10,870 research outputs found

    About Women And Men:The relevance of sex differences In cardiovascular diseases

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    How real-world data can facilitate the development of precision medicine treatment in psychiatry

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    Precision medicine has the ambition to improve treatment response and clinical outcomes through patient stratification, and holds great potential in mental disorders. However, several important factors are needed to transform current practice into a ‚Äúprecision psychiatry‚ÄĚ framework. Most important are (1) the generation of accessible large real-world training and test data including genomic data integrated from multiple sources, (2) the development and validation of advanced analytical tools for stratification and prediction, and (3) the development of clinically useful management platforms for patient monitoring that can be integrated into healthcare systems in real-life settings. This narrative review summarizes strategies for obtaining the key elements ‚Äď well-powered samples from large biobanks, integrated with electronic health records and health registry data using novel artificial intelligence algorithms ‚Äď to predict outcomes in severe mental disorders and translate these models into clinical management and treatment approaches. Key elements are massive mental health data and novel artificial intelligence algorithms. For the clinical translation of these strategies, we discuss a precision medicine platform for improved management of mental disorders. We include use cases to illustrate how precision medicine interventions could be brought into psychiatry to improve the clinical outcomes of mental disorders

    A genome-wide association study of 24-hour urinary excretion of endocrine disrupting chemicals

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    Ubiquitous exposure to environmental endocrine disrupting chemicals (EDCs) instigates a major public health problem, but much remains unknown on the inter-individual differences in metabolism and excretion of EDCs. To examine this we performed a two-stage genome-wide association study (GWAS) for 24-hour urinary excretions of four parabens, two bisphenols, and nine phthalate metabolites. Results showed five genome-wide significant (p-value < 5x10-8) and replicated single nucleotide polymorphisms (SNPs) representing four independent signals that associated with mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP). Three of the four signals were located on chromosome 10 in a locus harboring the cytochrome P450 (CYP) genes CYP2C9, CYP2C58P, and CYP2C19 (rs117529685, pMECPP = 5.38x10-25; rs117033379, pMECPP = 1.96x10-19; rs4918798, pMECPP = 4.01x10-71; rs7895726, pMEHHP = 1.37x10-15, r2 with rs4918798 = 0.93). The other signal was on chromosome 6 close to the solute carrier (SLC) genes SLC17A1, SLC17A3, SLC17A4, and SCGN (rs1359232, pMECPP = 7.6x10-16). These four SNPs explained a substantial part (8.3 % - 9.2 %) of the variance in MECPP in the replication cohort. Bioinformatics analyses supported a likely causal role of CYP2C9 and SLC17A1 in metabolism and excretion of MECPP and MEHHP. Our results provide biological insights into mechanisms of phthalate metabolism and excretion with a likely causal role for CYP2C9 and SLC17A1

    ROS-dependent catalytic mechanism of melatonin metabolism and its application in the measurement of reactive oxygen

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    Melatonin (Mel) is an endogenous active molecule whose metabolism progress significantly influences its bioactivity. However, the detailed metabolic pathway of Mel in the pathological state has not yet been fully illustrated. In this study, 16 metabolites of Mel in cancer cells and human liver microsomes were identified, of which seven novel metabolites were newly discovered. Among them, 2-hydroxymelatonin (2-O-Mel), as the major metabolite in cancer cells, was revealed for the first time, which was different from the metabolite found in the human liver. Furthermore, CYP1A1/1A2- and reactive oxygen species (ROS)-mediated 2-hydroxylation reactions of Mel were verified to be the two metabolic pathways in the liver and cancer cells, respectively. ROS-dependent formation of 2-O-Mel was the major pathway in cancer cells. Furthermore, the underlying catalytic mechanism of Mel to 2-O-Mel in the presence of ROS was fully elucidated using computational chemistry analysis. Therefore, the generation of 2-O-Mel from Mel could serve as another index for the endogenous reactive oxygen level. Finally, based on the ROS-dependent production of 2-O-Mel, Mel was successfully used for detecting the oxygen-carrying capacity of hemoglobin in human blood. Our investigation further enriched the metabolic pathway of Mel, especially for the ROS-dependent formation of 2-O-Mel that serves as a diagnostic and therapeutic target for the rational use of Mel in clinics

    Relationship between transcranial magnetic stimulation markers of motor control and clinical recovery in obsessive compulsive disorder/Gilles de la Tourette syndrome: a proof of concept case study

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    BackgroundObsessive compulsive disorder (OCD) and Gilles de la Tourette syndrome (GTS) are neurodevelopmental disorders characterized by difficulties in controlling intrusive thoughts (obsessions) and undesired actions (tics), respectively. Both conditions have been associated with abnormal inhibition but a tangible deficit of inhibitory control abilities is controversial in GTS.MethodsHere, we examined a 25 years-old male patient with severe OCD symptoms and a mild form of GTS, where impairments in motor control were central. Transcranial magnetic stimulation (TMS) was applied over the primary motor cortex (M1) to elicit motor-evoked potentials (MEPs) during four experimental sessions, allowing us to assess the excitability of motor intracortical circuitry at rest as well as the degree of MEP suppression during action preparation, a phenomenon thought to regulate movement initiation.ResultsWhen tested for the first time, the patient presented a decent level of MEP suppression during action preparation, but he exhibited a lack of intracortical inhibition at rest, as evidenced by reduced short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI). Interestingly, the patient’s symptomatology drastically improved over the course of the sessions (reduced obsessions and tics), coinciding with feedback given on his good motor control abilities. These changes were reflected in the TMS measurements, with a significant strengthening of intracortical inhibition (SICI and LICI more pronounced than previously) and a more selective tuning of MEPs during action preparation; MEPs became even more suppressed, or selectively facilitated depending on the behavioral condition in which they we probed.ConclusionThis study highlights the importance of better understanding motor inhibitory mechanisms in neurodevelopmental disorders and suggests a biofeedback approach as a potential novel treatment

    Impact of CYP2D6 and CYP2B6 phenotypes on the response to tramadol in patients with acute post‚Äźsurgical pain

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    Abstract Tramadol is an important minor opioid prescribed for pain management. In this study, we analyzed the well‚Äźknown impact of CYP2D6 genetic variation and 60 additional variants in eight candidate genes (i.e., ABCG2, SLCO1B1, CYP2D6, CYP2B6, CYP2C19, CYP2C9, CYP3A5, and CYP3A4) on tramadol efficacy and safety. Some 108 patients with pain after surgery admitted to a post‚Äźanesthesia care unit (PACU) and prescribed tramadol were recruited. They were genotyped, and tramadol M1/M2 metabolite concentrations were determined by a newly validated HPLC‚ÄźMS/MS method. CYP2D6 intermediate (IM) and poor (PM) metabolizers showed lower M1 concentrations adjusted for dose/weight at 30‚ÄČand 120‚ÄČmin compared to ultrarapid (UM) and normal (NM) metabolizers (univariate p‚ÄČ<‚ÄČ0.001 and 0.020, multivariate p‚ÄČ<‚ÄČ0.001 and 0.001, unstandardized ő≤ coefficients‚ÄČ=‚ÄČ0.386 and 0.346, R2‚ÄČ=‚ÄČ0.146 and 0.120, respectively). CYP2B6 PMs (n‚ÄČ=‚ÄČ10) were significantly related to a higher reduction in pain 30‚ÄČmin after tramadol intake (univariate p‚ÄČ=‚ÄČ0.038, multivariate p‚ÄČ=‚ÄČ0.016, unstandardized ő≤ coefficient‚ÄČ=‚ÄČ0.224, R2‚ÄČ=‚ÄČ0.178), to lower PACU admission time (p‚ÄČ=‚ÄČ0.007), and to lower incidence of adverse drug reactions (p‚ÄČ=‚ÄČ0.038) compared to the other phenotypes. CYP3A4 IMs and PMs showed a higher prevalence of drowsiness and dizziness (p‚ÄČ=‚ÄČ0.028 and 0.005, respectively). Our results suggest that the interaction of CYP2B6 and CYP2D6 phenotypes may be clinically relevant, pending validation of these results in large, independent cohorts. Additional research is required to clarify the impact of CYP3A4 genetic variation on tramadol response

    Targeted DPPC/DMPG surface-modified voriconazole lipid nanoparticles control invasive pulmonary aspergillosis in immunocompromised population: in-vitro and in-vivo assessment

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    Invasive pulmonary aspergillosis (IPA) is the most devastating Aspergillus-related lung disease. Voriconazole (VRZ) is the first-line treatment against IPA. Despite availability in oral and parenteral dosage forms, risks of systemic toxicity dictate alternative pulmonary administration. Inspired by natural lung surfactants, dipalmitoylphosphatidylcholine/dimyristoylphosphatidylglycerol (DPPC/DMPG) surface-modified lipid nanoparticles (LNPs) were scrutinized for pulmonary administration. DPPC/DMPG-VRZ-LNPs prepared using ultrasonication/thin film hydration were investigated for colloidal properties over 3-month shelf storage. They were stable with a slight change in entrapment efficiency. They provided a sustained VRZ release over 24 h, with a rapid initial release. In vitro aerosolization indicated higher percentages of VRZ deposited on stages corresponding to secondary bronchi and alveolar ducts. Moreover, intrapulmonary administration maintained high lung VRZ concentration (27 ¬Ī 1.14 ¬Ķg/g) after 6 h. A preclinical study using a cyclophosphamide-induced neutropenic rat model demonstrated a 3-fold reduction in BALF-Galactomannan down to 0.515 ¬Ī 0.22 ¬Ķg/L confirming DPPC/DMPG-VRZ-LNPs potential in hyphal growth inhibition. Histopathological examination of infected/nontreated lung sections exhibited dense fungal load inside alveoli and blood vessels indicating massive tissue and angio-invasiveness. Nevertheless, DPPC/DMPG-VRZ-LNPs-treated animals displayed minimal hyphae with no signs of invasiveness. The developed bioinspired nanoparticles serve as prospective bioactive nanocarrier candidates for pulmonary administration of VRZ in the management of IPA

    A neuroimaging investigation of bipolar disorder and the neurocognitive effects of 5-HT7 antagonists

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    Bipolar disorder is a psychiatric disorder characterised by pathological mood states, but there is growing recognition of the role of cognitive impairment and dysfunction of emotional processes, which has a profound impact on quality of life. Many people with bipolar disorders exhibit brain volume impairment associated with cognitive dysfunction and an increased risk of dementia. In this thesis, I conducted a systematic review to understand the relationships between mood disorders and the 5-HT7 receptor. The 5-HT7 receptor is related to depression and anxiety, but the relationship between 5-HT7 and mania remains unclear; in addition, sleep and memory were also related to the 5-HT7 receptor. Followed by these findings, in the next two chapters, I examined the effects of 5-HT7 antagonists, using JNJ-18038683, on emotional and cognitive functioning, as well as their neural substrates. I then reported on neuroimaging investigations examining the effects of 5-HT7 antagonists on emotional processing and cognitive function in healthy volunteers to gain insight into their potential mode of action and utility for bipolar disorder. In fMRI analyses, the drug acted on 5-HT7 receptors potentially improving cognitive performance by modulating the function of the Cognitive Control Network in healthy controls. In the above-mentioned chapters, I gained a better understanding of the 5-HT7 antagonist, JNJ-18038683, and the putative promising effects for pharmacological treatments. However, the approach taken has some limitations, including a small sample size, potential participant bias, and a lack of systematic control of medication dose and duration of administration. In addition, in Chapter 5, I explored the brain basis of bipolar disorder and its links to cognitive and emotional dysfunction using a new ‚Äėbrain age‚Äô approach. Individuals with bipolar disorder were found to have increased brain age compared to healthy controls. I hope that these findings can be applied to pharmacological treatment for individuals with bipolar disorder, ultimately allowing patients to benefit from the drug in the future

    Prevalence of CYP2C19*2 and CYP2C19*3 Allelic Variants and Clopidogrel Use in Patients with Cardiovascular Disease in Trinidad & Tobago

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    The above slide deck represents the opinions of the authors. For a full list of declarations, including funding and author disclosure statements, and copyright information, please see the full text online. (see ‚Äúread the peer-reviewed publication‚ÄĚ opposite).¬†</p
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