AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

TYYTYVÄISYYS SUKANVETOLAITTEESEEN : QUEST 2.0-kyselyn toteuttaminen Peruspalvelukeskus Oiva-liikelaitoksessa ja Parkanon kaupungissa

Opinnäytetyön tavoitteena oli selvittää sukanvetolaitteen käyttäjien tyytyväisyyttä saa¬maansa apuvälineeseen ja apuvälineprosessiin. Tutkimus toteutettiin hyödyntämällä QUEST 2.0-mittaria. QUEST (Quebec User Evaluation of Satisfaction with Assistive Technology) on 12 -kohtainen arviointimenetelmä, jonka avulla arvioidaan käyttäjän tyytyväisyyttä käyttämäänsä apuvälineeseen ja siihen liittyviin palveluihin. Toimintaterapian perusajatuksena on, että aktiivinen osallistuminen merkityksellisiin toimintoihin tukee ihmisen terveyttä sekä hyvinvointia. Apuvälineen avulla voidaan edistää toimintaan osallistumista ja sen suorittamista. Apuvälineen käytön ja tyytyväisyyden tutkiminen on tärkeää, koska siten ammattilaiset saavat tietoonsa käyttöä lisääviä tekijöitä. Tutkimus toteutettiin Peruspalvelukeskus Oiva-liikelaitoksessa ja Parkanon kaupungissa. Kysely lähetettiin 78 henkilölle, jotka olivat saaneet sukanvetolaitteen käyttöönsä vuoden 2004 jälkeen. 46 henkilöä vastasi ja palautti kyselyn, joten vastausprosentti oli 59 %. Niistä hyväksyttyjä vastauksia oli 36 vastaajalla. Keskiarvolla mitaten vastaajat olivat tyytyväisiä sekä sukanvetolaitteeseen että siihen liittyneeseen apuvälineprosessiin. Tyytyväisyydessä oli kuitenkin paljon hajontaa vastaajien välillä. Vastaajien mukaan tärkeimmät tekijät liittyen apuvälineeseen ja sen prosessiin olivat käytön helppous, tarkoituksenmukaisuus, paino, turvallisuus ja luotettavuus, kestävyys sekä apuvä¬lineen käyttöön saamisen prosessi. Tutkimuksen avulla saatujen tulosten perusteella yhteis¬työtahot pystyivät muokkaamaan sukanvetolaitteen apuvälineprosessia tarpeelliseen suun¬taan. He myös saivat käyttökokemuksen QUEST 2.0-kyselystä.The purpose of this study was to survey the satisfaction of stocking aid users with the device and with the related service process. The survey was conducted by using the QUEST 2.0 measurement tool. QUEST (Quebec User Evaluation of Satisfaction with Assistive Technology) is a 12-item assessment method and it is used to assess users’ satisfaction with their assistive devices and the related services. The basic principle in occupational therapy is that active participation in meaningful occupations supports people’s health as well as their well-being. By using assistive devices it is possible to support participation in and the performance of occupations. It is important to study the use of a device and the related satisfaction because this is how professionals will learn about the factors that will increase their use. The survey was conducted in the Basic Service Centre Oiva Ltd and the town of Parkano. A questionnaire was sent to 78 persons who had received a stocking aid for their use after the year 2004. 46 persons returned the questionnaire, which gave a response rate of 59 per cent. Out of them 36 persons had acceptable answers. Based on the mean value, the respondents were satisfied with the stocking aid and the related services. There was, however, a great deal of dispersion between the respondents. According to the respondents, the most important factors concerning the device and its services were simplicity of use, effectiveness, weight, safety, durability and delivery. With the results of this study the cooperation partners were able to modify the service process of the stocking aid to a necessary direction. They were also able to have a user experience of the QUEST 2.0 surve

Metals affect the structure and activity of human plasminogen activator inhibitor-1. I. Modulation of stability and protease inhibition

Human plasminogen activator inhibitor type 1 (PAI-1) is a serine protease inhibitor with a metastable active conformation. Under physiological conditions, half of the inhibitor transitions to a latent state within 1–2 h. The interaction between PAI-1 and the plasma protein vitronectin prolongs this active lifespan by ∼50%. Previously, our group demonstrated that PAI-1 binds to resins using immobilized metal affinity chromatography (Day, U.S. Pat. 7,015,021 B2, March 21, 2006). In this study, the effect of these metals on function and stability was investigated by measuring the rate of the transition from the active to latent conformation. All metals tested showed effects on stability, with the majority falling into one of two types depending on their effects. The first type of metal, which includes magnesium, calcium and manganese, invoked a slight stabilization of the active conformation of PAI-1. A second category of metals, including cobalt, nickel and copper, showed the opposite effects and a unique vitronectin-dependent modulation of PAI-1 stability. This second group of metals significantly destabilized PAI-1, although the addition of vitronectin in conjunction with these metals resulted in a marked stabilization and slower conversion to the latent conformation. In the presence of copper and vitronectin, the half-life of active PAI-1 was extended to 3 h, compared to a half-life of only ∼30 min with copper alone. Nickel had the largest effect, reducing the half-life to ∼5 min. Together, these data demonstrate a heretofore-unknown role for metals in modulating PAI-1 stability

Low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy: Rationale and design of the High-low study, a randomised trial of two doses

BACKGROUND: Women with a history of venous thromboembolism (VTE) have a 2% to 10% absolute risk of VTE recurrence during subsequent pregnancies. Therefore, current guidelines recommend that all pregnant women with a history of VTE receive pharmacologic thromboprophylaxis. The optimal dose of low-molecular-weight heparin (LMWH) for thromboprophylaxis is unknown. In the Highlow study (NCT 01828697; www.highlowstudy.org), we compare a fixed low dose of LMWH with an intermediate dose of LMWH for the prevention of pregnancy-associated recurrent VTE. We present the rationale and design features of this study. METHODS: The Highlow study is an investigator-initiated, multicentre, international, open-label, randomised trial. Pregnant women with a history of VTE and an indication for ante- and postpartum pharmacologic thromboprophylaxis are included before 14weeks of gestation. The primary efficacy outcome is symptomatic recurrent VTE during pregnancy and 6weeks postpartum. The primary safety outcomes are clinically relevant bleeding, blood transfusions before 6weeks postpartum and mortality. Patients are closely monitored to detect cutaneous reactions to LMWH and are followed for 3months after delivery. A central independent adjudication committee adjudicates all suspected outcome events. CONCLUSION: The Highlow study is the first large randomised controlled trial in pregnancy that will provide high-quality evidence on the optimal dose of LWMH thromboprophylaxis for the prevention of recurrent VTE in pregnant women with a history of VTE.publisher: Elsevier articletitle: Low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy: Rationale and design of the Highlow study, a randomised trial of two doses journaltitle: Thrombosis Research articlelink: http://dx.doi.org/10.1016/j.thromres.2016.06.001 content_type: article copyright: © 2016 Elsevier Ltd. All rights reserved.status: publishe

Low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy: Rationale and design of the High-low study, a randomised trial of two doses

Women with a history of venous thromboembolism (VTE) have a 2% to 10% absolute risk of VTE recurrence during subsequent pregnancies. Therefore, current guidelines recommend that all pregnant women with a history of VTE receive pharmacologic thromboprophylaxis. The optimal dose of low-molecular-weight heparin (LMWH) for thromboprophylaxis is unknown. In the Highlow study (NCT 01828697; www.highlowstudy.org), we compare a fixed low dose of LMWH with an intermediate dose of LMWH for the prevention of pregnancy-associated recurrent VTE. We present the rationale and design features of this study. The Highlow study is an investigator-initiated, multicentre, international, open-label, randomised trial. Pregnant women with a history of VTE and an indication for ante- and postpartum pharmacologic thromboprophylaxis are included before 14weeks of gestation. The primary efficacy outcome is symptomatic recurrent VTE during pregnancy and 6weeks postpartum. The primary safety outcomes are clinically relevant bleeding, blood transfusions before 6weeks postpartum and mortality. Patients are closely monitored to detect cutaneous reactions to LMWH and are followed for 3months after delivery. A central independent adjudication committee adjudicates all suspected outcome events. The Highlow study is the first large randomised controlled trial in pregnancy that will provide high-quality evidence on the optimal dose of LWMH thromboprophylaxis for the prevention of recurrent VTE in pregnant women with a history of VT

Intermediate-dose versus low-dose low-molecular-weight heparin in pregnant and post-partum women with a history of venous thromboembolism (Highlow study):an open-label, multicentre, randomised, controlled trial

BACKGROUND: Pregnancy-related venous thromboembolism is a leading cause of maternal morbidity and mortality, and thromboprophylaxis is indicated in pregnant and post-partum women with a history of venous thromboembolism. The optimal dose of low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy and the post-partum period is uncertain. METHODS: In this open-label, randomised, controlled trial (Highlow), pregnant women with a history of venous thromboembolism were recruited from 70 hospitals in nine countries (the Netherlands, France, Ireland, Belgium, Norway, Denmark, Canada, the USA, and Russia). Women were eligible if they were aged 18 years or older with a history of objectively confirmed venous thromboembolism, and with a gestational age of 14 weeks or less. Eligible women were randomly assigned (1:1), before 14 weeks of gestational age, using a web-based system and permuted block randomisation (block size of six), stratified by centre, to either weight-adjusted intermediate-dose or fixed low-dose low-molecular-weight heparin subcutaneously once daily until 6 weeks post partum. The primary efficacy outcome was objectively confirmed venous thromboembolism (ie, deep-vein thrombosis, pulmonary embolism, or unusual site venous thrombosis), as determined by an independent central adjudication committee, in the intention-to-treat (ITT) population (ie, all women randomly assigned to treatment). The primary safety outcome was major bleeding which included antepartum, early post-partum (within 24 h after delivery), and late post-partum major bleeding (24 h or longer after delivery until 6 weeks post partum), assessed in all women who received at least one dose of assigned treatment and had a known end of treatment date. This study is registered with ClinicalTrials.gov, NCT01828697, and is now complete. FINDINGS: Between April 24, 2013, and Oct 31, 2020, 1339 pregnant women were screened for eligibility, of whom 1110 were randomly assigned to weight-adjusted intermediate-dose (n=555) or fixed low-dose (n=555) low-molecular-weight heparin (ITT population). Venous thromboembolism occurred in 11 (2%) of 555 women in the weight-adjusted intermediate-dose group and in 16 (3%) of 555 in the fixed low-dose group (relative risk [RR] 0·69 [95% CI 0·32-1·47]; p=0·33). Venous thromboembolism occurred antepartum in five (1%) women in the intermediate-dose group and in five (1%) women in the low-dose group, and post partum in six (1%) women and 11 (2%) women. On-treatment major bleeding in the safety population (N=1045) occurred in 23 (4%) of 520 women in the intermediate-dose group and in 20 (4%) of 525 in the low-dose group (RR 1·16 [95% CI 0·65-2·09]). INTERPRETATION: In women with a history of venous thromboembolism, weight-adjusted intermediate-dose low-molecular-weight heparin during the combined antepartum and post-partum periods was not associated with a lower risk of recurrence than fixed low-dose low-molecular-weight heparin. These results indicate that low-dose low-molecular-weight heparin for thromboprophylaxis during pregnancy is the appropriate dose for the prevention of pregnancy-related recurrent venous thromboembolism. FUNDING: French Ministry of Health, Health Research Board Ireland, GSK/Aspen, and Pfizer