Despite a substantial genetic component, efforts to identify common genetic variation underlying depression have largely been unsuccessful. In the current study we aimed to identify rare genetic ...variants that might have large effects on depression in the general population. Using high-coverage exome-sequencing, we studied the exonic variants in 1265 individuals from the Rotterdam study (RS), who were assessed for depressive symptoms. We identified a missense Asn396Ser mutation (rs77960347) in the endothelial lipase (LIPG) gene, occurring with an allele frequency of 1% in the general population, which was significantly associated with depressive symptoms (P-value=5.2 × 10
, β=7.2). Replication in three independent data sets (N=3612) confirmed the association of Asn396Ser (P-value=7.1 × 10
, β=2.55) with depressive symptoms. LIPG is predicted to have enzymatic function in steroid biosynthesis, cholesterol biosynthesis and thyroid hormone metabolic processes. The Asn396Ser variant is predicted to have a damaging effect on the function of LIPG. Within the discovery population, carriers also showed an increased burden of white matter lesions (P-value=3.3 × 10
) and a higher risk of Alzheimer's disease (odds ratio=2.01; P-value=2.8 × 10
) compared with the non-carriers. Together, these findings implicate the Asn396Ser variant of LIPG in the pathogenesis of depressive symptoms in the general population.
A KINETIC DATABASE FOR ASTROCHEMISTRY (KIDA) Wakelam, V; Herbst, E; Loison, J-C ...
The Astrophysical journal. Supplement series,
03/2012, Letnik:
199, Številka:
1
Journal Article
Recenzirano
Odprti dostop
We present a novel chemical database for gas-phase astrochemistry. Named the KInetic Database for Astrochemistry (KIDA), this database consists of gas-phase reactions with rate coefficients and ...uncertainties that will be vetted to the greatest extent possible. Submissions of measured and calculated rate coefficients are welcome, and will be studied by experts before inclusion into the database. Besides providing kinetic information for the interstellar medium, KIDA is planned to contain such data for planetary atmospheres and for circumstellar envelopes. each year, a subset of the reactions in the database (kida.uva) will be provided as a network for the simulation of the chemistry of dense interstellar clouds with temperatures between 10 K and 300 K. We also provide a code, named Nahoon, to study the time-dependent gas-phase chemistry of zero-dimensional and one-dimensional interstellar sources.
Summary Background Many international guidelines on the prevention of venous thromboembolism recommend targeting heparin treatment at patients with stroke who have a high risk of venous thrombotic ...events or a low risk of haemorrhagic events. We sought to identify reliable methods to target anticoagulant treatment and so improve the chance of avoiding death or dependence after stroke. Methods We obtained individual patient data from the five largest randomised controlled trials in acute ischaemic stroke that compared heparins (unfractionated heparin, heparinoids, or low-molecular-weight heparin) with aspirin or placebo. We developed and evaluated statistical models for the prediction of thrombotic events (myocardial infarction, stroke, deep vein thrombosis, or pulmonary embolism) and haemorrhagic events (symptomatic intracranial or significant extracranial) in the first 14 days after stroke. We calculated the absolute risk difference for the outcome “dead or dependent” in patients grouped by quartiles of predicted risk of thrombotic and haemorrhagic events with random effect meta-analysis. Findings Patients with ischaemic stroke who were of advanced age, had increased neurological impairment, or had atrial fibrillation had a high risk of both thrombotic and haemorrhagic events after stroke. Additionally, patients with CT-visible evidence of recent cerebral ischaemia were at increased risk of thrombotic events. In evaluation datasets, the area under a receiver operating curve for prediction models for thrombotic events was 0·63 (95% CI 0·59–0·67) and for haemorrhagic events was 0·60 (0·55–0·64). We found no evidence that the net benefit from heparins increased with either increasing risk of thrombotic events or decreasing risk of haemorrhagic events. Interpretation There was no evidence that patients with ischaemic stroke who were at higher risk of thrombotic events or lower risk of haemorrhagic events benefited from heparins. We were therefore unable to define a targeted approach to select the patients who would benefit from treatment with early anticoagulant therapy. We recommend that guidelines for routine or selective use of heparin in stroke should be revised. Funding MRC.
To evaluate published evidence of efficacy and safety of pharmacologic treatments for childhood spasticity due to cerebral palsy.
A multidisciplinary panel systematically reviewed relevant literature ...from 1966 to July 2008.
For localized/segmental spasticity, botulinum toxin type A is established as an effective treatment to reduce spasticity in the upper and lower extremities. There is conflicting evidence regarding functional improvement. Botulinum toxin type A was found to be generally safe in children with cerebral palsy; however, the Food and Drug Administration is presently investigating isolated cases of generalized weakness resulting in poor outcomes. No studies that met criteria are available on the use of phenol, alcohol, or botulinum toxin type B injections. For generalized spasticity, diazepam is probably effective in reducing spasticity, but there are insufficient data on its effect on motor function and its side-effect profile. Tizanidine is possibly effective, but there are insufficient data on its effect on function and its side-effect profile. There were insufficient data on the use of dantrolene, oral baclofen, and intrathecal baclofen, and toxicity was frequently reported.
For localized/segmental spasticity that warrants treatment, botulinum toxin type A should be offered as an effective and generally safe treatment (Level A). There are insufficient data to support or refute the use of phenol, alcohol, or botulinum toxin type B (Level U). For generalized spasticity that warrants treatment, diazepam should be considered for short-term treatment, with caution regarding toxicity (Level B), and tizanidine may be considered (Level C). There are insufficient data to support or refute use of dantrolene, oral baclofen, or continuous intrathecal baclofen (Level U).
ABSTRACT
The Deep Extragalactic VIsible Legacy Survey (DEVILS) is an ongoing high-completeness, deep spectroscopic survey of ∼60 000 galaxies to Y < 21.2 mag, over ∼6 deg2 in three well-studied deep ...extragalactic fields: D10 (COSMOS), D02 (XMMLSS), and D03 (ECDFS). Numerous DEVILS projects all require consistent, uniformly derived and state-of-the-art photometric data with which to measure galaxy properties. Existing photometric catalogues in these regions either use varied photometric measurement techniques for different facilities/wavelengths leading to inconsistencies, older imaging data and/or rely on source detection and photometry techniques with known problems. Here, we use the ProFound image analysis package and state-of-the-art imaging data sets (including Subaru-HSC, VST-VOICE, VISTA-VIDEO, and UltraVISTA-DR4) to derive matched-source photometry in 22 bands from the FUV to 500 $\mu$m. This photometry is found to be consistent, or better, in colour analysis to previous approaches using fixed-size apertures (which are specifically tuned to derive colours), but produces superior total source photometry, essential for the derivation of stellar masses, star formation rates, star formation histories, etc. Our photometric catalogue is described in detail and, after internal DEVILS team projects, will be publicly released for use by the broader scientific community.
Context.
Detection of the electromagnetic emission from coalescing binary neutron stars (BNS) is important for understanding the merger and afterglow.
Aims.
We present a search for a radio ...counterpart to the gravitational-wave (GW) source GW190425, a BNS merger, using Apertif on the Westerbork Synthesis Radio Telescope (WSRT).
Methods.
We observed a field of high probability in the associated localisation region for three epochs at Δ
T
= 68, 90, 109 d post merger. We identified all sources that exhibit flux variations consistent with the expected afterglow emission of GW190425. We also looked for possible transients. These are sources that are only present in one epoch. In addition, we quantified our ability to search for radio afterglows in the fourth and future observing runs of the GW detector network using Monte Carlo simulations.
Results.
We found 25 afterglow candidates based on their variability. None of these could be associated with a possible host galaxy at the luminosity distance of GW190425. We also found 55 transient afterglow candidates that were only detected in one epoch. All of these candidates turned out to be image artefacts. In the fourth observing run, we predict that up to three afterglows will be detectable by Apertif.
Conclusions.
While we did not find a source related to the afterglow emission of GW190425, the search validates our methods for future searches of radio afterglows.
Pheochromocytomas are rare catecholamine-producing tumors derived in more than 30% of cases from mutations in 9 tumor-susceptibility genes identified to date, including von Hippel-Lindau tumor ...suppressor (VHL); succinate dehydrogenase complex, subunit B, iron sulfur (Ip) (SDHB); and succinate dehydrogenase complex, subunit D, integral membrane protein (SDHD). Testing of multiple genes is often undertaken at considerable expense before a mutation is detected. This study assessed whether measurements of plasma metanephrine, normetanephrine, and methoxytyramine, the O-methylated metabolites of catecholamines, might help to distinguish different hereditary forms of the tumor.
Plasma concentrations of O-methylated metabolites were measured by liquid chromatography with electrochemical detection in 173 patients with pheochromocytoma, including 38 with multiple endocrine neoplasia type 2 (MEN 2), 10 with neurofibromatosis type 1 (NF1), 66 with von Hippel-Lindau (VHL) syndrome, and 59 with mutations of SDHB or SDHD.
In contrast to patients with VHL, SDHB, and SDHD mutations, all patients with MEN 2 and NF1 presented with tumors characterized by increased plasma concentrations of metanephrine (indicating epinephrine production). VHL patients usually showed solitary increases in normetanephrine (indicating norepinephrine production), whereas additional or solitary increases in methoxytyramine (indicating dopamine production) characterized 70% of patients with SDHB and SDHD mutations. Patients with NF1 and MEN 2 could be discriminated from those with VHL, SDHB, and SDHD gene mutations in 99% of cases by the combination of normetanephrine and metanephrine. Measurements of plasma methoxytyramine discriminated patients with SDHB and SDHD mutations from those with VHL mutations in an additional 78% of cases.
The distinct patterns of plasma catecholamine O-methylated metabolites in patients with hereditary pheochromocytoma provide an easily used tool to guide cost-effective genotyping of underlying disease-causing mutations.
Aim
To estimate the number of treatment initiations, averted fatal opioid overdoses and the cost‐effectiveness associated with offering buprenorphine–naloxone (buprenorphine) treatment on‐site within ...existing syringe service programs (SSPs) in Massachusetts, USA.
Design, Setting and Participants
This was a cohort‐based mathematical model and cost‐effectiveness analysis. We derived model inputs from state and national surveillance data, clinical trials and observational cohort studies. We compared an intervention scenario where 30% of SSP clients initiated buprenorphine treatment on‐site at least once annually to a status quo scenario where no buprenorphine was available on‐site among community treatment providers in Massachusetts, 2020–30. In individuals with opioid use disorder (OUD) we assumed that 80% of SSP clients had recently injected drugs and that treatment within SSPs would have similar or improved retention compared with standard‐of‐care buprenorphine programs, but higher rates of active opioid use while in treatment.
Measurements
Number of treatment initiations (i.e. individuals began treatment on a medication for opioid use disorder or entered medically managed withdrawal), averted fatal opioid overdoses, quality‐adjusted life‐years (QALYs) and life‐time discounted costs from a health sector and a limited societal perspective.
Findings
The status quo scenario resulted in 23 051 fatal overdoses and 1 511 613 treatment initiations over a 10‐year simulation period. An intervention scenario with on‐site SSP buprenorphine treatment averted 4797 (−20.8%) fatal opioid overdoses and resulted in 129 359 (+8.6%) additional treatment initiations compared with the status quo. The intervention scenario was the dominating scenario: providing OUD treatment through Massachusetts SSPs cost less (−$3612 per person) with patients accumulating more QALYs (0.2 per person) compared with the status quo scenario.
Conclusions
Offering buprenorphine treatment on‐site within syringe service programs has the potential to decrease fatal overdoses substantially, improve treatment engagement and save on costs.
A supramolecular approach was undertaken to create functionally activatable cell‐penetrating peptides. Two tetra‐arginines were assembled into an active cell‐penetrating peptide by heterodimerizing ...leucine zippers. Three different leucine‐zipper pairs were evaluated: activation was found to depend on the association constant of the coiled‐coil peptides. The weaker‐binding peptides required an additional disulfide linkage to induce cell‐penetrating capability, whereas for the most‐stable coiled‐coil no additional stabilization was needed. The latter zipper pair was used to show that the induced formation of the coiled coils allows control over the uptake of an oligoarginine CPP‐conjugated cargo protein.
Springing into action: Activation of a cell‐penetrating peptide can be established through noncovalent coiled‐coil formation. Three different leucine‐zipper peptide pairs were tested for their cell‐penetration upon association by fluorescence analysis. This approach can be extended to whole proteins such GFP.
Summary Background The 2014 Zaire Ebola virus outbreak highlighted the need for a safe, effective vaccine with a rapid onset of protection. We report the safety and immunogenicity of the recombinant ...vesicular stomatitis virus-Zaire Ebola virus envelope glycoprotein vaccine (rVSV∆G-ZEBOV-GP) across a 6 log10 dose range in two sequential cohorts. Methods In this phase 1b double-blind, placebo-controlled, dose-response study we enrolled and randomly assigned healthy adults (aged 18–61 years) at eight study sites in the USA to receive a single injection of vaccine or placebo, administered by intramuscular injection. In cohort 1, participants were assigned to receive 3 × 103 , 3 × 104 , 3 × 105 , or 3 × 106 PFU doses of rVSV∆G-ZEBOV-GP or placebo. In cohort 2, participants were assigned to receive 3 × 106 , 9 × 106 , 2 × 107 , or 1 × 108 PFU doses of rVSV∆G-ZEBOV-GP or placebo. Participants were centrally allocated by the study statistician to vaccine groups or placebo through computer-generated randomisation lists. The primary safety outcome was incidence of adverse events within 14 days in the modified intention-to-treat population (all randomly assigned participants who received vaccine or placebo), and the primary outcome for immunogenicity was IgG ELISA antibody titres at day 28 in the per-protocol population. Surveillance was enhanced for arthritis and dermatitis through to day 56. This study is registered with ClinicalTrials.gov , number NCT02314923. Findings Between Dec 26, 2014, and June 8, 2015, 513 participants were enrolled and randomly assigned; one was not immunised because of unsuccessful phlebotomy. In cohort 1, 256 participants received vaccine (3 × 103 n=64, 3 × 104 n=64, 3 × 105 n=64, or 3 × 106 PFU n=64) and 74 received placebo. In cohort 2, 162 participants received vaccine (3 × 106 n=20, 9 × 106 n=47, 2 × 107 n=47, or 1 × 108 PFU n=48) and 20 received placebo. Most adverse events occurred in the first day after vaccination, and were mild to moderate in intensity, of a short duration, and more frequent at high vaccine doses (9 × 106 PFU and greater). At the 2 × 107 PFU dose (used in phase 3 trials), the most common local adverse events versus placebo within the first 14 days were arm pain (57·4% 27 of 47 vs 7·4% seven of 94) and local tenderness (59·6% 28 of 47 vs 8·5% eight of 94). The most common systemic adverse events at the 2 × 107 PFU dose versus placebo, occurring in the first 14 days, were headache (46·8% 22 of 47 vs 27·7% 26 of 94), fatigue (38·3% 18 of 47 vs 19·1% 18 of 94), myalgia (34·0% 16 of 47 vs 10·6% 10 of 94), subjective fever (29·8% 14 of 47 vs 2·1% two of 94), shivering or chills (27·7% 13 of 47 vs 7·4% seven of 94), sweats (23·4% 11 of 47 vs 3·2% three of 94), joint aches and pain (19·1% nine of 47 vs 7·4% seven of 94), objective fever (14·9% seven of 47 vs 1·1% one of 94), and joint tenderness or swelling (14·9% seven of 47 vs 2·1% two of 94). Self-limited, post-vaccination arthritis occurred in 4·5% (19 of 418) of vaccinees (median onset 12·0 days IQR 10–14; median duration 8·0 days 6–15) versus 3·2% (three of 94) of controls (median onset 15·0 days 6–20; median duration 47·0 days 37–339), with no apparent dose relationship. Post-vaccination dermatitis occurred in 5·7% (24 of 418) of vaccinees (median onset 9·0 days IQR 2–12; median duration 7·0 days 4–9) versus 3·2% (three of 94) of controls (median onset 5·0 days 3–53; median duration 33·0 days 5–370). A low-level, transient, dose-dependent viraemia occurred in concert with early reactogenicity. Antibody responses were observed in most participants by day 14. IgG and neutralising antibody titres were dose-related (p=0·0003 for IgG ELISA and p<0·0001 for the 60% plaque-reduction neutralisation test PRNT60 by linear trend). On day 28 at the 2 × 107 PFU dose, the geometric mean IgG ELISA endpoint titre was 1624 (95% CI 1146–2302) and seroconversion was 95·7% (95% CI 85·5–98·8); the geometric mean neutralising antibody titre by PRNT60 was 250 (176–355) and seroconversion was 95·7% (85·5–98·8). These robust immunological responses were sustained for 1 year. Interpretation rVSV∆G-ZEBOV-GP was well tolerated and stimulated a rapid onset of binding and neutralising antibodies, which were maintained through to day 360. The immunogenicity results support selection of the 2 × 107 PFU dose. Funding Biomedical Advanced Research and Development Authority, US Department of Health and Human Services.
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