Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide1, 2. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis3, 4, 5, several of which are currently in clinical trials6, 7, 8. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis

An Ontological Approach to Inform HMI Designs for Minimizing Driver Distractions with ADAS

ADAS (Advanced Driver Assistance Systems) are in-vehicle systems designed to enhance driving safety and efficiency as well as comfort for drivers in the driving process. Recent studies have noticed that when Human Machine Interface (HMI) is not designed properly, an ADAS can cause distraction which would affect its usage and even lead to safety issues. Current understanding of these issues is limited to the context-dependent nature of such systems. This paper reports the development of a holistic conceptualisation of how drivers interact with ADAS and how such interaction could lead to potential distraction. This is done taking an ontological approach to contextualise the potential distraction, driving tasks and user interactions centred on the use of ADAS. Example scenarios are also given to demonstrate how the developed ontology can be used to deduce rules for identifying distraction from ADAS and informing future designs

Search for stop and higgsino production using diphoton Higgs boson decays

Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top-quark (stop) and the Higgs boson (higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7 inverse femtobarns of proton-proton collision data at sqrt(s) = 8 TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the stop mass below 360 to 410 GeV, depending on the higgsino mass

Severe early onset preeclampsia: short and long term clinical, psychosocial and biochemical aspects

Preeclampsia is a pregnancy specific disorder commonly defined as de novo hypertension and proteinuria after 20 weeks gestational age. It occurs in approximately 3-5% of pregnancies and it is still a major cause of both foetal and maternal morbidity and mortality worldwide1. As extensive research has not yet elucidated the aetiology of preeclampsia, there are no rational preventive or therapeutic interventions available. The only rational treatment is delivery, which benefits the mother but is not in the interest of the foetus, if remote from term. Early onset preeclampsia (<32 weeks’ gestational age) occurs in less than 1% of pregnancies. It is, however often associated with maternal morbidity as the risk of progression to severe maternal disease is inversely related with gestational age at onset2. Resulting prematurity is therefore the main cause of neonatal mortality and morbidity in patients with severe preeclampsia3. Although the discussion is ongoing, perinatal survival is suggested to be increased in patients with preterm preeclampsia by expectant, non-interventional management. This temporising treatment option to lengthen pregnancy includes the use of antihypertensive medication to control hypertension, magnesium sulphate to prevent eclampsia and corticosteroids to enhance foetal lung maturity4. With optimal maternal haemodynamic status and reassuring foetal condition this results on average in an extension of 2 weeks. Prolongation of these pregnancies is a great challenge for clinicians to balance between potential maternal risks on one the eve hand and possible foetal benefits on the other. Clinical controversies regarding prolongation of preterm preeclamptic pregnancies still exist – also taking into account that preeclampsia is the leading cause of maternal mortality in the Netherlands5 - a debate which is even more pronounced in very preterm pregnancies with questionable foetal viability6-9. Do maternal risks of prolongation of these very early pregnancies outweigh the chances of neonatal survival? Counselling of women with very early onset preeclampsia not only comprises of knowledge of the outcome of those particular pregnancies, but also knowledge of outcomes of future pregnancies of these women is of major clinical importance. This thesis opens with a review of the literature on identifiable risk factors of preeclampsia

Measurement of nuclear modification factors of gamma(1S)), gamma(2S), and gamma(3S) mesons in PbPb collisions at root s(NN)=5.02 TeV

The cross sections for ϒ(1S), ϒ(2S), and ϒ(3S) production in lead-lead (PbPb) and proton-proton (pp) collisions at √sNN = 5.02 TeV have been measured using the CMS detector at the LHC. The nuclear modification factors, RAA, derived from the PbPb-to-pp ratio of yields for each state, are studied as functions of meson rapidity and transverse momentum, as well as PbPb collision centrality. The yields of all three states are found to be significantly suppressed, and compatible with a sequential ordering of the suppression, RAA(ϒ(1S)) > RAA(ϒ(2S)) > RAA(ϒ(3S)). The suppression of ϒ(1S) is larger than that seen at √sNN = 2.76 TeV, although the two are compatible within uncertainties. The upper limit on the RAA of ϒ(3S) integrated over pT, rapidity and centrality is 0.096 at 95% confidence level, which is the strongest suppression observed for a quarkonium state in heavy ion collisions to date. © 2019 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Funded by SCOAP3.Peer reviewe

An embedding technique to determine ττ backgrounds in proton-proton collision data

An embedding technique is presented to estimate standard model tau tau backgrounds from data with minimal simulation input. In the data, the muons are removed from reconstructed mu mu events and replaced with simulated tau leptons with the same kinematic properties. In this way, a set of hybrid events is obtained that does not rely on simulation except for the decay of the tau leptons. The challenges in describing the underlying event or the production of associated jets in the simulation are avoided. The technique described in this paper was developed for CMS. Its validation and the inherent uncertainties are also discussed. The demonstration of the performance of the technique is based on a sample of proton-proton collisions collected by CMS in 2017 at root s = 13 TeV corresponding to an integrated luminosity of 41.5 fb(-1).Peer reviewe

Azimuthal separation in nearly back-to-back jet topologies in inclusive 2-and 3-jet events in pp collisions at root s=13TeV

A measurement for inclusive 2- and 3-jet events of the azimuthal correlation between the two jets with the largest transverse momenta, Delta phi(12), is presented. The measurement considers events where the two leading jets are nearly collinear ("back-to-back") in the transverse plane and is performed for several ranges of the leading jet transverse momentum. Proton-proton collision data collected with the CMS experiment at a center-of-mass energy of 13 TeV and corresponding to an integrated luminosity of 35.9 fb(-1) are used. Predictions based on calculations using matrix elements at leading-order and next-to-leading-order accuracy in perturbative quantum chromodynamics supplemented with leading-log parton showers and hadronization are generally in agreement with themeasurements. Discrepancies between the measurement and theoretical predictions are as large as 15%, mainly in the region 177 degrees <Delta phi(12) <180 degrees. The 2- and 3-jet measurements are not simultaneously described by any of models.Peer reviewe

Search for dark matter particles produced in association with a Higgs boson in proton-proton collisions at √s = 13 TeV

© 2020, The Author(s). A search for dark matter (DM) particles is performed using events with a Higgs boson candidate and large missing transverse momentum. The analysis is based on proton- proton collision data at a center-of-mass energy of 13 TeV collected by the CMS experiment at the LHC in 2016, corresponding to an integrated luminosity of 35.9 fb−1. The search is performed in five Higgs boson decay channels: h → b b ¯ , γγ, τ+τ−, W+W−, and ZZ. The results from the individual channels are combined to maximize the sensitivity of the analysis. No significant excess over the expected standard model background is observed in any of the five channels or in their combination. Limits are set on DM production in the context of two simplified models. The results are also interpreted in terms of a spin-independent DM-nucleon scattering cross section and compared to those from direct-detection DM experiments. This is the first search for DM particles produced in association with a Higgs boson decaying to a pair of W or Z bosons, and the first statistical combination based on five Higgs boson decay channels. [Figure not available: see fulltext.].SCOAP

Evaluation of vibrotactile feedback for forward collision warning on the steering wheel and seatbelt

This study evaluated the efficacy of haptic feedback for Forward Collision Warning (FCW). Haptic FCW using vibrotactile feedback was delivered to the participants through a steering wheel or a seatbelt when the participants could possibly divert their visual attention from the road. In addition, we provided a no warning scenario as the control condition. A virtual driving simulator implementing the visually distracted driving situation and forward collision scenarios was developed. A visually distracted driving situation was simulated by having participants perform a text-entry task while they were following a preceding car. Participants in two age groups (30-40 years old and 50-60 years old) were recruited to define an age effect. The reaction time (RT) to the haptic FCW and the collision prevention rate (CPR) were used as performance measures while the participants&apos; perception on the usefulness of the haptic warnings and their overall satisfaction with the system were used as preference measures. The results show that participants had shorter RT and higher CPR with haptic warnings. The interaction between the haptic warning types and the age was significant to the CPR. The younger group showed lower CPR than the older group in the control condition, higher CPR with the haptic steering wheel, and similar CPR with the haptic seatbelt. Similar to the performance measures, the preference measure results demonstrate that the participants of both age groups felt the haptic FCWs were useful and satisfactory. We conclude that the haptic steering wheel and the haptic seatbelt could be effectively used as forward collision warnings. Relevance to industry: This study evaluates the effectiveness of haptic warning signals on a steering wheel and a seatbelt for FCW. The effect of the haptic warnings was evaluated by conducting an experiment using a driving simulator and the specifications of the warnings tested are laid out in this paper. The result of this study could be used for developing a haptic FCW by automobile manufacturers. © 2012 Elsevier B.V.X1118Nscopu

Efficacy of Haptic Blind Spot Warnings Applied through a Steering Wheel or a Seatbelt

This study evaluates the efficacy of haptic feedback for the Blind Spot Warnings (BSWs) that are delivered to a driver through a steering wheel or a seatbelt. To this end, we developed a virtual driving simulator that implemented potential side collision scenarios. Haptic BSWs were issued as a vibrotactile alert during lane changes if a car in the target lane approached from the participant’s blind spot at a faster speed. The two haptic warning types were assessed through a human factors experiment with participants of two age groups: younger (30–40 years) and older (50–60 years). No warning condition was also included as the control condition. As performance measures, the Collision Prevention Rate (CPR) and the Minimum Distance by which a collision was Avoided (MDA) were collected. As preference measures, the participants’ perception of usefulness of the haptic warnings and their overall satisfaction were used. Experimental results showed that the highest CPR, the longest MDA, and the highest preference were achieved when BSWs were delivered through the steering wheel. For the seatbelt BSW, the CPR and MDA did not increase with statistical significance than those of the no-warning condition, but the participants felt that the haptic seatbelt was useful with high satisfaction. Interestingly, the scores of perceived usefulness and satisfaction were higher with the older group, suggesting that older drivers can be more willing to accept these new types of warning. In addition, the experiment suggested several factors that need to be studied to further improve the performance and preference of haptic BSW, such as warning issue timing and vibration intensity.1111ssciscopu