Normal D-dimer levels after withdrawal of anticoagulant therapy are associated with a reduced risk for recurrence in patients with unprovoked venous thromboembolism (VTE) and may justify stopping ...treatment.
To determine whether patients with a first unprovoked VTE and negative D-dimer test result who stop anticoagulant therapy have a low risk for recurrence.
Prospective management study with blinded outcome assessment. (ClinicalTrials.gov: NCT00720915).
13 university-affiliated clinical centers.
410 adults aged 75 years or younger with a first unprovoked proximal deep venous thrombosis or pulmonary embolism who had completed 3 to 7 months of anticoagulant therapy.
Anticoagulant therapy was stopped if D-dimer test results were negative and was not restarted if results were still negative after 1 month.
Recurrent VTE during an average follow-up of 2.2 years.
In 319 patients (78%) who had 2 negative D-dimer results and did not restart anticoagulant therapy, rates of recurrent VTE were 6.7% (95% CI, 4.8% to 9.0%) per patient-year overall (42 of 319), 9.7% (CI, 6.7% to 13.7%) per patient-year in men (33 of 180), 5.4% (CI, 2.5% to 10.2%) per patient-year in women with VTE not associated with estrogen therapy (9 of 81), and 0.0% (CI, 0.0% to 3.0%) per patient-year in women with VTE associated with estrogen therapy (0 of 58) (P = 0.001 for the 3-group comparison).
Imprecision in female subgroups. Results may not be generalizable to different D-dimer assays from the one used in the study.
The risk for recurrence in patients with a first unprovoked VTE who have negative D-dimer results is not low enough to justify stopping anticoagulant therapy in men but may be low enough to justify stopping therapy in women.
Canadian Institutes of Health Research.
Vitamin A supplementation of 6-59 month old children is currently recommended by the World Health Organization based on evidence that it reduces mortality. There has been considerable interest in ...determining the benefits of neonatal vitamin A supplementation, but the results of existing trials are conflicting. A technical consultation convened by WHO pointed to the need for larger scale studies in Asia and Africa to inform global policy on the use of neonatal vitamin A supplementation. Three trials were therefore initiated in Ghana, India and Tanzania to determine if vitamin A supplementation (50,000 IU) given to neonates once orally on the day of birth or within the next two days will reduce mortality in the period from supplementation to 6 months of age compared to placebo.
The trials are individually randomized, double masked, and placebo controlled. The required sample size is 40,200 in India and 32,000 each in Ghana and Tanzania. The study participants are neonates who fulfil age eligibility, whose families are likely to stay in the study area for the next 6 months, who are able to feed orally, and whose parent(s) provide informed written consent to participate in the study. Neonates randomized to the intervention group receive 50,000 IU vitamin A and the ones randomized to the control group receive placebo at the time of enrollment. Mortality and morbidity information are collected through periodic home visits by a study worker during infancy. The primary outcome of the study is mortality from supplementation to 6 months of age. The secondary outcome of the study is mortality from supplementation to 12 months of age. The three studies will be analysed independent of each other. Subgroup analysis will be carried out to determine the effect by birth weight, sex, and timing of DTP vaccine, socioeconomic groups and maternal large-dose vitamin A supplementation.
The three ongoing studies are the largest studies evaluating the efficacy of vitamin A supplementation to neonates. Policy formulation will be based on the results of efficacy of the intervention from the ongoing randomized controlled trials combined with results of previous studies.
WHO guidelines recommend dolutegravir plus two nucleoside reverse transcriptase inhibitors (NRTIs) for second-line HIV therapy, with NRTI switching from first-line tenofovir to zidovudine. We aimed ...to examine whether dolutegravir is non-inferior to darunavir, the best-in-class protease inhibitor drug, and whether maintaining tenofovir in second-line therapy is non-inferior to switching to zidovudine.
In this prospective, multicentre, open-label, factorial, randomised, non-inferiority trial (NADIA), participants with confirmed HIV first-line treatment failure (HIV-1 RNA ≥1000 copies per mL) were recruited at seven clinical sites in Kenya, Uganda, and Zimbabwe. Following a 2 × 2 factorial design and stratified by site and screening HIV-1 RNA concentration, participants were randomly assigned (1:1:1:1) to receive a 96-week regimen containing either dolutegravir (50 mg once daily) or ritonavir-boosted darunavir (800 mg of darunavir plus 100 mg of ritonavir once daily) in combination with either tenofovir (300 mg once daily) plus lamivudine (300 mg once daily) or zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily). The NRTI drugs allocated by randomisation were administered orally in fixed-dose combination pills; other drugs were administered orally as separate pills. The previously reported primary outcome was the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 48 weeks. Here, we report the main secondary outcome: the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 96 weeks (non-inferiority margin 12%). We analysed this outcome and safety outcomes in the intention-to-treat population, which excluded only those who were randomly assigned in error and withdrawn before receiving trial drugs. This study was registered at ClinicalTrials.gov, NCT03988452, and is complete.
Between July 30 and Dec 18, 2019, we screened 783 patients and enrolled 465. One participant was randomly assigned in error and immediately withdrawn. The remaining 464 participants were randomly assigned to receive either dolutegravir (n=235) or ritonavir-boosted darunavir (n=229) and to receive lamivudine plus either tenofovir (n=233) or zidovudine (n=231). At week 96, 211 (90%) of 235 participants in the dolutegravir group and 199 (87%) of 229 participants in the darunavir group had HIV-1 RNA less than 400 copies per mL (percentage point difference 2·9, 95% CI −3·0 to 8·7), indicating non-inferiority. Nine (4%) participants (all in the dolutegravir group) developed dolutegravir resistance; no participants developed darunavir resistance (p=0·0023). In the other randomised comparison, 214 (92%) of 233 patients in the tenofovir group and 196 (85%) of 231 patients in the zidovudine group had HIV-1 RNA less than 400 copies per mL (percentage point difference 7·0, 95% CI 1·2 to 12·8), showing non-inferiority and indicating the superiority of tenofovir (p=0·019). The proportions of participants with any grade 3–4 adverse event were similar between the dolutegravir (26 11%) and darunavir (28 12%) groups and between the tenofovir (22 9%) and zidovudine (32 14%) groups. There were no deaths related to study medication.
Dolutegravir-based and darunavir-based regimens maintain good viral suppression during 96 weeks; dolutegravir is non-inferior to darunavir but is at greater risk of resistance in second-line therapy. Tenofovir should be continued in second-line therapy, rather than being switched to zidovudine.
Janssen.
BackgroundBiannual vitamin A supplementation is a well-established survival tool for preschool children 6 months and older in vitamin A deficient populations but this schedule misses the opportunity ...to intervene on most young infant deaths. Randomised trials of neonatal vitamin A supplementation (NVAS) in the first few days of life to assess its impact on under 6-month mortality in low/middle-income countries have had varying results.MethodsInvestigators of 11 published randomised placebo-controlled NVAS trials (n=163 567 children) reanalysed their data according to an agreed plan and pooled the primary outcomes of mortality from supplementation through 6 and 12 months of age using random effects models and meta-regression. One investigator withdrew but allowed use of the data.FindingsOverall there was no effect of NVAS on infant survival through 6 (risk ratio (RR) 0.97; 95% CI 0.89 to 1.06) or 12 months of age (RR 1.00; 95% CI 0.93 to 1.08) but results varied by study population characteristics.NVAS significantly reduced 6-month mortality among the trials conducted in Southern Asia (RR 0.87; 95% CI 0.77 to 0.98), in contexts with moderate or severe vitamin A deficiency (defined as 10% or higher proportion of women with serum retinol <0.7 µmol/L or 5% or more women with night blindness) (RR 0.87; 95% CI 0.80 to 0.94), early infant mortality was 30 or more per 1000 live births (RR 0.91; 95% CI 0.85 to 0.98), 75% or more of infant mortality occurred in the first 6 months of life (RR 0.92; 95% CI 0.84 to 1.01), or where >32% mothers had no schooling (RR 0.88; 95% CI 0.80 to 0.96). NVAS did not reduce mortality in the first 6 months of life in trials conducted in Africa, in contexts characterised by a low prevalence of vitamin A deficiency, lower rates of infant mortality and where maternal education was more prevalent. There was a suggestion of increased infant mortality in trials conducted in Africa (RR 1.07; 95% CI 1.00 to 1.15).Individual-level characteristics such as sex, birth weight, gestational age and size, age at dosing, parity, time of breast feeding initiation, maternal education and maternal vitamin A supplementation did not modify the impact of NVAS.ConclusionNVAS reduced infant mortality in South Asia, in contexts where the prevalence of maternal vitamin A deficiency is moderate to severe and early infant mortality is high; but it had no beneficial effect on infant survival in Africa, in contexts where the prevalence of maternal vitamin A deficiency is lower, early infant mortality is low.
The defensive slime of hagfishes contains thousands of intermediate filament protein threads that are manufactured within specialized gland thread cells. The material properties of these threads ...rival those of spider dragline silks, which makes them an ideal model for biomimetic efforts to produce sustainable protein materials, yet how the thread is produced and organized within the cell is not well understood. Here we show how changes in nuclear morphology, size and position can explain the three-dimensional pattern of thread coiling in gland thread cells, and how the ultrastructure of the thread changes as very young thread cells develop into large cells with fully mature coiled threads. Our model provides an explanation for the complex process of thread assembly and organization that has fascinated and perplexed biologists for over a century, and provides valuable insights for the quest to manufacture high-performance biomimetic protein materials.
ObjectivesGlobal vaccination policy advocates for identifying and targeting groups who are underserved by vaccination to increase equity and uptake. We investigated whether birth weight and other ...factors are determinants of neonatal BCG vaccination in order to identify infants underserved by vaccination.MethodsWe used logistic regression to calculate adjusted ORs (AORs) for the association between birth weight (categorised as non-low birth weight (NLBW) (≥2.50 kg) and low birth weight (LBW) (2–2.49 kg, 1.50–1.99 kg and <1.50 kg)) and non-vaccination with BCG at the end of the neonatal period (0–27 days). We assessed whether this association varied by place of delivery and infant illness. We calculated how BCG timing and uptake would improve by ensuring the vaccination of all facility-born infants prior to discharge.ResultsThere was a strong dose–response relationship between LBW and not receiving BCG in the neonatal period (p-trend<0.0001). Infants weighing 1.50–1.99 kg had odds of non-vaccination 1.6 times (AOR 1.64; 95% CI 1.30 to 2.08), and those weighing <1.50 kg 2.4 times (AOR 2.42; 95% CI 1.50 to 3.88) those of NLBW infants. Other determinants included place of delivery, distance to the health facility and socioeconomic status. Neither place of delivery nor infant illness modified the association between birth weight and vaccination (p-interaction all >0.19). Facility-born infants were vaccinated at a mean of 6 days, suggesting that they were not vaccinated in the facility at birth but were referred for vaccination.ConclusionsLBW is a risk factor for neonatal under-vaccination, even for facility-born infants. Ensuring vaccination at facility births would substantively improve timing and equitable BCG vaccination.
The goal of this roadmap paper is to summarize the state-of-the-art and to identify critical challenges for the systematic software engineering of self-adaptive systems. The paper is partitioned into ...four parts, one for each of the identified essential views of self-adaptation: modelling dimensions, requirements, engineering, and assurances. For each view, we present the state-of-the-art and the challenges that our community must address. This roadmap paper is a result of the Dagstuhl Seminar 08031 on “Software Engineering for Self-Adaptive Systems,” which took place in January 2008.
Abstract
Acute Rheumatic Fever (ARF) is an autoimmune condition resulting from untreated Group A Streptococcal (GAS) infection of the upper respiratory tract and possibly skin. Repeated untreated and ...severe episodes of ARF can cause permanent cardiac damage known as Rheumatic Heart Disease (RHD). Rates of ARF in New Zealand and Australia are among the highest in the world, particularly amongst Māori and Pacific and Indigenous Aboriginal children. Monthly injections of Benzathine Penicillin G (BPG) are given intramuscularly to prevent GAS infections that can lead to ARF and cause RHD. Early studies exploring the Pharmacokinetics (PK) properties of BPG were conducted in healthy, fit, young military recruits without ARF/RHD. BPG bioavailability, metabolism may differ in paediatric populations groups with ARF who have comorbidities and vary in Body Mass Index. This project seeks to determine the PK characteristics in a paediatric population currently receiving monthly injections of BPG while at the same time monitoring antibody immune responses to possible GAS infections. This is a prospective cohort study in a paediatric population of Wellington based children and teens (aged 5–21 years of predominantly Pasifika and Māori heritage) with a previous diagnosis of ARF and are receiving monthly BPG injections via community services. Participants will contribute finger prick blood samples over time for Dried Blood Spot assays designed to quantify penicillin G levels in the blood and measure streptococcal serology. Routine throat swab samples will also be collected with ASOT antibody levels monitored for GAS breakthrough infections. This is the first population PK study exploring use of BPG in Māori and Pacific children previously diagnosed with ARF.
Electric fields are a ubiquitous feature of the ionosphere and are intimately linked with aurora through particle precipitation and field-aligned currents. They exhibit order-of-magnitude changes on ...temporal and spatial scales of seconds and kilometres respectively which are not easy to measure; knowing their true magnitude and temporal variability is important for a theoretical understanding of auroral processes. We present a unique method to estimate ionospheric electric fields in the region close to (kilometre scale) a dynamic auroral arc by solving the continuity equation for the metastable O+(2P) ions, which emit as they move under the influence of electric fields during their 5 s lifetime. The main advantage of this optical method is the increase in temporal resolution over other methods such as ground-based radars.
Simultaneous measurements of emission at 732.0 nm (from the O+(2P) ions) and prompt emissions at 673.0 nm (N2) and 777.4 nm (O), all at high spatial (100 m) and temporal (0.05 s) resolution,
are used in the solution of the continuity equation, which gives the dynamic changes of the O+ ion population at all heights in a 3D volume close to the magnetic zenith. Perspective effects are taken into account by a new geometric method, which is based on an accurate estimate of the magnetic zenith position.
The emissions resulting from the metastable ions are converted to brightness images by projecting them onto the plane of the ground, and the projected images are then compared with the measured images. The flow velocity of the ions is a free parameter in the solution of the continuity equation; the value that minimises the difference between the modelled and observed images is the extracted flow velocity at each time step.
We demonstrate the method with an example event during the passage of a brightening arc feature, lasting about 10 s, in which the inferred electric fields vary between 20 and 120 mV m−1.
These inferred electric fields are compared with SuperDARN measurements, which have an average value of 30 mV m−1.
An excellent agreement is found in the magnitude and direction of the background electric field; an increase in magnitude during the brightening of the arc feature supports theories of small-scale auroral arc formation and electrodynamics.
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