Comparative epidemiology and quantitative neuroimaging of neuromyelitis optica spectrum disorder and multiple sclerosis

Background: Central Nervous System (CNS) inflammatory syndromes represent a spectrum of diseases caused by infiltration of inflammatory cells into the tissue of the brain and spinal cord. They comprise a group of diseases that can be acute or chronic, including optic neuritis, transverse myelitis, acute disseminated encephalomyelitis (ADEM), neuromyelitis optica (NMO) and its spectrum disorders (NMOSD), clinically isolated syndrome (CIS) and multiple sclerosis (MS). MS is the most common one while NMO/NMOSD is relatively rare although the exact population-based epidemiological parameters are lacking. The distinction of MS and NMO/NMOSD in adult patients and of MS and ADEM in paediatric patients is important for considerations of prognosis and treatment. This thesis aims to differentiate NMO/NMOSD from MS using epidemiology analyses and quantitative magnetic resonance imaging at 7 Tesla. The hypothesis of the thesis is that NMO/NMOSD can be differentiated from MS by disease incidence, prevalence, severity, and the quantitative characteristics of the lesion and non-lesion white matter of the brain. Methods: The thesis firstly employed a comparative epidemiological study to estimate incidence and prevalence of MS and NMO/NMOSD, and to estimate risks for associated comorbidities and mortality between NMO/NMOSD and MS. The thesis then applied two quantitative techniques to compare the white matter lesions and non-lesion white matter (so-called normal-appearing white matter [NAWM]) of both NMO/NMOSD and MS. Results: The results are presented in seven chapters. Chapter 1 provides a general review of CNS inflammatory syndromes. Chapter 2 shows the estimated incidence and prevalence of CNS inflammatory diseases in 2012 using the Clinical Practice Research Datalink (CPRD). MS is estimated to be the most prevalent and the NMO/NMOSD the rarest. Chapter 3 shows the case-controlled analytic results on the impact of the burden of comorbidity in MS. The burden is cumulative after MS diagnosis and impacts on patient survival compared to non-MS patients. With an interest of new-onset epilepsy in the course of MS compared to non-MS controls, chapter 4 shows that MS patients have a higher risk of having the first medical recorded epilepsy at and after MS diagnosis. Chapter 5 shows the comorbidity burden in NMO/NMOSD, and estimates the risk for mortality between NMO/NMOSD and age- and gender-matched MS populations. Chapter 6 compares in vivo white matter lesions and NAWM of the brain between adult patients with NMO/NMOSD or MS and healthy subjects using quantitative T1 relaxation time and magnetisation transfer ratio (MTR) magnetic resonance imaging at 7 Tesla. The results show that myelin content of white matter lesions is relatively better-preserved in NMO/NMOSD than that in MS; and they also show some changes in the NAWM of NMO/NMOSD, despite the fact that the metrics of the histogram of both sequences are not different to those in MS. Conclusions: In the UK, NMO/NMOSD is rare with a higher disease severity compared to MS, which is the most prevalent inflammatory disease. In vivo, using T1 relaxation time and MTR imaging at 7 Tesla, the white matter lesions of the brain have more preserved myelin in patients with NMO/NMOSD than in those with MS. There is at least a small proportion of intracranial NAWM having subtle changes in patients with NMO/NMOSD that is detectable, but the changes could not be differentiated from MS in the current study. This thesis helps to better understand the epidemiology of NMO/NMOSD and MS, and MRI detectable changes of lesions and NAWM in NMO/NMOSD

Association between use of non–vitamin k oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation

Importance:  Non–vitamin K oral anticoagulants (NOACs) are commonly prescribed with other medications that share metabolic pathways that may increase major bleeding risk. Objective:  To assess the association between use of NOACs with and without concurrent medications and risk of major bleeding in patients with nonvalvular atrial fibrillation. Design, Setting, and Participants:  Retrospective cohort study using data from the Taiwan National Health Insurance database and including 91 330 patients with nonvalvular atrial fibrillation who received at least 1 NOAC prescription of dabigatran, rivaroxaban, or apixaban from January 1, 2012, through December 31, 2016, with final follow-up on December 31, 2016. Exposures:  NOAC with or without concurrent use of atorvastatin; digoxin; verapamil; diltiazem; amiodarone; fluconazole; ketoconazole, itraconazole, voriconazole, or posaconazole; cyclosporine; erythromycin or clarithromycin; dronedarone; rifampin; or phenytoin. Main Outcomes and Measures:  Major bleeding, defined as hospitalization or emergency department visit with a primary diagnosis of intracranial hemorrhage or gastrointestinal, urogenital, or other bleeding. Adjusted incidence rate differences between person-quarters (exposure time for each person during each quarter of the calendar year) of NOAC with or without concurrent medications were estimated using Poisson regression and inverse probability of treatment weighting using the propensity score. Results:  Among 91 330 patients with nonvalvular atrial fibrillation (mean age, 74.7 years [SD, 10.8]; men, 55.8%; NOAC exposure: dabigatran, 45 347 patients; rivaroxaban, 54 006 patients; and apixaban, 12 886 patients), 4770 major bleeding events occurred during 447 037 person-quarters with NOAC prescriptions. The most common medications co-prescribed with NOACs over all person-quarters were atorvastatin (27.6%), diltiazem (22.7%), digoxin (22.5%), and amiodarone (21.1%). Concurrent use of amiodarone, fluconazole, rifampin, and phenytoin with NOACs had a significant increase in adjusted incidence rates per 1000 person-years of major bleeding than NOACs alone: 38.09 for NOAC use alone vs 52.04 for amiodarone (difference, 13.94 [99% CI, 9.76-18.13]); 102.77 for NOAC use alone vs 241.92 for fluconazole (difference, 138.46 [99% CI, 80.96-195.97]); 65.66 for NOAC use alone vs 103.14 for rifampin (difference, 36.90 [99% CI, 1.59-72.22); and 56.07 for NOAC use alone vs 108.52 for phenytoin (difference, 52.31 [99% CI, 32.18-72.44]; P < .01 for all comparisons). Compared with NOAC use alone, the adjusted incidence rate for major bleeding was significantly lower for concurrent use of atorvastatin, digoxin, and erythromycin or clarithromycin and was not significantly different for concurrent use of verapamil; diltiazem; cyclosporine; ketoconazole, itraconazole, voriconazole, or posaconazole; and dronedarone. Conclusions and Relevance:  Among patients taking NOACs for nonvalvular atrial fibrillation, concurrent use of amiodarone, fluconazole, rifampin, and phenytoin compared with the use of NOACs alone, was associated with increased risk of major bleeding. Physicians prescribing NOAC medications should consider the potential risks associated with concomitant use of other drugs

Splitting of Folded Strings in AdS_4*CP^3

We study classically splitting of two kinds of folded string solutions in AdS_4*CP^3. Conserved charges of the produced fragments are computed for each case. We find interesting patterns among these conserved charges.Comment: minor changes, 14 pages, no figure

Urate-lowering treatment and risk of total joint replacement in patients with gout

Objectives: To examine whether gout is an independent risk factor for total joint replacement (TJR) and whether urate-lowering treatment (ULT) reduces this risk. Methods: Using the Taiwan National Health Insurance database and the UK Clinical Practice Research Datalink, 74 560 Taiwan patients and 34 505 UK patients with incident gout were identified and age and sex matched to people without gout. Cox proportional hazards models and condition logistic regression were used to examine the risk of TJR in gout patients and the association between cumulative defined daily dose (cDDD) of ULT and TJR.Results: The prevalence rates of TJR in the patients at the time of diagnosis of gout and in people without gout were 1.16% vs 0.82% in Taiwan and 2.61% vs 1.76% in the UK. After a gout diagnosis, the incidence of TJR was higher in the patients with gout compared with those without (3.23 vs 1.91 cases/1000 person-years in Taiwan and 6.87 vs 4.61 cases/1000 person-years in the UK), with adjusted HRs of 1.56 (95% CI 1.45, 1.68) in Taiwan and 1.14 (1.05, 1.22) in the UK. Compared with patients with gout with 180 cDDD ULT in Taiwan. In the UK, the respective ORs were 1.09 (0.83, 1.42), 0.93 (0.68, 1.27) and 1.08 (0.94, 1.24).Conclusion: This population-based study provides evidence from two nation populations that gout confers significant TJR risk, which was not reduced by current ULT

SLC37A1 and SLC37A2 Are Phosphate-Linked, Glucose-6-Phosphate Antiporters

Blood glucose homeostasis between meals depends upon production of glucose within the endoplasmic reticulum (ER) of the liver and kidney by hydrolysis of glucose-6-phosphate (G6P) into glucose and phosphate (Pi). This reaction depends on coupling the G6P transporter (G6PT) with glucose-6-phosphatase-α (G6Pase-α). Only one G6PT, also known as SLC37A4, has been characterized, and it acts as a Pi-linked G6P antiporter. The other three SLC37 family members, predicted to be sugar-phosphate:Pi exchangers, have not been characterized functionally. Using reconstituted proteoliposomes, we examine the antiporter activity of the other SLC37 members along with their ability to couple with G6Pase-α. G6PT- and mock-proteoliposomes are used as positive and negative controls, respectively. We show that SLC37A1 and SLC37A2 are ER-associated, Pi-linked antiporters, that can transport G6P. Unlike G6PT, neither is sensitive to chlorogenic acid, a competitive inhibitor of physiological ER G6P transport, and neither couples to G6Pase-α. We conclude that three of the four SLC37 family members are functional sugar-phosphate antiporters. However, only G6PT/SLC37A4 matches the characteristics of the physiological ER G6P transporter, suggesting the other SLC37 proteins have roles independent of blood glucose homeostasis

Reduced Myelin Signal in Normal-appearing White Matter in Neuromyelitis Optica Measured by 7T Magnetic Resonance Imaging

Whether the integrity of normal-appearing white matter (NAWM) is preserved in neuromyelitis optica spectrum disorders (NMOSD) is open to debate. To examine whether the tissue integrity of NAWM in NMOSD is compromised compared to that in healthy controls and patients with multiple sclerosis (MS), we prospectively enrolled 14 patients with NMOSD, 12 patients with MS, and 10 controls for clinical functional assessments and quantitative imaging, including T1 relaxation time (T1) and magnetization transfer ratio (MTR) at 7 Tesla. Cognitive performance on the Paced Auditory Serial Addition Test with a 3-second interstimulus interval (PASAT-3) was significantly lower in the NMOSD compared to the MS group (mean number of correct answers, 34.1 vs. 47.6; p=.006), but there were no differences in disease duration or disability. Histograms of T1 and MTR maps of NAWM demonstrated a decreased peak height in patients with NMOSD compared to the healthy controls, but not compared to patients with MS. Using 7T quantitative magnetic resonance imaging (MRI), this study showed that the NAWM in patients with NMOSD is abnormal, with reduced myelin signal; this was not previously observed using MRI at a lower field strength

Constraints on the Mass and Mixing of the 4th Generation Quark From Direct CP Violationϵ′/ϵ\epsilon^{\prime}/\epsilon and Rare K Decays

We investigate the $\epsilon^{\prime} /\epsilon$ for $K\to \pi\pi$ in a sequential fourth generation model. By giving the basic formulae for $\epsilon^{\prime}/\epsilon$ in this model, we analyze the numerical results which are dependent of $m_{t^{\prime}}$ and imaginary part of the fourth CKM factor, ${Im}V^{*}_{t^{'}s}V_{t^{'}d}$ (or $V^{*}_{t^{'}s}V_{t^{'}d}$ and the fourth generation CKM matrix phase $\theta$). We find that, unlike the SM, when taking the central values of all parameters for $\epsilon^{\prime}/\epsilon$, the values of $\epsilon^{\prime}/ \epsilon$ can easily fit to the current experimental data for all values of hadronic matrix elements estimated from various approaches. Also, we show that the experimental values of $\epsilon^{\prime}/\epsilon$ and rare K decays can provide a strong constraint on both mass and mixing of the fourth generation quark. When taking the values of hadronic matrix elements from the lattice or 1/N expansion calculations, a large region of the up-type quark mass $m_{t^{\prime}}$ is excluded.Comment: 18 pages, 4 eps figure

Familial aggregation and heritability of schizophrenia and co-aggregation of psychiatric illnesses in affected families

Strong familial aggregation of schizophrenia has been reported but there is uncertainty concerning the degree of genetic contribution to the phenotypic variance of the disease. This study aimed to examine the familial aggregation and heritability of schizophrenia, and the relative risks (RRs) of other psychiatric diseases, in relatives of people with schizophrenia using the Taiwan National Health Insurance Database. The study population included individuals with affected first-degree or second-degree relatives identified from all beneficiaries (n = 23 422 955) registered in 2013. Diagnoses of schizophrenia made by psychiatrists were ascertained between January 1, 1996 and December 31, 2013. Having an affected co-twin, first-degree relative, second-degree relative, or spouse was associated with an adjusted RR (95% CI) of 37.86 (30.55-46.92), 6.30 (6.09-6.53), 2.44 (1.91-3.12), and 1.88 (1.64-2.15), respectively. Compared with the general population, individuals with one affected first-degree relative had a RR (95% CI) of 6.00 (5.79-6.22) and those with 2 or more had a RR (95% CI) of 14.66 (13.00-16.53) for schizophrenia. The accountability for the phenotypic variance of schizophrenia was 47.3% for genetic factors, 15.5% for shared environmental factors, and 37.2% for non-shared environmental factors. The RR (95% CI) in individuals with a first-degree relative with schizophrenia was 3.49 (3.34-3.64) for mood disorders and 3.91 (3.35-4.57) for delusional disorders. A family history of schizophrenia is therefore associated with a higher risk of developing schizophrenia, mood disorders, and delusional disorders. Heritability and environmental factors each account for half of the phenotypic variance of schizophrenia

Measurement of the Dipion Mass Spectrum in X(3872) -> J/Psi Pi+ Pi- Decays

We measure the dipion mass spectrum in X(3872)--> J/Psi Pi+ Pi- decays using 360 pb-1 of pbar-p collisions at 1.96 TeV collected with the CDF II detector. The spectrum is fit with predictions for odd C-parity (3S1, 1P1, and 3DJ) charmonia decaying to J/Psi Pi+ Pi-, as well as even C-parity states in which the pions are from Rho0 decay. The latter case also encompasses exotic interpretations, such as a D0-D*0Bar molecule. Only the 3S1 and J/Psi Rho hypotheses are compatible with our data. Since 3S1 is untenable on other grounds, decay via J/Psi Rho is favored, which implies C=+1 for the X(3872). Models for different J/Psi-Rho angular momenta L are considered. Flexibility in the models, especially the introduction of Rho-Omega interference, enable good descriptions of our data for both L=0 and 1.Comment: 7 pages, 4 figures -- Submitted to Phys. Rev. Let