The ideas underlying this thesis are that lipidomics may improve the diagnosis of liver metabolic diseases, and can provide further insights into the underlying pathophysiology of these diseases.... Show moreThe ideas underlying this thesis are that lipidomics may improve the diagnosis of liver metabolic diseases, and can provide further insights into the underlying pathophysiology of these diseases. However to achieve this, the measurement of lipids should be further improved by enabling comprehensive coverage, accurate identification and quantitation. Therefore, in this thesis, new analytical methodologies using LC-MS for the accurate detection and quantitation of lipids are developed. These methods are then applied to MCADD samples to identify lipid biomarkers, which are further correlated with gene expression analysis to understand the underlying biochemical pathways. Show less
Singh, M.; Kiyuna, L.A.; Odendaal, C.; Bakker, B.M.; Harms, A.C.; Hankemeier, T. 2024
BackgroundChronic daily headaches (CDH) are common and associated with significant morbidity, poor quality of life, and substantial burden on the healthcare system. CDH tends to be refractory to... Show moreBackgroundChronic daily headaches (CDH) are common and associated with significant morbidity, poor quality of life, and substantial burden on the healthcare system. CDH tends to be refractory to conventional medical management and/or patients cannot afford expensive treatments. It is stipulated that CDH share a mechanism of central sensitization in the trigeminocervical complex, mediated by activation of the N-methyl-d-aspartate (NMDA) receptors. Ketamine, a non-competitive NMDA antagonist, has been used in the treatment of chronic pain, but its role in CDH has not been completely established. This trial aims to evaluate the effect of high-dose IV ketamine infusions (compared to placebo) on the number of headache days at 28 days post-infusion.MethodsA multicenter, placebo-controlled, randomized controlled trial will be conducted with two parallel groups and blinding of participants and outcome assessors. The study will include 56 adults with a CDH diagnosis as per ICHD-3 criteria. Participants will be randomized (1:1) to either ketamine (1 mg. kg−1 bolus followed by infusion of 1 mg. kg−1. h−1 for 6 h) or placebo (0.9% saline in the same volume and infusion rate as the trial medication) bolus and infusion for 6 h. The impact on the number of monthly headache days, headache intensity, physical activity, mood, sleep, quality of life, analgesic consumption, and adverse effects will be recorded at baseline, immediately post-infusion, and from 1 to 28 days, 29 to 56 days, and 57 to 84 days after the infusionDiscussionDespite advancements in treatment, many patients continue to suffer from CDH. This trial investigates whether high-dose IV ketamine infusions can effectively and safely improve the CDH burden as compared to a placebo infusion. This treatment could become a safe, affordable, and widely available option for patients living with refractory headache. Show less
Background: Antibodies against mycobacterial proteins are highly specific, but lack sensitivity, whereas cytokines have been shown to be sensitive but not very specific in the diagnosis of... Show moreBackground: Antibodies against mycobacterial proteins are highly specific, but lack sensitivity, whereas cytokines have been shown to be sensitive but not very specific in the diagnosis of tuberculosis (TB). We assessed combinations between antibodies and cytokines for diagnosing TB. Methods: Immuoglubulin (Ig) A and IgM antibody titres against selected mycobacterial antigens including Apa, NarL, Rv3019c, PstS1, LAM, "Kit 1" (MTP64 and Tpx)", and "Kit 2" (MPT64, Tpx and 19 kDa) were evaluated by ELISA in plasma samples obtained from individuals under clinical suspicion for TB. Combinations between the antibody titres and previously published cytokine responses in the same participants were assessed for diagnosing active TB. Results: Antibody responses were more promising when used in combination (AUC of 0.80), when all seven antibodies were combined. When anti-"Kit 1"-IgA levels were combined with five host cytokine biomarkers, the AUC increased to 97% (92-100%) with a sensitivity of 95% (95% CI, 73-100%), and specificity of 88.5% (95% CI, 68.7-97%) achieved after leave-one-out cross validation. Conclusion: When used in combination, IgA titres measured with ELISA against multiple Mycobacterium tuberculosis antigens may be useful in the diagnosis of TB. However, diagnostic accuracy may be improved if the antibodies are used in combination with cytokines. Show less
Sagastizabal, R.; Bonet Monroig, X.; Singh, M.; Rol, M.A.; Bultink, C.C.; Fu, X.; ... ; DiCarlo, L. 2019
Variational quantum eigensolvers offer a small-scale testbed to demonstrate the performance of error mitigation techniques with low experimental overhead. We present successful error mitigation by... Show moreVariational quantum eigensolvers offer a small-scale testbed to demonstrate the performance of error mitigation techniques with low experimental overhead. We present successful error mitigation by applying the recently proposed symmetry verification technique to the experimental estimation of the ground-state energy and ground state of the hydrogen molecule. A finely adjustable exchange interaction between two qubits in a circuit QED processor efficiently prepares variational ansatz states in the single-excitation subspace respecting the parity symmetry of the qubit-mapped Hamiltonian. Symmetry verification improves the energy and state estimates by mitigating the effects of qubit relaxation and residual qubit excitation, which violate the symmetry. A full-density-matrix simulation matching the experiment dissects the contribution of these mechanisms from other calibrated error sources. Enforcing positivity of the measured density matrix via scalable convex optimization correlates the energy and state estimate improvements when using symmetry verification, with interesting implications for determining system properties beyond the ground-state energy. Show less
Post-menopausal women exhibit an exponential increase in the incidence of heart failure with preserved ejection fraction compared with men of the same age, which indicates a potential role of... Show morePost-menopausal women exhibit an exponential increase in the incidence of heart failure with preserved ejection fraction compared with men of the same age, which indicates a potential role of hormonal changes in subclinical and clinical diastolic dysfunction. This paper reviews the preclinical evidence that demonstrates the involvement of estrogen in many regulatory molecular pathways of cardiac diastolic function and the clinical data that investigates the effect of estrogen on diastolic function in post-menopausal women. Published reports show that estrogen deficiency influences both early diastolic relaxation via calcium homeostasis and the late diastolic compliance associated with cardiac hypertrophy and fibrosis. Because of the high risk of diastolic dysfunction and heart failure with preserved ejection fraction in post-menopausal women and the positive effects of estrogen on preserving cardiac function, further clinical studies are needed to clarify the role of endogenous estrogen or hormone replacement in mitigating the onset and progression of heart failure with preserved ejection fraction in women. (C) 2019 Published by Elsevier on behalf of the American College of Cardiology Foundation. Show less
Bonet-Monroig, X.; Sagastizabal, R.; Singh, M.; O'Brien, T.E. 2018
We investigate the performance of error mitigation via measurement of conserved symmetries on near-term devices. We present two protocols to measure conserved symmetries during the bulk of an... Show moreWe investigate the performance of error mitigation via measurement of conserved symmetries on near-term devices. We present two protocols to measure conserved symmetries during the bulk of an experiment, and develop a third, zero-cost, post-processing protocol which is equivalent to a variant of the quantum subspace expansion. We develop methods for inserting global and local symmetries into quantum algorithms, and for adjusting natural symmetries of the problem to boost the mitigation of errors produced by different noise channels. We demonstrate these techniques on two- and four-qubit simulations of the hydrogen molecule (using a classical density-matrix simulator), finding up to an order of magnitude reduction of the error in obtaining the ground-state dissociation curve. Show less
Zhang, Y.; Blasco-Colmenares, E.; Harms, A.C.; London, B.; Halder, I.; Singh, M.; ... ; Cheng, A. 2016
