat diets (HFDs), with different fatty acid compositions and impact on fasting glucose levels. Statistically significant elevations (in the skeletal muscle, heart and kidney) or reductions (in the thyroid) of the levels of either AEA or 2-AG, or both, were found. Depending on the diet, these changes preceded or accompanied the development of overt obesity and/or hyperglycemia. In the adrenal gland, first a reduction and then an elevation of EC levels were observed. In the brown fat, a very early elevation of both AEA and 2-AG normalized levels was observed with one of the diets, whereas delayed decreases were explained by an increase of the amount of fat tissue weight induced by the HFDs. The potential implications of these and previous findings in the general framework of the proposed roles of the EC system in the control of metabolic, endocrine and cardiovascular and renal functions are discussed.
Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular ...disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally.
The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005.
Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12·0 years (IQR 5·5–27·0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14·7 mmol/L (IQR 11·6–18·4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3·93 mmol/L, IQR 2·6–5·8) versus non-high-income countries (9·3 mmol/L, 6·7–12·7), with greater use of three or more lipid-lowering therapies (LLT; high-income 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24·5 years (IQR 17·0–34·5) versus 37·0 years (29·0–49·0) in high-income countries (adjusted hazard ratio 1·64, 95% CI 1·13–2·38).
Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH.
Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; and European Atherosclerosis Society
Parkinson's disease (PD) patients are affected by hypokinetic dysarthria, characterized by hypophonia and dysprosody, which worsens with disease progression. Levodopa's (l-dopa) effect on quality of ...speech is inconclusive; no data are currently available for late-stage PD (LSPD).
To assess the modifications of speech and voice in LSPD following an acute l-dopa challenge.
LSPD patients Schwab and England score <50/Hoehn and Yahr stage >3 (MED ON) performed several vocal tasks before and after an acute l-dopa challenge. The following was assessed: respiratory support for speech, voice quality, stability and variability, speech rate, and motor performance (MDS-UPDRS-III). All voice samples were recorded and analyzed by a speech and language therapist blinded to patients' therapeutic condition using
5.1 software.
24/27 (14 men) LSPD patients succeeded in performing voice tasks. Median age and disease duration of patients were 79 IQR: 71.5-81.7 and 14.5 IQR: 11-15.7 years, respectively. In MED OFF, respiratory breath support and pitch break time of LSPD patients were worse than the normative values of non-parkinsonian. A correlation was found between disease duration and voice quality (
= 0.51;
= 0.013) and speech rate (
= -0.55;
= 0.008). l-Dopa significantly improved MDS-UPDRS-III score (20%), with no effect on speech as assessed by clinical rating scales and automated analysis.
Speech is severely affected in LSPD. Although l-dopa had some effect on motor performance, including axial signs, speech and voice did not improve. The applicability and efficacy of non-pharmacological treatment for speech impairment should be considered for speech disorder management in PD.
We investigated blocking the TGF-β signaling pathway in HCC using two small molecule inhibitors (LY2157299, LY2109761) and a neutralizing humanized antibody (D10) against TGF-βRII. LY2157299 and ...LY2109761 inhibited HCC cell migration on Laminin-5, Fibronectin, Vitronectin, Fibrinogen and Collagen-I and de novo phosphorylation of pSMAD2. LY2157299 inhibited HCC migration and cell growth independently of the expression levels of TGF-βRII. In contrast to LY2157299, D10 showed a reduction in pSMAD2 only after a short exposure. This study supports the use of LY2157299 in clinical trials, and presents new insights into TGF-β receptor cycling in cancer cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Increasing evidence supports a relationship between lipid metabolism and mental health. In particular, the biostatus of polyunsaturated fatty acids (PUFAs) correlates with some symptoms of ...psychiatric disorders, as well as the efficacy of pharmacological treatments. Recent findings highlight a direct association between brain PUFA levels and dopamine transmission, a major neuromodulatory system implicated in the etiology of psychiatric symptoms. However, the mechanisms underlying this relationship are still unknown. Here we demonstrate that membrane enrichment in the n-3 PUFA docosahexaenoic acid (DHA), potentiates ligand binding to the dopamine D2 receptor (D2R), suggesting that DHA acts as an allosteric modulator of this receptor. Molecular dynamics simulations confirm that DHA has a high preference for interaction with the D2R and show that membrane unsaturation selectively enhances the conformational dynamics of the receptor around its second intracellular loop. We find that membrane unsaturation spares G protein activity but potentiates the recruitment of β-arrestin in cells. Furthermore, in vivo n-3 PUFA deficiency blunts the behavioral effects of two D2R ligands, quinpirole and aripiprazole. These results highlight the importance of membrane unsaturation for D2R activity and provide a putative mechanism for the ability of PUFAs to enhance antipsychotic efficacy.
The desulfurization of carbons modified with SO2 was studied as a dispersion in boiling cyclohexane (81°C) using activated carbon (mAC) and graphene oxide (mGO), modified by SO2. The steady‐state ...species in the carbon matrix after the catalytic reduction of SO2 was considered a trisulfane. For mAC, there was a burst of a sulfur species identified as S2 by UV spectrum with a maximum at 217 nm (εM at 217 nm = 2.56 × 103) that showed a second‐order decay of absorbance with
kS2 = 47.29 M‐1·sec‐1 (
ΔG354‡= 18.1 kcal·mol‐1). The product was postulated to be S4. No other consecutive reaction was observed because of the possible adsorption of S4 in the carbon matrix. The desulfurization of mGO was shown by XPS and the kinetics were a second‐order decay up to 16 min (
kS2= 18.41 M‐1·sec‐1;
ΔG354‡= 18.8 kcal·mol‐1) followed by a second‐order increase of absorbance with
kS4 = 3.84 M‐1·sec‐1 (
ΔG354‡= 19.9), where the product showed a double maximum at 260‐285 nm typical of S8. These results are consistent with a mechanism of consecutive thermodynamically favorable dimerizations of S2 and S4 and with the desulfurization mechanism that has been previously postulated.
The desulfurization of carbons modified with SO2 occurred in boiling cyclohexane from a trisulfane inserted in the carbon matrix, with a burst of disulfur S2 that dimerized to tetrasulfur and finally to S8. The desulfurization path is largely more energetically favorable than the decarboxylation route.
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